Risk of dental disease non-battle injuries and severity of dental disease in deployed U.S. Army personnel.

Dental Disease and Non-Battle Injuries (D-DNBI) continue to be a problem among U.S. Army active duty (AD), U.S. Army National Guard (ARNG), and U.S. Army Reserve (USAR) deployed soldiers to Operation Iraqi Freedom/Operation New Dawn in Iraq and Operation Enduring Freedom in Afghanistan. A previous study reported the annual rates to be 136 D-DNBI per 1,000 personnel for AD, 152 for ARNG, and 184 for USAR. The objectives of this study were to describe D-DNBI incidence and to determine risk factors for dental encounters and high severity diagnoses for deployed soldiers. The 78 diagnoses were classified into three categories based on severity. Poisson regression was used to compare D-DNBI rates and logistic regression was used to analyze the risk of high severity D-DNBI. In both campaigns, Reserve had a higher risk of D-DNBI than active duty. For Afghanistan, ARNG and USAR demonstrated over 50% increased risk of D-DNBI compared to AD. In Iraq, USAR had a 17% increased risk over AD. Females had a higher risk of D-DNBI (>50%) compared to males in both campaigns. High severity D-DNBI made up 2.77% of all diagnoses. Within Afghanistan, there was a 4.6% increased risk of high severity D-DNBI for each additional deployment month.

The incidence of dental disease nonbattle injuries in deployed U.S. Army personnel.

BACKGROUND: In the past, the U.S. Army Reserve (USAR) and Army National Guard (ARNG) have exhibited lower levels of medical and dental readiness than active duty (AD) Soldiers when activated for deployment. OBJECTIVE: The objective was to compare dental disease and nonbattle injury (D-DNBI) incidence rates and describe the most common D-DNBI diagnoses in Army AD, ARNG, and USAR Soldiers deployed to Iraq (Operation Iraqi Freedom/Operation New Dawn) and Afghanistan or Kuwait (Operation Enduring Freedom). METHODS: Data from the Center for AMEDD Strategic Studies (CASS) were used to determine D-DNBI encounter rates and diagnoses for deployed Army Soldiers. RESULTS: "Dental Caries" was the leading diagnosis (10.00%) for Soldiers in both theaters. For Operation Iraqi Freedom, D-DNBI rates were highest in 2010 at 144.05 per 1,000 Soldiers per year (AD 135.77, ARNG 151.39 and USAR 183.76). In comparison, D-DNBI rates in Operation Enduring Freedom were highest in 2012 with an overall rate of 85.77 per 1,000 Soldiers per year (AD 72.48, ARNG 129.38 and USAR 129.52). CONCLUSIONS: In both campaigns, the data suggest that ARNG and USAR Soldiers had higher D-DNBI rates when compared to AD Soldiers. Further investigation is needed to decrease D-DNBI rates and to determine risk factors that may influence D-DNBI rates among Army components during deployments.

Correlation as a determinant of configurational entropy in supramolecular and protein systems.

For biomolecules in solution, changes in configurational entropy are thought to contribute substantially to the free energies of processes like binding and conformational change. In principle, the configurational entropy can be strongly affected by pairwise and higher-order correlations among conformational degrees of freedom. However, the literature offers mixed perspectives regarding the contributions that changes in correlations make to changes in configurational entropy for such processes. Here we take advantage of powerful techniques for simulation and entropy analysis to carry out rigorous in silico studies of correlation in binding and conformational changes. In particular, we apply information-theoretic expansions of the configurational entropy to well-sampled molecular dynamics simulations of a model host-guest system and the protein bovine pancreatic trypsin inhibitor. The results bear on the interpretation of NMR data, as they indicate that changes in correlation are important determinants of entropy changes for biologically relevant processes and that changes in correlation may either balance or reinforce changes in first-order entropy. The results also highlight the importance of main-chain torsions as contributors to changes in protein configurational entropy. As simulation techniques grow in power, the mathematical techniques used here will offer new opportunities to answer challenging questions about complex molecular systems.

Evaluation of irritancy and sensitization potential of metalworking fluid mixtures and components.

There are approximately 1.2 million workers exposed to metalworking fluids (MWF), which are used to reduce the heat and friction associated with industrial machining and grinding operations. Irritancy and sensitization potential of 9 National Toxicology Program (NTP) nominated MWFs (TRIM 229, TRIM VX, TRIM SC210, CIMTECH 310, CIMPERIAL 1070, CIMSTAR 3800, SYNTILO 1023, SUPEREDGE 6768, and CLEAREDGE 6584) were examined in a combined local lymph node assay (LLNA). BALB/c mice were dermally exposed to each MWF at concentrations up to 50%. Significant irritation was observed after dermal exposure to all MWFs except CIMTECH 310 and SYNTILO 1023. Of the 9 MWFs, 6 induced greater than a 3-fold increase in lymphocyte proliferation and 7 tested positive in the irritancy assay. TRIM VX yielded the lowest EC3 value (6.9%) with respect to lymphocyte proliferation. Chemical components of TRIM VX identified using HPLC were screened for sensitization potential using structural activity relationship (SAR) modeling and the LLNA. TOPKAT predicted triethanolamine (TEA) as a sensitizer while Derek for Windows predicted only 4-chloro-3-methylphenol (CMP) to be positive for sensitization. When tested in the LLNA only CMP (EC3 = 11.6%) and oleic acid (OA) (EC3 = 29.7%) were identified as sensitizers. Exposure to all tested TRIM VX components resulted in statistically significant irritation. An additive proliferative response was observed when mixtures of the two identified sensitizing TRIM VX components, OA and CMP, were tested in the LLNA. This is one explanation of why the EC3 value of TRIM VX, with respect to lymphocyte proliferation, is lower than those assigned to its sensitizing components.

Physical-chemical and solvent considerations in evaluating the influence of carbon chain length on the skin sensitization activity of 1-bromoalkanes.

The murine local lymph node assay (LLNA) is an internationally accepted assay for identification of contact allergens. The LLNA has also been used in research studies to evaluate contact allergen potency, as well as chemical structural-allergenic activity relationships. The 1-bromoalkanes have been used in such a manner as they represent a chemical series with generally the same chemical reactivity but differing in alkane carbon chain length-dependent lipid solubilities. Previous reports noted a biphasic LLNA response with increasing carbon chain length that peaked at the 16-carbon chain (C16) of 1-bromohexadecane (delivered in an acetone-olive oil [AOO] vehicle; 4:1). In the present study, this biphasic LLNA response was confirmed, and 1-bromoalkane chemical-physical factors were explored using both modeling tools and further laboratory studies to help understand this finding. Volatility and effect of vehicle on 1-bromoalkanes' sensitizations were assessed. Selected 1-bromoalkanes were tested in the LLNA using the polar, protic vehicle, tetrahydrofuran-butanol (THF-BuOH; 1:1), to compare to the nonpolar (aprotic) vehicle AOO 1-bromoalkanes-LLNA responses. Enhanced 1-bromoalkane LLNA responses were observed using the THF-BuOH vehicle but with the greatest activity still observed for 1-bromohexadecane (C16). The shorter 1-bromoalkanes were subject to volatile losses upon application with approximately 75% volatile loss from a surface of 1-bromohexane (C6) within 5 min at room temperature. It is concluded that multiple factors, in addition to lipid solubility, including vehicle, solvation, and retention on the skin surface contribute to the apparent potency of 1-bromoalkanes in the LLNA.

Evaluation of the contact and respiratory sensitization potential of volatile organic compounds generated by simulated indoor air chemistry.

Up to 60 million people working indoors experience symptoms such as eye, nose and throat irritation, headache, and fatigue. Investigations into these complaints have ascribed the effects to volatile organic compounds (VOCs) emitted from building materials, cleaning formulations, or other consumer products. New compounds can result when the VOCs react with hydroxyl or nitrate radicals or ozone present in indoor environments. Several oxygenated organic compounds, such as glyoxal, methylglyoxal, glycolaldehyde, and diacetyl, have been identified as possible reaction products of indoor environment chemistry. Although research has previously identified diacetyl and glyoxal as sensitizers, additional experiments were conducted in these studies to further classify their sensitization potential. Sensitization potential of these four compounds was assessed using quantitative structure-activity relationship (QSAR) programs. Derek for Windows and National Institute for Occupational Safety and Health logistic regression predicted all compounds to be sensitizers, while TOPKAT 6.2 predicted all compounds except for methylglyoxal. All compounds were tested in a combined irritancy and local lymph node assay (LLNA). All compounds except for glyoxal were found to be irritants and all tested positive in the LLNA with EC3 values ranging from 0.42 to 1.9%. Methylglyoxal significantly increased both the B220(+) and IgE(+)B220(+) cell populations in the draining lymph nodes and total serum IgE levels. The four compounds generated by indoor air chemistry were predicted by QSAR and animal modeling to be sensitizers, with the potential for methylglyoxal to induce IgE. The identification of these compounds as sensitizers may help to explain some of the health effects associated with indoor air complaints.

Nearest-neighbor nonparametric method for estimating the configurational entropy of complex molecules.

A method for estimating the configurational (i.e., non-kinetic) part of the entropy of internal motion in complex molecules is introduced that does not assume any particular parametric form for the underlying probability density function. It is based on the nearest-neighbor (NN) distances of the points of a sample of internal molecular coordinates obtained by a computer simulation of a given molecule. As the method does not make any assumptions about the underlying potential energy function, it accounts fully for any anharmonicity of internal molecular motion. It provides an asymptotically unbiased and consistent estimate of the configurational part of the entropy of the internal degrees of freedom of the molecule. The NN method is illustrated by estimating the configurational entropy of internal rotation of capsaicin and two stereoisomers of tartaric acid, and by providing a much closer upper bound on the configurational entropy of internal rotation of a pentapeptide molecule than that obtained by the standard quasi-harmonic method. As a measure of dependence between any two internal molecular coordinates, a general coefficient of association based on the information-theoretic quantity of mutual information is proposed. Using NN estimates of this measure, statistical clustering procedures can be employed to group the coordinates into clusters of manageable dimensions and characterized by minimal dependence between coordinates belonging to different clusters.

Application of the random forest method in studies of local lymph node assay based skin sensitization data.

The random forest and classification tree modeling methods are used to build predictive models of the skin sensitization activity of a chemical. A new two-stage backward elimination algorithm for descriptor selection in the random forest method is introduced. The predictive performance of the random forest model was maximized by tuning voting thresholds to reflect the unbalanced size of classification groups in available data. Our results show that random forest with a proposed backward elimination procedure outperforms a single classification tree and the standard random forest method in predicting Local Lymph Node Assay based skin sensitization activity. The proximity measure obtained from the random forest is a natural similarity measure that can be used for clustering of chemicals. Based on this measure, the clustering analysis partitioned the chemicals into several groups sharing similar molecular patterns. The improved random forest method demonstrates the potential for future QSAR studies based on a large number of descriptors or when the number of available data points is limited.

Structure-activity models for contact sensitization.

Allergic contact dermatitis (ACD) is a widespread cause of workers' disabilities. Although some substances found in the workplace are rigorously tested, the potential of the vast majority of chemicals to cause skin sensitization remains unknown. At the same time, exhaustive testing of all chemicals in workplaces is costly and raises ethical concerns. New approaches to developing information for risk assessment based on computational (quantitative) structure-activity relationship [(Q)SAR] methods may be complementary to and reduce the need for animal testing. Virtually any number of existing, de novo, and even preconceived compounds can be screened in silico at a fraction of the cost of animal testing. This work investigates the utility of ACD (Q)SAR modeling from the occupational health perspective using two leading software products, DEREK for Windows and TOPKAT, and an original method based on logistic regression methodology. It is found that the correct classification of (Q)SAR predictions for guinea pig data achieves values of 73.3, 82.9, and 87.6% for TOPKAT, DEREK for Windows, and the logistic regression model, respectively. The correct classification using LLNA data equals 73.0 and 83.2% for DEREK for Windows and the logistic regression model, respectively.

Estimation of the absolute internal-rotation entropy of molecules with two torsional degrees of freedom from stochastic simulations.

A method of statistical estimation is applied to the problem of evaluating the absolute entropy of internal rotation in a molecule with two torsional degrees of freedom. The configurational part of the entropy is obtained as that of the joint probability density of an arbitrary form represented by a two-dimensional Fourier series, the coefficients of which are statistically estimated using a sample of the torsional angles of the molecule obtained by a stochastic simulation. The internal rotors in the molecule are assumed to be attached to a common frame, and their reduced moments of inertia are initially calculated as functions of the two torsional angles, but averaged over all the remaining internal degrees of freedom using the stochastic-simulation sample of the atomic configurations of the molecule. The torsional-angle dependence of the reduced moments of inertia can be also averaged out, and the absolute internal-rotation entropy of the molecule is obtained in a good approximation as the sum of the configurational entropy and a kinetic contribution fully determined by the averaged reduced moments of inertia. The method is illustrated using Monte Carlo simulations of isomers of stilbene and halogenated derivatives of propane. The two torsional angles in cis-stilbene are found to be much more strongly correlated than those in trans-stilbene, while the degree of the angular correlation in propane increases strongly on substitution of hydrogen atoms with chlorine.

Search for new lead structures in the isoxazole heterocyclic system.

Looking for active immunosuppressant, a series of substituted phenylamides of 5-aminomethinimino-3-methylisoxazole-4-carboxylic acid was obtained, which showed immunosuppressory activities in the in vitro and in vivo tests, comparable with that of cyclosporine A. Rentgenostructural studies of three most representative derivatives were performed and the molecular modelling of compounds, demonstrating most characteristic biological activities, was performed. In the next stage, quantum-chemical investigations were conducted in order to determine structure-activity relationships.

Statistical thermodynamics of internal rotation in a hindering potential of mean force obtained from computer simulations.

A method of statistical estimation is applied to the problem of one-dimensional internal rotation in a hindering potential of mean force. The hindering potential, which may have a completely general shape, is expanded in a Fourier series, the coefficients of which are estimated by fitting an appropriate statistical-mechanical distribution to the random variable of internal rotation angle. The function of reduced moment of inertia of an internal rotation is averaged over the thermodynamic ensemble of atomic configurations of the molecule obtained in stochastic simulations. When quantum effects are not important, an accurate estimate of the absolute internal rotation entropy of a molecule with a single rotatable bond is obtained. When there is more than one rotatable bond, the "marginal" statistical-mechanical properties corresponding to a given internal rotational degree of freedom are reduced. The method is illustrated using Monte Carlo simulations of two public health relevant halocarbon molecules, each having a single internal-rotation degree of freedom, and a molecular dynamics simulation of an immunologically relevant polypeptide, in which several dihedral angles are analyzed.