Physical Exercise Improves Total Antioxidant Capacity and Gene Expression in Rat Hippocampal Tissue.

Exercise may exert beneficial effects on cognitive functions and play an important role in the prevention of neurodegenerative diseases. Such effects seem to be mediated by changes in anti-oxidative status, but limited information is available on the nature of molecular pathways supporting the antioxidant effects of exercise in the brain. In this study 3-5-month-old male Wistar albino rats were subjected to three times/week moderate intensity exercise on a rodent treadmill for a period of 6 weeks. The tissue antioxidant activity towards various reactive oxygen species (ROS) was determined in the hippocampus. In addition, to identify the molecular pathways that may be involved in ROS metabolism, the expression of nerve growth factor (NGF) and sirtuins (SIRT1 and SIRT3) were measured. Our results showed a higher antioxidant activity in the hippocampus of physically trained rats compared to sedentary controls. Furthermore, exercise induced an up-regulation of NGF, possibly related to an improved redox balance in the hippocampus. These results suggest that physical exercise might prevent age-induced oxidative damage in the hippocampus.

Studies of metabolism and disposition of potent human immunodeficiency virus (HIV) integrase inhibitors using 19F-NMR spectroscopy.

(19)F-nuclear magnetic resonance (NMR) has been extensively used in a drug-discovery programme to support the selection of candidates for further development. Data on an early lead compound, N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(4-methylmorpholin-3-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide (compound A (+)), and MK-0518 (N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1-{[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino}ethyl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide), a potent inhibitor of this series currently in phase III clinical trials, are described. The metabolic fate and excretion balance of compound A (+) and MK-0518 were investigated in rats and dogs following intravenous and oral dosing using a combination of (19)F-NMR-monitored enzyme hydrolysis and solid-phase extraction chromatography and NMR spectroscopy (SPEC-NMR). Dosing with the (3)H-labelled compound A (+) enabled the comparison of standard radiochemical analysis with (19)F-NMR spectroscopy to obtain quantitative metabolism and excretion data. Both compounds were eliminated mainly by metabolism. The major metabolite identified in rat urine and bile and in dog urine was the 5-O-glucuronide.

Derivation of temporary emergency exposure limits (TEELs).

Short-term chemical concentration limits are used in a variety of applications, including emergency planning and response, hazard assessment and safety analysis. Development of emergency response planning guidelines (ERPGs) and acute exposure guidance levels (AEGLs) are predicated on this need. Unfortunately, the development of peer-reviewed community exposure limits for emergency planning cannot be done rapidly (relatively few ERPGs or AEGLs are published each year). To be protective of Department of Energy (DOE) workers, on-site personnel and the adjacent general public, the DOE Subcommittee on Consequence Assessment and Protective Actions (SCAPA) has developed a methodology for deriving temporary emergency exposure limits (TEELs) to serve as temporary guidance until ERPGs or AEGLs can be developed. These TEELs are approximations to ERPGs to be used until peer-reviewed toxicology-based ERPGs, AEGL or equivalents can be developed. Originally, the TEEL method used only hierarchies of published concentration limits (e.g. PEL- or TLV-TWAs, -STELs or -Cs, and IDLHs) to provide estimated values approximating ERPGs. Published toxicity data (e.g. lc(50), lc(LO), ld(50) and ld(LO) for TEEL-3, and tc(LO) and td(LO) for TEEL-2) are included in the expanded method for deriving TEELs presented in this paper. The addition here of published toxicity data (in addition to the exposure limit hierarchy) enables TEELs to be developed for a much wider range of chemicals than before. Hierarchy-based values take precedence over toxicity-based values, and human toxicity data are used in preference to animal toxicity data. Subsequently, default assumptions based on statistical correlations of ERPGs at different levels (e.g. ratios of ERPG-3s to ERPG-2s) are used to calculate TEELs where there are gaps in the data. Most required input data are available in the literature and on CD ROMs, so the required TEELs for a new chemical can be developed quickly. The new TEEL hierarchy/toxicity methodology has been used to develop community exposure limits for over 1200 chemicals to date. The new TEEL methodology enables emergency planners to develop useful approximations to peer-reviewed community exposure limits (such as the ERPGs) with a high degree of confidence. For definitions and acronyms, see Appendix.

Recommended default methodology for analysis of airborne exposures to mixtures of chemicals in emergencies.

Emergency planning and hazard assessment of Department of Energy (DOE) facilities require consideration of potential exposures to mixtures of chemicals released to the atmosphere. Exposure to chemical mixtures may lead to additive, synergistic, or antagonistic health effects. In the past, the consequences of exposures to each chemical have been analyzed separately. This approach may not adequately protect the health of persons exposed to mixtures. This article presents default recommendations for use in emergency management and safety analysis within the DOE complex where potential exists for releases of mixtures of chemicals. These recommendations were developed by the DOE Subcommittee on Consequence Assessment and Protective Actions (SCAPA). It is recommended that hazard indices (e.g., HIi = Ci/Limiti, where Ci is the concentration of chemical "i") be calculated for each chemical, and unless sufficient toxicological knowledge is available to indicate otherwise, that they be summed, that is, sigma i(n) = 1HIi = HI1 + HI2 + ... + HIn. A sum of 1.0 or less means the limits have not been exceeded. To facilitate application of these recommendations for analysis of exposures to specific mixtures, chemicals are classified according to their toxic consequences. This is done using health code numbers describing toxic effects by target organ for each chemical. This methodology has been applied to several potential releases of chemicals to compare the resulting hazard indices of a chemical mixture with those obtained when each chemical is treated independently. The methodology used and results obtained from analysis of one mixture are presented in this article. This article also demonstrates how health code numbers can be used to sum hazard indices only for those chemicals that have the same toxic consequence.