Discovery of treatment for nerve agents targeting a new metabolic pathway.

The inhibition of acetylcholinesterase is regarded as the primary toxic mechanism of action for chemical warfare agents. Recently, there have been numerous reports suggesting that metabolic processes could significantly contribute to toxicity. As such, we applied a multi-omics pipeline to generate a detailed cascade of molecular events temporally occurring in guinea pigs exposed to VX. Proteomic and metabolomic profiling resulted in the identification of several enzymes and metabolic precursors involved in glycolysis and the TCA cycle. All lines of experimental evidence indicated that there was a blockade of the TCA cycle at isocitrate dehydrogenase 2, which converts isocitrate to α-ketoglutarate. Using a primary beating cardiomyocyte cell model, we were able to determine that the supplementation of α-ketoglutarate subsequently rescued cells from the acute effects of VX poisoning. This study highlights the broad impacts that VX has and how understanding these mechanisms could result in new therapeutics such as α-ketoglutarate.

Biological monitoring for depleted uranium exposure in U.S. Veterans.

BACKGROUND: As part of an ongoing medical surveillance program for U.S. veterans exposed to depleted uranium (DU), biological monitoring of urine uranium (U) concentrations is offered to any veteran of the Gulf War and those serving in more recent conflicts (post-Gulf War veterans). OBJECTIVES: Since a previous report of surveillance findings in 2004, an improved methodology for determination of the isotopic ratio of U in urine ((235)U:(238)U) has been developed and allows for more definitive evaluation of DU exposure. This report updates previous findings. METHODS: Veterans provide a 24-hr urine specimen and complete a DU exposure questionnaire. Specimens are sent to the Baltimore Veterans Affairs Medical Center for processing. Uranium concentration and isotopic ratio are measured using ICP-MS at the Armed Forces Institute of Pathology. RESULTS: Between January 2003 and June 2008, we received 1,769 urine specimens for U analysis. The mean urine U measure was 0.009 microg U/g creatinine. Mean urine U concentrations for Gulf War and post-Gulf War veterans were 0.008 and 0.009 microg U/g creatinine, respectively. Only 3 of the 1,700 (0.01%) specimens for which we completed isotopic determination showed evidence of DU. Exposure histories confirmed that these three individuals had been involved in "friendly fire" incidents involving DU munitions or armored vehicles. CONCLUSIONS: No urine U measure with a "depleted" isotopic signature has been detected in U.S. veterans without a history of retained DU embedded fragments from previous injury. These findings suggest that future DU-related health harm is unlikely in veterans without DU fragments.

Comparison of patella lead with blood lead and tibia lead and their associations with neurobehavioral test scores.

OBJECTIVE: Lead exposure in adults is associated with worse cognitive function in cross-sectional and longitudinal studies. Previous studies have mainly examined relations with blood lead or cortical bone lead; few have examined trabecular bone lead. METHODS: We performed a cross-sectional analysis of the relations of patella lead and other lead biomarkers with measures of neurobehavioral and peripheral nervous system function in 652 lead workers. RESULTS: Patella lead was found to be associated with worse performance on seven of 19 tests of manual dexterity, sensory vibration threshold, and depressive symptoms. The associations of patella lead with cognitive function were essentially similar to those with blood lead or tibia lead but of somewhat lower magnitude. CONCLUSIONS: In this study, measurement of patella lead did not aid causal inference regarding cognitive effects when compared with blood lead and tibia lead.