Sport specialisation and performance-enhancing substance use by young athletes.

Objectives: To investigate the association of reported legal performance enhancing substance (PES) use and consideration of banned PES use among sport-specialised and non-sport-specialised young athletes. Methods and design: Cross-sectional study of 1049 young athletes enrolled in an injury prevention programme from 2013 to 2020. We used logistic regression modelling to determine the independent association between sports specialisation. We reported (1) legal PES use and (2) consideration of banned PES use after adjusting for the effects of gender, age, having a relative as a coach, unrestricted internet access, use of a weight training regimen, and weeknight hours of sleep. Results: The final cohort consisted of 946 athletes with a mean age of 14. 56% were female, and 80% were sport-specialised athletes. 14% reported legal PES use, and 3% reported consideration of banned PES use. No difference was found between sport-specialised athletes who reported legal PES use (OR=1.4; 95% CI 0.81 to 2.43; p=0.23) or consideration of banned PES use (OR=3.2; 95% CI 0.78 to 14.92; p=0.1) compared with non-sport-specialised athletes. Reported legal PES use was more common among athletes who were male, older, used weight training, and slept less. Reported consideration of banned PES use was more common among male and older athletes. Conclusions: PES use is not independently associated with sport specialisation in young athletes. Athlete sex, age, training, and sleep patterns are important factors for young athletes to consider in PES use.

Radionuclide resuspension across ecosystems and environmental disturbances.

Exposure assessment from radionuclides and other soil-bound contaminants often requires quantifying the amount of contaminant resuspended in the air. Rates and controlling factors of radionuclide resuspension and wind erosion of soil are clearly related but have largely been studied separately. Here, we review both and then integrate wind erosion measurements with the radiological resuspension paradigm to provide better estimates of resuspension factors across a broad range of ecosystems and environmental conditions. Radionuclide resuspension by wind was initially investigated during the era of aboveground nuclear weapons testing. Predictive dose models were developed from empirically-derived ratios of air and soil concentrations, otherwise called the resuspension factor. Resuspension factors were shown to generally predict radionuclide concentrations in air, but they were site-specific and largely derived from the arid and semi-arid environments surrounding nuclear weapons testing locations. In contrast, wind erosion studies from the agricultural and environmental sciences have produced more mechanistic models and a relatively robust data set of wind erosion rates and model parameters across a range of ecosystems. We sequentially show the mathematics linking measured sediment flux from wind erosion rate measurements to resuspension factors using the concept of transport capacity and its relationship to the deposition velocity. We also describe the conceptual framework describing how resuspension factors change through time and the mathematical models describing this decrease. We then show how vertical mass flux measurements across ecosystems were categorized and used to calculate ecosystem-based resuspension factors. These calculations allow generalized estimation of radionuclide resuspension factors across ecosystem types as a function of disturbance and as input for dose calculations.

Validation Tests of Resuspension Models for a Finite and Infinite Site.

Dose assessment for deposited radionuclides often requires estimates of air concentrations that are derived from measured soil concentrations. For this, dose assessors typically use literature resuspension values that, while empirically based, can vary by orders of magnitude making it difficult to provide accurate dose estimates. Despite the complexities of the physical processes involved in resuspension, the models generally used for dose assessment are relatively simplistic and rarely are the models validated for a specific site, thus making prediction of air concentrations or airborne emissions highly uncertain. Additionally, the size of the contaminated area can have an impact on downwind concentrations, yet literature values do not account for smaller-sized contaminated sites adding additional uncertainty. To test resuspension models for soil-bound radionuclides at finite and infinite spatial scales, measurements of soil and air concentrations are made at (1) a location downwind of a former outfall where Pu was released into the environment (a finite site), and (2) uncontaminated locations where regional air sampling provides background measurements of naturally occurring U in sampled dust (an infinite site). Measured air concentrations were compared to those predicted using the resuspension factor model and the mass loading model. An area factor was applied to the smaller contaminated site to account for dilution of dust from the contaminated site with dust originating from offsite locations. Results show that when properly parameterized to site conditions, resuspension models can predict air concentrations to within a factor of 10.

Discovery of Indole Derivatives as Novel and Potent Dengue Virus Inhibitors.

3-Acyl-indole derivative 1 was identified as a novel dengue virus (DENV) inhibitor from a DENV serotype 2 (DENV-2) phenotypic antiviral screen. Extensive SAR studies led to the discovery of new derivatives with improved DENV-2 potency as well as activity in nanomolar to micromolar range against the other DENV serotypes. In addition to the potency, physicochemical properties and metabolic stability in rat and human microsomes were improved during the optimization process. Chiral separation of the racemic mixtures showed a clear preference for one of the two enantiomers. Furthermore, rat pharmacokinetics of two compounds will be discussed in more detail, demonstrating the potential of this new series of pan-serotype-DENV inhibitors.

Gamma-Ray Dose From an Overhead Plume.

Standard plume models can underestimate the gamma-ray dose when most of the radioactive material is above the heads of the receptors. Typically, a model is used to calculate the air concentration at the height of the receptor, and the dose is calculated by multiplying the air concentration by a concentration-to-dose conversion factor. Models indicate that if the plume is emitted from a stack during stable atmospheric conditions, the lower edges of the plume may not reach the ground, in which case both the ground-level concentration and the dose are usually reported as zero. However, in such cases, the dose from overhead gamma-emitting radionuclides may be substantial. Such underestimates could impact decision making in emergency situations. The Monte Carlo N-Particle code, MCNP, was used to calculate the overhead shine dose and to compare with standard plume models. At long distances and during unstable atmospheric conditions, the MCNP results agree with the standard models. At short distances, where many models calculate zero, the true dose (as modeled by MCNP) can be estimated with simple equations.

Accuracy of Cloudshine Gamma Dose Calculations in the CAP-88 Dispersion Model.

The U.S. Environmental Protection Agency dispersion model, CAP-88, calculates ground-level dose using the ground-level concentration and the semi-infinite cloud approximation. Doses can be underestimated for elevated plumes during stable atmospheric conditions at receptor locations within a kilometer downwind of a stack. The purpose of this paper is to identify when CAP-88 calculations of gamma dose from cloudshine are inaccurate and provide estimates of the inaccuracy. The method used compares CAP-88 estimates with Monte Carlo N-Particle (MCNP) estimates. Comparisons were made at distances of 800 m and 3,000 m downwind of the stack and for plume heights from 0 to 50 m. For these conditions, the annual dose calculated by CAP-88 is greater than or equal to that calculated by MCNP.

2-(2-oxo-morpholin-3-yl)-acetamide derivatives as broad-spectrum antifungal agents.

From a fungicidal screen, we identified 2-(2-oxo-morpholin-3-yl)-acetamide derivatives as fungicidal agents against Candida species, additionally characterized by antifungal activity against Aspergillus species. However, development of this series was hampered by low plasmatic stability. Introduction of a gem-dimethyl on the 6-position of the morpholin-2-one core led to considerable improvement in plasmatic stability while maintaining in vitro antifungal activity. Further optimization of the series resulted in the discovery of N-(biphenyl-3-ylmethyl)-2-(4-ethyl-6,6-dimethyl-2-oxomorpholin-3-yl)acetamide (87), which, in addition to fungicidal activity against Candida species, shows promising and broad antifungal in vitro activity against various fungi species, such as molds and dermatophytes. In vivo efficacy was also demonstrated in a murine model of systemic Candida albicans infection with a significant fungal load reduction in kidneys.

Validation test for CAP88 predictions of tritium dispersion at Los Alamos National Laboratory.

Gaussian plume models, such as CAP88, are used regularly for estimating downwind concentrations from stack emissions. At many facilities, the U.S. Environmental Protection Agency (U.S. EPA) requires that CAP88 be used to demonstrate compliance with air quality regulations for public protection from emissions of radionuclides. Gaussian plume models have the advantage of being relatively simple and their use pragmatic; however, these models are based on simplifying assumptions and generally they are not capable of incorporating dynamic meteorological conditions or complex topography. These limitations encourage validation tests to understand the capabilities and limitations of the model for the specific application. Los Alamos National Laboratory (LANL) has complex topography but is required to use CAP88 for compliance with the Clean Air Act Subpart H. The purpose of this study was to test the accuracy of the CAP88 predictions against ambient air measurements using released tritium as a tracer. Stack emissions of tritium from two LANL stacks were measured and the dispersion modeled with CAP88 using local meteorology. Ambient air measurements of tritium were made at various distances and directions from the stacks. Model predictions and ambient air measurements were compared over the course of a full year's data. Comparative results were consistent with other studies and showed the CAP88 predictions of downwind tritium concentrations were on average about three times higher than those measured, and the accuracy of the model predictions were generally more consistent for annual averages than for bi-weekly data.

Addressing nuclides not in the CAP88-PC Version-3 library.

Versions of the computer program, CAP88, are widely used to calculate the radiological doses from radionuclides emitted into the air. CAP88-PC Version-3 includes an extensive library of radionuclides, but there are many more that are not included. Surrogates are often used to substitute for nuclides not in the library, though the results are usually overestimates. This paper addresses nuclides that are not in the library and describes methods to obtain more accurate results.

Operational experience of continuous air monitoring of smoke for ²³9Pu during a wildfire.

Smoke from a wildfire in northern New Mexico that moved along the border of the Los Alamos National Laboratory (LANL) was monitored for ²³9Pu in the event that the fire might cross into LANL property containing locations with low, but greater than background, levels of ²³9Pu and other alpha-emitting radionuclides. Three Environmental Continuous Air Monitors (ECAMs) in operation at LANL at the time of the fire provided near real-time measurements of the ²³9Pu in the smoke. Sampling data from routine measurements of PM-10 and PM-2.5 concentrations in the city of Los Alamos showed that smoke in the air rose during the fire to several hundred µg m⁻³, which produced limited visibility (several hundred meters) and resulted in poor air quality alerts for about a week-long period. Previous studies have shown that airborne dust can significantly impair continuous air monitors, so the purpose of this study was to assess the performance of the ECAMs under smoky conditions, which is important for many emergency response scenarios. Additionally, ECAMs are not required to be tested in smoke by ANSI standards, so there is little to no published data on performance of any ECAM while sampling smoke. Results show that the deployed ECAMs had reduced flow as the filter clogged with fine particles, but the goodness-of-fit parameter of the peak shape fitting algorithms and the minimum detectable concentration and dose were not impacted until the flow was reduced by more than about 20%, and even then they were within tolerable limits. Overall, ECAM performance was not impacted during the fire even under heavy smoke conditions and fluctuating radon levels, though changing the filters to limit any reductions in flow to less than 20% would maintain optimal ECAM performance.

Corrections for measurements of tritium in subterranean vapor using silica gel.

Hazardous contaminants buried within vadose zones can accumulate in soil gas. The concentrations and spatial extent of these contaminants are measured to evaluate potential transport to groundwater for public risk evaluation. Tritium is an important contaminant found and monitored for in vadose zones across numerous sites within the US nuclear weapons complex, including Los Alamos National Laboratory. The extraction, collection, and laboratory analysis of tritium from subterranean soil gas presents numerous technical challenges that have not been fully studied. Particularly, the lack of moisture in the soil gas in the vadose zone makes it difficult to obtain enough sample (e.g., > 5 g) to provide for the required measurement sensitivity, and often, only small amounts of moisture can be collected. Further, although silica gel has high affinity for water vapor and is prebaked prior to sampling, there is still sufficient residual moisture in the prebaked gel to dilute the relatively small amount of sampled moisture; thereby, significantly lowering the "true" tritium concentration in the soil gas. This paper provides an evaluation of the magnitude of the bias from dilution, provides methods to correct past measurements by applying a correction factor (CF), and evaluates the uncertainty of the CF values. For this, 10,000 Monte Carlo calculations were performed, and distribution parameters of CF values were determined and evaluated. The mean and standard deviation of the distribution of CF values were 1.53 ± 0.36, and the minimum, median, and maximum values were 1.14, 1.43, and 5.27, respectively.

Work to save dose: contrasting effective dose rates from radon exposure in workplaces and residences against the backdrop of public and occupational regulatory limits.

Office workers are exposed to radon while at work and at home. Though there are a multitude of studies reporting radon concentrations and potential lung and effective doses associated with radon progeny exposure in homes, similar studies in non-mine workplaces are lacking. Additionally, there are few, if any, comparative analyses of radon exposures at more "typical" workplace with residential exposures within the same county. The purposes of this study were to measure radon concentrations in office and residential spaces in the same county and explore the radiation dose implications. Sixty-five track-etch detectors were deployed for 3-mo sampling periods in office spaces and 47 were deployed in residences, all within Los Alamos County, New Mexico. The measured concentrations were used to calculate and compare effective dose rates resulting from exposure while at work and at home. Results showed that full-time office workers receive on average about 8 times greater exposure at home than while in the office (2.3 mSv y-1 vs. 0.3 mSv y-1). The estimated effective dose rate for a more homebound person was about 3 mSv y-1. Estimating effective doses from background radon exposure in the same county as Los Alamos National Laboratory, with thousands of "radiological workers," highlights interesting contrasts in radiation protection standards that span public and occupational settings. For example, the effective dose rate from background radon exposure in unregulated office spaces ranged up to 1.1 mSv y-1, which is similar to the 1 mSv y-1 threshold for regulation of a "radiological worker," as defined in the Department of Energy regulations for occupational exposure. Additionally, the estimated average effective dose total of >3 mSv y-1 from radon background exposure in homes stands in contrast to the 0.1 mSv y-1 air pathway effective public dose limit regulated by the Environmental Protection Agency for radioactive air emissions, and both these are substantially lower than effective doses associated with priority radon levels in homes of "tens of pCi L-1 and greater" (>370 Bq m-3), as suggested by the Health Physics Society.

Measurement of the activity per unit mass with hand-held alpha and beta detectors.

This paper describes how to use hand-held alpha and beta detectors to measure volume or mass contamination (Bq g-1) instead of the usual surface activity (Bq cm-2). As a proof of principle, measurements with a hand-held detector of the specific activity of K in potassium chloride yielded the expected result. Field measurements agree well with the results from analytical laboratories.

Synthesis of bivalent beta2-adrenergic and adenosine A1 receptor ligands.

Research in the area of simutaneously targeting more than one G protein-coupled receptor (GPCR) has increased in recent times. By exploiting the cross talk between the beta2-adrenergic (beta2AR) and adenosine A1 receptors (A1AR) on adenylate cyclase activity, we synthesized a series of bivalent agonists for both GPCRs to generate responses from more than one receptor. We have demonstrated a relationship between the various beta2-adrenergic and A1 adenosine bivalent parameters of linker and bifunctionality by using data that are drawn from in vitro assays. The hexyl-linked 12e (K(i), 311 nM) and butyl-linked 12c ( K(i), 863 nM) bivalent compounds displayed reasonable binding affinities for the beta2AR when compared with the control (-)isoproterenol (K(i), 136 nM), and both compounds also exhibited a persuasive bifunctional trend for both receptors at various drug concentrations. The bivalent compound 12e was also found to have significant EC50 potency (6 nM) at the beta2AR in DDT cells.

N-Arylmethyl substituted iminoribitol derivatives as inhibitors of a purine specific nucleoside hydrolase.

A key enzyme within the purine salvage pathway of parasites, nucleoside hydrolase, is proposed as a good target for new antiparasitic drugs. We have developed N-arylmethyl-iminoribitol derivatives as a novel class of inhibitors against a purine specific nucleoside hydrolase from Trypanosoma vivax. Several of our inhibitors exhibited low nanomolar activity, with 1,4-dideoxy-1,4-imino-N-(8-quinolinyl)methyl-d-ribitol (UAMC-00115, K(i) 10.8nM), N-(9-deaza-adenin-9-yl)methyl-1,4-dideoxy-1,4-imino-d-ribitol (K(i) 4.1nM), and N-(9-deazahypoxanthin-9-yl)methyl-1,4-dideoxy-1,4-imino-d-ribitol (K(i) 4.4nM) being the three most active compounds. Docking studies of the most active inhibitors revealed several important interactions with the enzyme. Among these interactions are aromatic stacking of the nucleobase mimic with two Trp-residues, and hydrogen bonds between the hydroxyl groups of the inhibitors and amino acid residues in the active site. During the course of these docking studies we also identified a strong interaction between the Asp40 residue from the enzyme and the inhibitor. This is an interaction which has not previously been considered as being important.

Thioredoxin reductase and cancer cell growth inhibition by organogold(III) compounds.

Thioredoxin (Trx) expression is increased in several human primary cancers associated with aggressive tumor growth and decreased patient survival, and the Trx/Trx reductase (TrxR) system therefore provides an attractive target for cancer drug development. Various gold(III) compounds with none, one, two or three carbon-gold bonds were evaluated for their capacity to inhibit TrxR and the growth of MCF-7 cancer cells in vitro. Compounds with up to two carbon-gold bonds were often potent inhibitors of TrxR with IC50 values as low as 2 nmol/l. In the presence of Trx and insulin the inhibiting capacity was much lower. However, the inhibitory concentrations of the compounds did not correlate with the ability to kill cells. Out of the organometallics tested, only compound 8 with two carbon-gold bonds was able to inhibit colony formation by MCF-7 breast cancer cells at low micromolar concentrations (IC50=1.6 micromol/l). Unfortunately, the compound did not show any anti-tumor activity against MCF-7 breast cancer and HT-29 colon cancer xenografts in scid mice.

Substrate-assisted leaving group activation in enzyme-catalyzed N-glycosidic bond cleavage.

In enzymatic depurination of nucleosides, the 5'-OH group of the ribose moiety of the substrate is often shown to contribute substantially to catalysis. The purine-specific nucleoside hydrolase from Trypanosoma vivax (TvNH) fixes the 5'-OH group in a gauche,trans orientation about the C4'-C5' bond, enabling the 5'-oxygen to accept an intramolecular hydrogen bond from the C8-atom of the purine leaving group. High level ab initio quantum chemical calculations indicate that this interaction promotes protonation of the purine at N7. Steady state kinetics comprising engineered substrates confirm that a considerable fraction of the catalytic 5'-OH effect can be attributed to leaving group activation.

Cyclodextrin-derived diorganyl tellurides as glutathione peroxidase mimics and inhibitors of thioredoxin reductase and cancer cell growth.

Water-soluble diorganyl tellurides of the alkyl aryl or dialkyl type were prepared by treatment of mono-6-tosyl-beta-cyclodextrin with sodium alkanetellurolates or arenetellurolates or sodium telluride. The novel cyclodextrin-derived organotelluriums were evaluated for their capacity to catalyze the reduction of hydrogen peroxide, tert-butyl hydroperoxide, and cumene hydroperoxide in the presence of glutathione, NADPH, and GSSG-reductase (coupled reductase assay). Cyclodextrins 4d and 4e, carrying 4-(N,N-dimethylamino)phenyltelluro and n-butyltelluro groups, respectively, were the most efficient glutathione peroxidase mimics. Reduction of lipophilic cumene hydroperoxide often proceeded 10-20 times faster than reduction of the more hydrophilic hydroperoxides, which cannot bind into the hydrophobic interior of the cyclodextrin. Thus, it seems that the carbohydrate moiety acts as a binding site for the hydroperoxide substrate. The cyclodextrin derivatives were also evaluated for their capacity to inhibit thioredoxin reductase/thioredoxin and cancer cell growth in culture. IC(50) values for inhibition of thioredoxin or thioredoxin/thioredoxin reductase were in the submicromolar range for the best inhibitors (compounds 4d and 5). Two of the compounds (4c and 5) were found to inhibit the growth of MCF-7 cells in culture with IC(50) values in the low micromolar range.

Thioredoxin reductase and cancer cell growth inhibition by organotellurium compounds that could be selectively incorporated into tumor cells.

The thioredoxins are small ubiquitous redox proteins with the conserved redox catalytic sequence-Trp-Cys-Gly-Pro-Cys-Lys, where the Cys residues undergo reversible NADPH dependent reduction by selenocysteine containing flavoprotein thioredoxin reductases. Thioredoxin expression is increased in several human primary cancers including lung, colon, cervix, liver, pancreatic, colorectal and squamous cell cancer. The thioredoxin/thioredoxin reductase pathway therefore provides an attractive target for cancer drug development. Organotellurium steroid, lipid, amino acid, nucleic base, and polyamine inhibitors were synthesized on the basis that they might be selectively or differentially incorporated into tumor cells. Some of the newly prepared classes of tellurium-based inhibitors (lipid-like compounds 3b and 3e, amino acid derivative 5b, nucleic base derivative 8b, and polyamine derivatives 14a and 14b) inhibited TrxR/Trx and cancer cell growth in culture with IC(50) values in the low micromolar range.