Medical Evaluation Board for Mental Health Condition: U.S. Army Officer Medical Evaluation Board Data by Branch and Component.

OBJECTIVE: A retrospective review of Medical Evaluation Board (MEB) data to determine the effect of career field or Army component on the relative risk for mental health (MH) related MEBs among Army Officers, may identify specific populations for enhanced screening before accession, or groups that may require targeted preventive resources during their careers. METHOD: 4 years' of data available on Army Officers from the Department of the Army's Electronic Disability Evaluation System database, contained specific information on the officers' physical profiles, career fields, and service component. This information was compared with a dataset provided by the Defense Manpower Data Center (DMDC), reporting documented force strength by career field and service component for the corresponding years, allowing for calculation and comparison of MEB and MH-MEB rates between Army components and between career fields. RESULTS: Significant differences in MEB and MH-MEB rates were found between Army components, but database gaps make this assessment uncertain. When comparing MEB and MH-MEB rates between career fields (regardless of service component), 9 career fields had statistically significant higher risk rates of MEB and/or MH-MEB, whereas 13 career fields showed significantly lower rates of MEB and/or MH-MEB. CONCLUSION: Frequency of Army Officer MEBs and/or MH-MEBs were variable and career field dependent; the underlying causes of these variations warrant further research. The use of the Electronic Disability Evaluation System database for the Integrated Disability Evaluation System process is a rich source of data for in-depth analysis, but the program itself and the procedures for its use need to be improved to obtain more complete information.

Effect of compound plate composition on measurement of hERG current IC(50) using PatchXpress.

Inhibition of the human ether-a-go-go-related gene (hERG) potassium channel by pharmaceutical agents can lead to acquired long QT syndrome and the generation of potentially lethal arrhythmias. Higher throughput automated patch clamp systems, such as PatchXpress, can greatly increase the speed and capacity of evaluation of pharmaceutical compounds for hERG blocking activity. A factor that may affect the IC(50) value of a compound measured in this system is the composition of the multi-well compound plate. Hydrophobic compounds may adsorb to the surfaces of multi-well plates resulting in a reduction in the effective concentration of the compound delivered to the cell and altered IC(50) values. In the present study, we investigated the effects of four different compound plates--glass vials, non-binding polystyrene, hydrophilic polystyrene, and polystyrene--on determination of IC(50)s for four compounds--sotalol, dofetilide, cisapride, and bepridil--which ranged in hydrophobicity. In addition, we investigated the effects of incubation time in the compound plate on determination of IC(50)s. hERG currents were measured using the PatchXpress 7000A Automated Parallel Patch Clamp System (Molecular Devices Corporation; Sunnyvale, CA) and hERG channels stably expressed in HEK293 cells. The results suggest that more hydrophobic compounds may adsorb to non-binding polystyrene, hydrophilic, and polystyrene compound plates versus glass plates, especially with increasing time on the plates, resulting in altered IC(50) values.

Effects of octamethylcyclotetrasiloxane (D4) on the luteinizing hormone (LH) surge and levels of various reproductive hormones in female Sprague-Dawley rats.

The objectives of this study were to assess the potential for D(4) to suppress the pre-ovulatory lutenizing hormone (LH) surge, to block or delay ovulation, and to evaluate potential effects on reproductive hormones in rats. Female Sprague-Dawley Crl:CD (SD) IGS BR rats received whole-body vapor inhalation exposure to D(4) (0, 700, or 900ppm) 6h per day for 3 days. Trunk blood obtained on proestrus at 10a.m. was evaluated for levels of follicle stimulating hormone (FSH), estradiol (E2), estrone (E1), and progesterone (P4). Other rats had serial blood samples collected via cannula at 2, 4, 6, 8, and 10p.m. on the day of proestrus and plasma evaluated for LH and prolactin (PRL). Trunk blood was collected at 8a.m. of estrus and plasma evaluated for FSH, E2, E1, and P4. At 10a.m. on proestrus, significant increases in E1 levels in the 700 and 900ppm groups and significant increases in P4 levels in the 900ppm group were noted. At 8a.m. on estrus, significant increases in E1, E2, in the E1/E2 ratio and decreases in FSH were noted in the 700 and 900ppm groups. The major effect on the LH profile was observed most clearly when the rats were grouped by ovulatory status, animals that did or did not ovulate. Regardless of treatment, suppression of the LH surge correlated with blocked ovulation. The percentage of rats that ovulated was (700ppm, 42%; 900ppm, 31%) compared to controls (79%). Overall, the data indicate that high exposures to D(4) attenuated the pre-ovulatory LH surge and significantly decreased the portion of female rats that ovulated.

Chlorosilane acute inhalation toxicity and development of an LC50 prediction model.

The acute inhalation toxicity of 10 chlorosilanes was investigated in Fischer 344 rats using a 1-h whole-body vapor inhalation exposure and a 14-day recovery period. The median lethal concentration (LC50(1)) for each material was calculated from the nominal exposure concentrations and mortality. Experimentally derived LC50(1) values for monochlorosilanes (4257-4478 ppm) were greater than those for dichlorosilanes (1785-2092 ppm), which were greater than those for trichlorosilanes (1257-1611 ppm). Apparent was a strong structure-activity relationship (r2 = .97) between chlorine content and LC50(1) value. Estimated LC50(1) values for mono-, di-, and trichlorosilanes were determined to be 3262, 1639, and 1066 ppm, respectively, utilizing this relationship and the lower limit of the 95% prediction interval. The LC50(1) values determined in this series of studies were greater than that reported for hydrogen chloride (3124 ppm), when expressed on a chlorine equivalence basis (3570-5248 ppm), demonstrating that the acute toxicity of these chlorosilanes is similar to or less than that for hydrogen chloride. The good correlation between chlorine content and LC50(1) provides a sound basis for estimation of LC50(1) for chlorosilanes not already evaluated. The use of structure-activity relationships is consistent with the chemical industry and federal agency initiatives to reduce, refine, and/or replace the use of animals in testing without compromising the quality of health and safety assessments.

Evaluation of the rubidium efflux assay for preclinical identification of HERG blockade.

Inhibition of the delayed-rectifier potassium channel current, human ether-a-go-go (hERG), by pharmaceutical agents can lead to acquired long QT syndrome and the generation of potentially lethal arrhythmias and sudden death. There remains an unmet need for higher-throughput assays to screen compounds in preclinical development for the potential to block hERG and cause QT prolongation. We evaluated the rubidium efflux assay for its ability to determine block of the hERG potassium channel. hERG-transfected human embryonic kidney-293 cells were cultured on 96-well assay plates and loaded with rubidium ion by incubating in media in which potassium was replaced by 5.4 mM Rb+. Cells were exposed to test compounds and then depolarized with a K+ channel opening buffer containing 50 mM K+. The supernatant was removed, and cells were lysed using 0.1% Triton X-100. Concentration-response curves were generated for test agents by determining the Rb+ efflux using a flame atomic absorption spectrometer. Multiple trials with cisapride yielded 50% inhibitory concentration values between 308.1 +/- 11 nM to 456.3 +/- 24 nM for inhibition of Rb+ efflux and a Z factor of 0.80 +/- 0.07 (n = 5 plates, 12 wells per plate). The values for inhibition of the hERG channel exhibited a rightward shift in potency as compared to those measured using electrophysiological techniques. In addition, we evaluated 19 blinded compounds at 10 microM in the Rb+ efflux assay, and compared results to those using patch clamp electrophysiology and the dofetilide displacement binding assay. The dofetilide displacement binding assay yielded a good correlation with electrophysiological measurements of hERG block. The rubidium efflux assay lacked sensitivity to consistently identify significant channel blockade. In conclusion, the rubidium efflux assay provides a higher-throughput means to identify potent hERG channel blocking agents, but lacks the sensitivity required to accurately determine the potency of blockade.

A multiple in silico program approach for the prediction of mutagenicity from chemical structure.

We have conducted an evaluation of three of the most widely used commercial toxicity prediction programs, Toxicity Prediction by Komputer Assisted Technology (TOPKAT), Deductive Estimation of Risk from Existing Knowledge (DEREK) for Windows (DfW) and CASETOX. The three programs were evaluated for their ability to predict Ames test mutagenicity using 520 proprietary drug candidate (Test set 1) and 94 commercial (Test set 2) compounds. The study demonstrates that these three commercially available programs are useful, with limitations in their ability to predict mutagenicity over a wide range of chemical space, i.e. global predictivity. Individually, each of the programs performed at an acceptable level for overall accuracy, i.e. the ability to predict the correct outcome. However, analysis of the predictions indicates that the overall accuracy figure is heavily weighted by the ability of the programs to correctly predict non-mutagens, whereas none of the programs individually performed well in the prediction of novel mutagenic structures, i.e. Ames positive compounds. The performance of these programs' in predicting Ames positive mutagens appeared to be independent of the chemical utility of the compound, i.e. industrial, agricultural or pharmaceutical. The combination of program predictions provided some improvement in overall accuracy, sensitivity and specificity.