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Sample records for agents nerve agents

  1. Organophosphate nerve agent detection with europium complexes.

    PubMed

    Schwierking, Jake R; Menzel, Laird W; Menzel, E Roland

    2004-11-05

    We explore the detection of paraoxon, a model compound for nonvolatile organophosphate nerve agents such as VX. The detection utilizes europium complexes with 1,10 phenanthroline and thenoyltrifluoroacetone as sensitizing ligands. Both europium luminescence quenching and luminescence enhancement modalities are involved in the detection, which is simple, rapid, and sensitive. It is adaptable as well to the more volatile fluorophosphate nerve agents. It involves nothing more than visual luminescence observation under sample illumination by an ordinary hand-held ultraviolet lamp.

  2. Fate of Nerve Agent Simulants on Concrete

    DTIC Science & Technology

    2005-10-01

    2.0 µL range was detected. INTRODUCTION The rate of decomposition of chemical warfare agents on substrates commonly present in a...Edgewood Chemical Biological Center (ECBC) ABSTRACT The nerve agent VX (O-ethyl S-[2-(diisopropylamino)ethyl]methylphosphonothiolate) has...from Aldrich Chemical Company and used as received. 31P NMR of the starting materials indicated that it was the correct compound. Concrete samples

  3. Human Carboxylesterase 1 Stereoselectively Binds the Nerve Agent Cyclosarin and Spontaneously Hydrolyzes the Nerve Agent Sarin

    SciTech Connect

    Hemmert, Andrew C.; Otto, Tamara C.; Wierdl, Monika; Edwards, Carol C.; Fleming, Christopher D.; MacDonald, Mary; Cashman, John R.; Potter, Philip M.; Cerasoli, Douglas M.; Redinbo, Matthew R.

    2010-10-28

    Organophosphorus (OP) nerve agents are potent toxins that inhibit cholinesterases and produce a rapid and lethal cholinergic crisis. Development of protein-based therapeutics is being pursued with the goal of preventing nerve agent toxicity and protecting against the long-term side effects of these agents. The drug-metabolizing enzyme human carboxylesterase 1 (hCE1) is a candidate protein-based therapeutic because of its similarity in structure and function to the cholinesterase targets of nerve agent poisoning. However, the ability of wild-type hCE1 to process the G-type nerve agents sarin and cyclosarin has not been determined. We report the crystal structure of hCE1 in complex with the nerve agent cyclosarin. We further use stereoselective nerve agent analogs to establish that hCE1 exhibits a 1700- and 2900-fold preference for the P{sub R} enantiomers of analogs of soman and cyclosarin, respectively, and a 5-fold preference for the P{sub S} isomer of a sarin analog. Finally, we show that for enzyme inhibited by racemic mixtures of bona fide nerve agents, hCE1 spontaneously reactivates in the presence of sarin but not soman or cyclosarin. The addition of the neutral oxime 2,3-butanedione monoxime increases the rate of reactivation of hCE1 from sarin inhibition by more than 60-fold but has no effect on reactivation with the other agents examined. Taken together, these data demonstrate that hCE1 is only reactivated after inhibition with the more toxic P{sub S} isomer of sarin. These results provide important insights toward the long-term goal of designing novel forms of hCE1 to act as protein-based therapeutics for nerve agent detoxification.

  4. Human carboxylesterase 1 stereoselectively binds the nerve agent cyclosarin and spontaneously hydrolyzes the nerve agent sarin.

    PubMed

    Hemmert, Andrew C; Otto, Tamara C; Wierdl, Monika; Edwards, Carol C; Fleming, Christopher D; MacDonald, Mary; Cashman, John R; Potter, Philip M; Cerasoli, Douglas M; Redinbo, Matthew R

    2010-04-01

    Organophosphorus (OP) nerve agents are potent toxins that inhibit cholinesterases and produce a rapid and lethal cholinergic crisis. Development of protein-based therapeutics is being pursued with the goal of preventing nerve agent toxicity and protecting against the long-term side effects of these agents. The drug-metabolizing enzyme human carboxylesterase 1 (hCE1) is a candidate protein-based therapeutic because of its similarity in structure and function to the cholinesterase targets of nerve agent poisoning. However, the ability of wild-type hCE1 to process the G-type nerve agents sarin and cyclosarin has not been determined. We report the crystal structure of hCE1 in complex with the nerve agent cyclosarin. We further use stereoselective nerve agent analogs to establish that hCE1 exhibits a 1700- and 2900-fold preference for the P(R) enantiomers of analogs of soman and cyclosarin, respectively, and a 5-fold preference for the P(S) isomer of a sarin analog. Finally, we show that for enzyme inhibited by racemic mixtures of bona fide nerve agents, hCE1 spontaneously reactivates in the presence of sarin but not soman or cyclosarin. The addition of the neutral oxime 2,3-butanedione monoxime increases the rate of reactivation of hCE1 from sarin inhibition by more than 60-fold but has no effect on reactivation with the other agents examined. Taken together, these data demonstrate that hCE1 is only reactivated after inhibition with the more toxic P(S) isomer of sarin. These results provide important insights toward the long-term goal of designing novel forms of hCE1 to act as protein-based therapeutics for nerve agent detoxification.

  5. Rapid fluorophosphate nerve agent detection with lanthanides.

    PubMed

    Menzel, E Roland; Menzel, Laird W; Schwierking, Jake R

    2005-08-15

    We explore the detection of vapors of diisopropylfluorophosphate, a model compound for nerve agents such as Sarin, by means of photoluminescence quenching of filter paper impregnated with sensitized complexes of lanthanides, involving thenoyltrifluoroacetone and 1,10-phenanthroline as sensitizing ligands. We find that the presence of the fluorophosphate vapor is detectable in as little as 2s, by simple visual observation under illumination with a hand-held low intensity ultraviolet lamp.

  6. Organophosphate nerve agent toxicity in Hydra attenuata.

    PubMed

    Lum, Karin T; Huebner, Henry J; Li, Yingchun; Phillips, Timothy D; Raushel, Frank M

    2003-08-01

    The toxicity for analogues of sarin (GB), soman (GD), and VX was evaluated using Hydra attenuata as a model organism. The organophosphate nerve agent analogue simulants used in this investigation included the following: isopropyl p-nitrophenyl methylphosphonate (for GB); pinacolyl p-nitrophenyl methylphosphonate (for GD); and diisopropyl S-(2-diisopropylaminoethyl)phosphorothioate, diethyl S-(2-diisopropylaminoethyl)phosphorothioate, and diethyl S-(2-trimethylaminoethyl)phosphorothioate (for VX). The toxicity of each organophosphate nerve agent was assessed quantitatively by measuring the minimal effective concentration within 92 h in H. attenuata. There is a positive correlation between the molecular hydrophobicity of the compound and its ability to cause toxicity. Results from this study indicate the potential for application of this assay in the field of organophosphate chemical warfare agent detection, as well as for the prediction of toxicity of structurally similar organophosphate compounds. The minimal effective concentration for two of the VX analogues was 2 orders of magnitude more toxic than the analogue for GD and 4 orders of magnitude more toxic than the analogue for GB.

  7. Agents.

    PubMed

    Chambers, David W

    2002-01-01

    Although health care is inherently an economic activity, it is inadequately described as a market process. An alternative, grounded in organizational economic theory, is to view professionals and many others as agents, contracted to advance the best interests of their principals (patients). This view untangles some of the ethical conflicts in dentistry. It also helps identify major controllable costs in dentistry and suggests that dentists can act as a group to increase or decrease agency costs, primarily by controlling the bad actors who damage the value of all dentists.

  8. Detection of nerve agent via perturbation of supramolecular gel formation.

    PubMed

    Hiscock, Jennifer R; Piana, Francesca; Sambrook, Mark R; Wells, Neil J; Clark, Alistair J; Vincent, Jack C; Busschaert, Nathalie; Brown, Richard C D; Gale, Philip A

    2013-10-14

    The formation of tren-based tris-urea supramolecular gels in organic solvents is perturbed by the presence of the nerve agent soman providing a new method of sensing the presence of organophosphorus warfare agents.

  9. Nanomotors responsive to nerve-agent vapor plumes.

    PubMed

    Singh, Virendra V; Kaufmann, Kevin; Esteban-Fernández de Ávila, Berta; Uygun, Murat; Wang, Joseph

    2016-02-25

    Enzyme-powered nanomotors responsive to the presence of nerve agents in the surrounding atmosphere are employed for remote detection of chemical vapor threats. Distinct changes in the propulsion behavior, associated with the partition of the sarin simulant diethyl chlorophosphate (DCP), offer reliable and rapid detection of the nerve-agent vapor threat.

  10. Analysis of Nerve Agent Metabolites from Hair for Long-Term Verification of Nerve Agent Exposure.

    PubMed

    Appel, Amanda S; McDonough, John H; McMonagle, Joseph D; Logue, Brian A

    2016-06-21

    Several methods for the bioanalysis of nerve agents or their metabolites have been developed for the verification of nerve agent exposure. However, parent nerve agents and known metabolites are generally rapidly excreted from biological matrixes typically used for analysis (i.e., blood, urine, and tissues), limiting the amount of time after an exposure that verification is feasible. In this study, hair was evaluated as a long-term repository of nerve agent hydrolysis products. Pinacolyl methylphosphonic acid (PMPA; hydrolysis product of soman) and isopropyl methylphosphonic acid (IMPA; hydrolysis product of sarin) were extracted from hair samples with N,N-dimethylformamide and subsequently analyzed by liquid chromatography-tandem mass spectrometry. Limits of detection for PMPA and IMPA were 0.15 μg/kg and 7.5 μg/kg and linear ranges were 0.3-150 μg/kg and 7.5-750 μg/kg, respectively. To evaluate the applicability of the method to verify nerve agent exposure well after the exposure event, rats were exposed to soman, hair was collected after approximately 30 days, and stored for up to 3.5 years prior to initial analysis. PMPA was positively identified in 100% of the soman-exposed rats (N = 8) and was not detected in any of the saline treated animals (N = 6). The hair was reanalyzed 5.5 years after exposure and PMPA was detected in 6 of the 7 (one of the soman-exposed hair samples was completely consumed in the analysis at 3.5 years) rat hair samples (with no PMPA detected in the saline exposed animals). Although analysis of CWA metabolites from hair via this technique is not appropriate as a universal method to determine exposure (i.e., it takes time for the hair to grow above the surface of the skin and typical analysis times are >24 h), it complements existing methods and could become the preferred method for verification of exposure if 10 or more days have elapsed after a suspected exposure.

  11. In Vivo Cholinesterase Inhibitory Specificity of Organophosphorus Nerve Agents

    DTIC Science & Technology

    2005-10-26

    of the hydrolysis products of V-agents are presumably phoric acid anhydrides , and their structures are very simi- toxic. Also, V-agents may be...slowly with carboxylesterases and phospho- anhydrides . GF contains a cyclohexyl substituent. rylphosphatases than do G-agents [3]. The G-type nerve agents...USA). Tris(hydroxymethyl) 2.4. AChE analysis amino methane was purchased from Fischer Scientific (Fair Lawn, NJ, USA). The bicinchronic (BCA) protein

  12. Using Nanotechnology to Detect Nerve Agents

    DTIC Science & Technology

    2011-01-01

    Analysis , Industrial Hygiene Branch, “Chemical Warfare Agent Health Risk Assessment Guidance Document,” 61, 2 April 2003, https://afkm.wpafb.af.mil... Bartling et al., “Enzyme-Kinetic Investiga- tion of Different Sarin Analogues Reacting with Hu- man Acetylcholinesterase and Butyrylcholinesterase

  13. Calculated infrared spectra of nerve agents and simulants

    NASA Astrophysics Data System (ADS)

    Mott, Adam J.; Rez, Peter

    2012-06-01

    Since organophosphorus nerve agents are among the most toxic known chemical warfare agents, it is desirable to have a way to distinguish between one and another. Infrared spectroscopy is a common tool for identifying molecules. Given the difficulty in handling these chemicals, calculated IR spectra can be useful. Calculated IR spectra are presented for G agents, V agents, and simulants. Quantum chemistry calculations were performed using the Gaussian 03 package at the B3LYP/6-31+G(d,p) level of theory. The most prominent IR lines are due to vibrations of Psbnd Osbnd C and Pdbnd O groups within the molecules. It should be possible to distinguish between the G-series and V-series agents using IR spectroscopy, but unique identification of individual chemical agents is unlikely.

  14. Assessment of nerve agent exposure: existing and emerging methods.

    PubMed

    Langenberg, Jan P; van der Schans, Marcel J; Noort, Daan

    2009-07-01

    The perceived threat of the use of nerve agents by terrorists against civilian targets implies the need for methods for point-of-care (POC) diagnosis. This review presents an overview of methods that are currently available for the assessment of exposure to nerve agents. Since these methods are mostly MS based, they require complex and expensive equipment and well-trained personnel and, consequently, they are not very suitable for rapid POC diagnosis. However, new technologies are emerging that allow, among others, immunochemical detection of acetylcholinesterase inhibited by nerve agents. Also, lab-on-a-chip methodologies are under development. It is anticipated that MS methods will be suitable for POC diagnosis within a few years, due to the miniaturization of equipment and the emergence of methodologies that enable mass spectrometric analysis with little sample pretreatment and that are potentially fieldable, such as direct analysis in real time and desorption electrospray ionization MS.

  15. Lewis acid-assisted detection of nerve agents in water.

    PubMed

    Butala, Rahul R; Creasy, William R; Fry, Roderick A; McKee, Michael L; Atwood, David A

    2015-06-07

    The five-coordinate compound, Salen((t)Bu)Al(Ac), prepared in situ from Salen((t)Bu)AlBr and NH4Ac, forms Lewis acid-base adducts in aqueous solution with the G-type nerve agents, Sarin and Soman, and the VX hydrolysis product, ethylmethylphosphonate (EMPA). The resulting compounds, [Salen((t)Bu)Al(NA)](+)[Ac] (-) (with NA = Sarin, Soman, and EMPA) are sufficiently stable to be identified by ESI-MS. Molecular ion peaks were detected for every compound with little or no fragmentation. The distinctive MS signatures for the [Salen((t)Bu)Al(NA)](+) compounds provide a new technique for identifying nerve agents from aqueous solution. The energetics of the displacement of Ac(-) by the nerve agents to form [Salen((t)Bu)Al(NA)](+)[Ac](-) were determined computationally.

  16. Fingerprinting malathion vapor: a simulant for VX nerve agent

    NASA Astrophysics Data System (ADS)

    Song, Renbo; Ding, Yujie J.; Zotova, Ioulia B.

    2008-04-01

    Being motivated by the possibility of fingerprinting and detecting VX nerve agent, we have investigated its stimulant, i.e. malathion vapor, which is less toxic and commercially available, in the far-infrared/THz transition region and THz frequency range. Such a spectroscopic study was carried out by using Fourier transform infrared spectroscopy (FTIR). Our intention is to obtain a specific spectroscopic signature of VX nerve agent as a chemical warfare agent. Following our experimental result, we have successfully observed eleven new absorption peaks from malathion vapor in the spectral ranges from 15 cm -1 to 68 cm -1 and from 75 cm -1 to 640 cm -1. Specifically, in the far-infrared/THz transition region, we have observed eight peaks and whereas in the THz region we have identified three relatively weak transition peaks. In addition, we have investigated the dependence of the absorption spectra on temperature in the range from room temperature to 60°C. In both of the frequency ranges, we have found that absorption coefficients significantly increase with increasing temperature. By comparing the transition peaks in the two frequency ranges, we have concluded that the frequency range of 400-640cm -1 is an optimal range for fingerprinting this chemical specie. We have designated two peaks for effectively and accurately identifying the VX nerve agents and one peak for differentiating between malathion and VX nerve agent.

  17. Nerve agent-induced seizures and their pharmacological modulation

    SciTech Connect

    McDonough, J.H.; Shih, T.M.; Adams, N.L.; Koviak, T.A.; Cook, L.A.

    1993-05-13

    Intoxication with nerve agents produces prolonged central nervous system seizures (status epilepticus) that can produce irreversible brain pathology (15). This report summarizes our recent findings regarding the neurotransmitter changes that occur in discrete brain regions as a function of seizure duration and the differential effectiveness of anticholinergic, benzodiazepine and excitatory amino acid (EAA) antagonist drugs in terminating soman-induced seizures when given at different times after seizure onset. These results are discussed in relation to a model we have proposed to explain the sequence of electrophysiological, biochemical and neurochemical events and mechanisms controlling nerve agent-induced seizures.

  18. Extraction of nerve agent VX from soils.

    PubMed

    Montauban, Cécile; Bégos, Arlette; Bellier, Bruno

    2004-05-15

    The development and optimization of a method allowing the extraction of intact organophosphorus chemical warfare agent O-ethyl S-(2-diisopropylaminoethyl) methylphosphonothiolate (VX) from several types of soils are presented here. This involved the selection of an appropriate buffer to bring the sample to a pH close to the pK(a) of VX but sufficiently low to avoid its basic hydrolysis. Buffering with Tris (pH 9) and subsequent extraction of the aqueous layer by a 85:15 (v/v) hexane/dichloromethane mixture allows rapid and sensitive flame photometric detection of VX at spiking levels lower than 10 microg x g(-1), even after 3 months of aging. Extraction yields were close to 60% in complex matrixes. This method also allows recovery and identification of a characteristic degradation product of VX, bis(2-diisopropylaminoethyl) disulfide, which appears to be formed during the aging process. The performance of this method is far better than that of OPCW reference operating procedure, which does not allow extraction of detectable amounts of VX (spiked at 10 microg x g(-1)) in one of the soils used for this study.

  19. MICROCHIP ENZYMATIC ASSAY OF ORGANOPHOSPHATE NERVE AGENTS. (R830900)

    EPA Science Inventory

    An on-chip enzymatic assay for screening organophosphate (OP) nerve agents, based on a pre-column reaction of organophosphorus hydrolase (OPH), electrophoretic separation of the phosphonic acid products, and their contactless-conductivity detection, is described. Factors affec...

  20. Evaluation of Decontamination Systems Challenged With Nerve Agents

    DTIC Science & Technology

    2006-11-01

    may have contributed to the Gulf War Syndrome (Winkenwerder, 2000). The most notable use of nerve agents occurred in 1995 when a Japanese terrorist...were sheared with Oster brand animal clippers , blade #40, and anesthetized with a combination of 32 mg/ml ketamine and 4 mg/ml xylazine in saline

  1. Investigation of the Persistence of Nerve Agent Degradation ...

    EPA Pesticide Factsheets

    Journal Article The persistence of chemical warfare nerve agent degradation analytes on surfaces is important for reasons ranging from indicating the presence of nerve agent on that surface to environmental restoration of a site after nerve agent release. This study investigates the persistence of several chemical warfare nerve agent degradation analytes on a number of indoor surfaces and presents an approach for wipe sampling of surfaces, followed by wipe extraction and liquid chromatography-tandem mass spectrometry detection. Multiple commercially available wipe materials were investigated to determine optimal wipe recoveries. Tested surfaces, including several porous/permeable and largely nonporous/impermeable surfaces, were investigated to determine recoveries from these indoor surface materials. Wipe extracts were analyzed by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and compared with high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) results. UPLC provides a sensitive separation of targeted degradation analytes in addition to being nearly four times faster than HPLC, allowing for greater throughput during a widespread release concerning large-scale contamination and subsequent remediation events. Percent recoveries from nonporous/impermeable surfaces were 60-103% for isopropyl methylphosphonate (IMPA), 61-91 % for ethyl methylphosphonate (EMPA), and 60-98% for pinacolyl methylphosphona

  2. Detoxification of organophosphate nerve agents by bacterial phosphotriesterase

    SciTech Connect

    Ghanem, Eman; Raushel, Frank M. . E-mail: raushel@tamu.edu

    2005-09-01

    Organophosphates have been widely used as insecticides and chemical warfare agents. The health risks associated with these agents have necessitated the need for better detoxification and bioremediation tools. Bacterial enzymes capable of hydrolyzing the lethal organophosphate nerve agents are of special interest. Phosphotriesterase (PTE) isolated from the soil bacteria Pseudomonas diminuta displays a significant rate enhancement and substrate promiscuity for the hydrolysis of organophosphate triesters. Directed evolution and rational redesign of the active site of PTE have led to the identification of new variants with enhanced catalytic efficiency and stereoselectivity toward the hydrolysis of organophosphate neurotoxins. PTE has been utilized to protect against organophosphate poisoning in vivo. Biotechnological applications of PTE for detection and decontamination of insecticides and chemical warfare agents are developing into useful tools. In this review, the catalytic properties and potential applications of this remarkable enzyme are discussed.

  3. Chemical approaches for detection and destruction of nerve agents.

    PubMed

    Ajami, Dariush; Rebek, Julius

    2013-06-28

    Since the introduction of organophosphorus (OP) compounds as nerve agents and pesticides, methods of dealing with their toxicity to humans have been intensely researched. There are studies on sensing, pretreatments, prophylactics, antidotes and therapies. There is some overlap in all of these endeavors because they have to deal with the reactivity of the phosphorus atom in various contexts. The contexts range from large spaces, the thinly spread vapors in the air, to very small spaces in the active sites of enzymes - acetylcholinesterase (AChE) or butyrylcholinesterase (BuChE) - that have reacted with the OP agent.

  4. Intercostal nerve blockade for evaluation of local anaesthetic agents.

    PubMed

    Bridenbaugh, P O

    1975-02-01

    Bilateral intercostal nerve block provides the opportunity to subject as many as 16 separate peripheral nerves in a single subject to known or unknown local anaesthetic agents in a variety of concentrations, volumes, and additives. It permits the observation of local (e.g., neuritis), clinical (e.g., onset and duration), and systemic (e.g., toxicity and blood concentration) effects of these variables. In double-blind studies, bilateral intercostal nerve block allows the use of each side of the trunk for comparison of two experimental drugs, a new drug against a standard, or two new drugs. Subtle differences in clinical properties as well as simultaneous blood concentrations may be detected in these studies. The advantages of this technique in evaluating local anaesthetic agents are primarily the use of a single subject as his own control while studying may separate peripheral nerves. This aids appreciably in limiting the variable of age, temperature, and perfusion, as well as techniques of administration and evaluation. The constancy of the anatomy of the intercostal nerve provides a highly reliable and reproducible block technique.

  5. Multidimensional conducting polymer nanotubes for ultrasensitive chemical nerve agent sensing.

    PubMed

    Kwon, Oh Seok; Park, Seon Joo; Lee, Jun Seop; Park, Eunyu; Kim, Taejoon; Park, Hyun-Woo; You, Sun Ah; Yoon, Hyeonseok; Jang, Jyongsik

    2012-06-13

    Tailoring the morphology of materials in the nanometer regime is vital to realizing enhanced device performance. Here, we demonstrate flexible nerve agent sensors, based on hydroxylated poly(3,4-ethylenedioxythiophene) (PEDOT) nanotubes (HPNTs) with surface substructures such as nanonodules (NNs) and nanorods (NRs). The surface substructures can be grown on a nanofiber surface by controlling critical synthetic conditions during vapor deposition polymerization (VDP) on the polymer nanotemplate, leading to the formation of multidimensional conducting polymer nanostructures. Hydroxyl groups are found to interact with the nerve agents. Representatively, the sensing response of dimethyl methylphosphonate (DMMP) as a simulant for sarin is highly sensitive and reversible from the aligned nanotubes. The minimum detection limit is as low as 10 ppt. Additionally, the sensor had excellent mechanical bendability and durability.

  6. Mass Spectrometry to Identify New Biomarkers of Nerve Agent Exposure

    DTIC Science & Technology

    2009-04-01

    Carrera, V., and Vilanova, E. (2004) Hydrolysis of carbaryl by human serum albumin. Arch. Toxicol. 78, 629–634. (15) Sogorb, M. A., Diaz-Alejo, N...the critical role of serum albumin in the detoxication of the carbamate carbaryl at in vivo toxicologically relevant concentrations. Arch. Toxicol. 81...pesticides (12), carbaryl (13), o-nitrotriflu- oroacetanilide (14), o-nitroacetanilide (15), and nerve agents (16). One site in albumin is rapidly acetylated

  7. Development of a Rapid Decontamination System for the Nerve Agents

    DTIC Science & Technology

    2006-09-15

    using Ag+ and Fe2O3 as dopants on sodalite , Y zeolite and MCM-41 supports were investigated in order to develop a...more efficient and safe catalyst for the photodecomposition of dangerous nerve agents. Ag- sodalite , Ag/Fe2O3- sodalite , Ag-Y zeolite, Ag-MCM-41 and Ag...at the Edgewood Chemical and Biological Center. While catalysts perform differently depending on the excitation wavelength used, the Ag- sodalite

  8. Using NMR Spectroscopy to Investigate the Solution Behavior of Nerve Agents and Their Binding to Acetylcholinesterase

    DTIC Science & Technology

    2016-01-01

    USING NMR SPECTROSCOPY TO INVESTIGATE THE SOLUTION BEHAVIOR OF NERVE AGENTS AND THEIR BINDING TO...Solution Behavior of Nerve Agents and Their Binding to Acetylcholinesterase 5a. CONTRACT NUMBER CB3889 5b. GRANT NUMBER 5c. PROGRAM ELEMENT...dynamics (MD) Nerve agent Nuclear magnetic relaxation Nuclear Overhauser effect (NOE) Solution behavior 16

  9. Being prepared: emergency treatment following a nerve agent release.

    PubMed

    Bailey, Abby M; Baker, Stephanie N; Baum, Regan A; Chandler, Hannah E; Weant, Kyle A

    2014-01-01

    Nerve agents are extremely toxic and are some of the most lethal substances on earth. This group of chemicals consists of sarin, cyclosarin, soman, tabun, VX, and VR. It is currently unknown how many countries possess these chemicals and in what quantities. These agents work through altering the transmission and breakdown of acetylcholine by binding to, and inactivating, acetylcholinesterase. This results in an uncontrolled and overwhelming stimulation of both muscarinic and nicotinic receptors. Receptor activation at these sites can lead to a wide variety of clinical symptoms, with death frequently resulting from pulmonary edema. Antidotal therapy in this setting largely consists of atropine, pralidoxime, and benzodiazepines, all of which must be administered emergently to limit the progression of symptoms and prevent the enzyme inactivation from becoming permanent. This article reviews the mechanism of action of the nerve agents and their effects on the human body, the currently available therapies to mitigate their impact, and important therapeutic considerations for health care practitioners in the emergency department.

  10. Predicting Infrared Spectra of Nerve Agents Using Density Functional Theory

    NASA Astrophysics Data System (ADS)

    Zhang, Y.-P.; Wang, H.-T.; Zheng, W.-P.; Sun, C.; Bai, Y.; Guo, X.-D.; Sun, H.

    2016-09-01

    Vibration frequencies of four nerve agents and two simulators are calculated using B3LYP coupled with ten basis sets. To evaluate the accuracy of calculated spectra, root mean square error (RMSE) and weighted cross-correlation average (WCCA) are considered. The evaluation shows that B3LYP/6-311+g(d,p) performs best in predicting infrared spectra, and polarization functions are found to be more important than diffusion functions in spectra simulation. Moreover, B3LYP calculation underestimates frequencies related to the P atom. The WCCA metric derives 1.008 as a unique scaling factor for calculated frequencies. The results indicate that the WCCA metric can identify six agents based on calculated spectra.

  11. Interaction of nerve agent antidotes with cholinergic systems.

    PubMed

    Soukup, O; Tobin, G; Kumar, U K; Binder, J; Proska, J; Jun, D; Fusek, J; Kuca, K

    2010-01-01

    The poisoning with organophosphorus compounds represents a life threatening danger especially in the time of terroristic menace. No universal antidote has been developed yet and other therapeutic approaches not related to reactivation of acetylcholinesterase are being investigated. This review describes the main features of the cholinergic system, cholinergic receptors, cholinesterases and their inhibitors. It also focuses on the organophosphorus nerve agents, their properties, effects and a large part describes various possibilities in treatments, mainly traditional oxime therapies based on reactivation of AChE. Furthermore, non-cholinesterase coupled antidotal effects of the oximes are thoroughly discussed. These antidotal effects principally include oxime interactions with muscarinic and nicotinic receptors.

  12. Microglia as Primary Mediators of Nerve Agent Neuropathy

    DTIC Science & Technology

    2010-01-01

    COX-2 expression in brain regions known to be damaged by nerve agents (e.g., hippocampus, amygdala, piriform cortex and thalamus). COX-2 expression was...hippocampal CA3 regions and especially the dentate gyrus (Fig. 1A and 1B) as well as in the amygdala (Fig. 1C) and piriform cortex (Fig. 1D). By 7 days COX... piriform cortex and amygdala also showed substantial increases in the number of COX-2 immunoreactive cells after soman (Fig 3). These cells were somewhat

  13. New Chemically Functionalized Nanomaterials for Electrical Nerve Agents Sensors

    NASA Astrophysics Data System (ADS)

    Simonato, Jean-Pierre; Clavaguera, Simon; Carella, Alexandre; Delalande, Michael; Raoul, Nicolas; Lenfant, Stephane; Vuillaume, Dominique; Dubois, Emmanuel

    2011-08-01

    A chemical receptor specific to traces of organophosphorus nerve agents (OPs) has been synthesized and grafted to carbon nanotubes and silicon nanowires in order to make electrical sensors. Our results show that it is possible to detect efficiently sub-ppm traces of OPs with excellent selectivity notably with the use of silicon nanowires by monitoring the Drain-Source current of the SiNW-FET at an optimum back Gate voltage as a function of time. First developments of a prototype have also been realized.

  14. Modifications to the organophosphorus nerve agent-protein adduct refluoridation method for retrospective analysis of nerve agent exposures.

    PubMed

    Holland, Kerry E; Solano, Maria I; Johnson, Rudolph C; Maggio, Vincent L; Barr, John R

    2008-01-01

    Organophosphorus nerve agents (OPNAs) continue to pose a threat to military personnel and the general public because of their toxicity and their potential use as weapons of mass destruction. An effective method for the detection of human exposure to OPNAs involves the refluoridation of nerve agents adducted to the serum protein butyrylcholinesterase. The regenerated agents are then enriched by solid-phase extraction and quantified by isotope-dilution gas chromatography-mass spectrometry. We have previously reported improvements that resulted in a 10-fold increase in sensitivity. We have now made further changes to the method that include the addition of confirmation ions, the addition of soman (GD) to the assay, the expansion of the linear range, and the elimination of high-volume injection to decrease background noise and run time while improving sensitivity. This report includes the standard operating procedures for this method for tabun, sarin, soman, cyclohexylsarin, and VX and validation studies. The method's limits of detection ranged from 5.5 to 16.5 pg/mL for the G analogue of VX and GD, respectively. Characterization of quality control (QC) materials resulted in an average coefficient of variation of 15.1% for the five analytes in low QC pools and 11.7% in high QC pools.

  15. Quantification of nerve agent biomarkers in human serum and urine.

    PubMed

    Røen, Bent Tore; Sellevåg, Stig Rune; Lundanes, Elsa

    2014-12-02

    A novel method for rapid and sensitive quantification of the nerve agent metabolites ethyl, isopropyl, isobutyl, cyclohexyl, and pinacolyl methylphosphonic acid has been established by combining salting-out assisted liquid-liquid extraction (SALLE) and online solid phase extraction-liquid chromatography-tandem mass spectrometry (SPE-LC-MS/MS). The procedure allows confirmation of nerve agent exposure within 30 min from receiving a sample, with very low detection limits for the biomarkers of 0.04-0.12 ng/mL. Sample preparation by SALLE was performed in less than 10 min, with a common procedure for both serum and urine. Analyte recoveries of 70-100% were obtained using tetrahydrofuran as extraction solvent and Na2SO4 to achieve phase separation. After SALLE, selective analyte retention was obtained on a ZrO2 column by Lewis acid-base and hydrophilic interactions with acetonitrile/1% CH3COOH (82/18) as the loading mobile phase. The phosphonic acids were backflush-desorbed onto a polymeric zwitterionic column at pH 9.8 and separated by hydrophilic interaction liquid chromatography. The method was linear (R(2) ≥ 0.995) from the limits of quantification to 50 ng/mL, and the within- and between-assay repeatability at 20 ng/mL were below 5% and 10% relative standard deviation, respectively.

  16. Non-cholinergic intervention of sarin nerve agent poisoning.

    PubMed

    Sawyer, Thomas W; Mikler, John; Tenn, Catherine; Bjarnason, Stephen; Frew, Robert

    2012-04-11

    The protective effects of selected anesthetic regimens on sarin (GB) were investigated in domestic swine. At 30% oxygen, the toxicity of this agent in isoflurane anesthetized animals (LD(50)=10.1μg/kg) was similar to literature sited values in awake swine (LD(50)=11.8μg/kg) and slightly higher than that of both ketamine (LD(50)=15.6μg/kg) and propofol (LD(50)=15.3μg/kg) anesthetized swine. Use of 100% oxygen in ketamine anesthetized animals resulted in three-fold protective effects compared to 30% oxygen. Use of 100% oxygen in both isoflurane and propofol anesthetized animals, compared to 30% resulted in profound protection against GB poisoning (>33×). There were no differences in the severity of the poisoning or recovery time in animals treated over dose ranges of 10-350μg/kg (isoflurane) or 15-500μg/kg GB (propofol). Survivors of high GB challenges that were revived from propofol anesthetic exhibited no signs of cognitive impairment seven days later. Protective treatments did not attenuate cholinesterase (ChE) inhibition; survivors of otherwise supralethal GB concentrations exhibited very low blood ChE activities. This work indicates that propofol has protective effects against GB, and that oxygen tension may have an important role in treating nerve agent casualties. More importantly, it demonstrates that non-cholinergic protective mechanisms exist that may be exploited in the future development of medical countermeasures against organophosphorous nerve agents.

  17. Direct detection of the hydrolysis of nerve agent model compounds using a fluorescent probe.

    PubMed

    Zheng, Xueying; Okolotowicz, Karl; Wang, Beilin; Macdonald, Mary; Cashman, John R; Zhang, Jun

    2010-09-06

    Nerve agents are highly toxic organophosphorus compounds (OPs) that are used as chemical warfare agents. Developing a catalytic bioscavenger to efficiently detoxify nerve agents in the bloodstream of affected individuals has been recognized as an attractive approach to prevent nerve agent toxicity. However, the search for nerve agent catalysts has been hindered by the lack of efficient direct assays for nerve agent hydrolysis. In addition, authentic nerve agents are restricted and access to use for experiments by the general research community is prohibited. Herein we report development of a method that combines use of novel nerve agent model compounds possessing a thiocholine leaving group that reacts with the fluorescent thio-detection probe, BES-Thio, to afford detection of sub-micromolar amounts of nerve agent model compounds hydrolysis products. The detection sensitivity of BES-Thio assay was approximately 10 times better than the Ellman assay. This developed method is useful as a direct, sensitive screening method for evaluating OP hydrolysis efficiency from catalytic cholinesterases. When the assay was assembled in the presence of oxime, OP-inhibited cholinesterases that were able to be reactivated by specific oxime showed oxime-assisted enzyme-mediated OP hydrolysis. Therefore, this method is also useful to screen oxime analogs to identify novel agents that can reactivate OP-inhibited cholinesterases or to screen various enzymes to identify pseudo-catalytic bioscavengers that can be readily reactivated by clinically approved oximes.

  18. Surface Analysis of Nerve Agent Degradation Products by ...

    EPA Pesticide Factsheets

    Report This sampling and analytical procedure was developed and applied by a single laboratory to investigate nerve agent degradation products, which may persist at a contaminated site, via surface wiping followed by analytical characterization. The performance data presented demonstrate the fitness-for-purpose regarding surface analysis in that single laboratory. Surfaces (laminate, glass, galvanized steel, vinyl tile, painted drywall and treated wood) were wiped with cotton gauze wipes, sonicated, extracted with distilled water, and filtered. Samples were analyzed with direct injection electrospray ionization liquid chromatography tandem mass spectrometry (ESI-LC/MS/MS) without derivatization. Detection limit data were generated for all analytes of interest on a laminate surface. Accuracy and precision data were generated from each surface fortified with these analytes.

  19. Portable Sensor for Chemical Nerve Agents and Organophosphorus Compounds

    DTIC Science & Technology

    2015-08-18

    as pesticides in crop, livestock, and poultry products and as chemical and biological warfare agents. As a result of the high toxicity and the...agents have been exploited for use as pesticides in crop, livestock, and poultry products and as chemical and biological warfare agents. As a result of

  20. Flexible carbon nanotube sensors for nerve agent simulants

    NASA Astrophysics Data System (ADS)

    Cattanach, Kyle; Kulkarni, Rashmi D.; Kozlov, Mikhail; Manohar, Sanjeev K.

    2006-08-01

    Chemiresistor-based vapour sensors made from network films of single-walled carbon nanotube (SWNT) bundles on flexible plastic substrates (polyethylene terephthalate, PET) can be used to detect chemical warfare agent simulants for the nerve agents Sarin (diisopropyl methylphosphonate, DIMP) and Soman (dimethyl methylphosphonate, DMMP). Large, reproducible resistance changes (75-150%), are observed upon exposure to DIMP or DMMP vapours, and concentrations as low as 25 ppm can be detected. Robust sensor response to simulant vapours is observed even in the presence of large equilibrium concentrations of interferent vapours commonly found in battle-space environments, such as hexane, xylene and water (10 000 ppm each), suggesting that both DIMP and DMMP vapours are capable of selectively displacing other vapours from the walls of the SWNTs. Response to these interferent vapours can be effectively filtered out by using a 2 µm thick barrier film of the chemoselective polymer polyisobutylene (PIB) on the SWNT surface. These network films are composed of a 1-2 µm thick non-woven mesh of SWNT bundles (15-30 nm diameter), whose sensor response is qualitatively and quantitatively different from previous studies on individual SWNTs, or a network of individual SWNTs, suggesting that vapour sorption at interbundle sites could be playing an important role. This study also shows that the line patterning method used in device fabrication to obtain any desired pattern of films of SWNTs on flexible substrates can be used to rapidly screen simulants at high concentrations before developing more complicated sensor systems.

  1. Biocatalytic nerve agent detoxification in fire fighting foams.

    PubMed

    LeJeune, K E; Russell, A J

    1999-03-20

    Current events across the globe necessitate rapid technological advances to combat the epidemic of nerve agent chemical weapons. Biocatalysis has emerged as a viable tool in the detoxification of organophosphorus neurotoxins, such as the chemical weapons VX and sarin. Efficient detoxification of contaminated equipment, machinery, and soils are of principal concern. This study describes the incorporation of a biocatalyst (organophosphorus hydrolase, E.C. 3.1.8.1) into conventional formulations of fire fighting foam. The capacity of fire fighting foams to decrease volatilization of contained contaminants, increase surface wettability, and control the rate of enzyme delivery to large areas makes them useful vehicles for enzyme application at surfaces. The performance of enzyme containing foams has been shown to be not only reproducible but also predictable. An empirical model provides reasonable estimations for the amounts of achievable surface decontamination as a function of the important parameters of the system. Theoretical modeling illustrates that the enzyme-containing foam is capable of extracting agent from the surface and is catalytically active at the foam-surface interface and throughout the foam itself. Biocatalytic foam has proven to be an effective, "environmentally friendly" means of surface and soil decontamination.

  2. [The nerve agent sarin: history, clinical manifestations, and treatment].

    PubMed

    Yanagisawa, Nobuo

    2014-05-01

    Organic phosphate pesticides were used worldwide after World War II and experiences on poisoning and treatment have been accumulated. An organic phosphate "nerve agent" Sarin was used in two terrorist attacks in Japan in the 1990s. Sarin effects on humans were well documented in these two incidents. Sarin gas inhalation caused instantaneous death by respiratory arrest in several victims in Matsumoto. Severely injured victims presenting with coma and generalized convulsion were resuscitated and recovered rapidly without sequelae. Miosis and blurred-dark vision, ocular pain, copious secretions from respiratory and gastrointestinal tract (muscarinic effects), and headache were common in severely to slightly affected victims. Plasma cholinesterase (ChE) activity decreased in parallel with the severity of signs and symptoms in victims. Oximes, atropine sulphate, diazepam, and ample intravenous infusion were effective treatments. Follow-up examinations on victims were conducted up to 10 years in Matsumoto, and 5 years in Tokyo. No neurological sequelae or abnormalities were observed after 1 year, except for a few EEG abnormalities or delay in sensory nerve conduction velocity. Posttraumatic stress disorder (PTSD) was observed in several of the victims in the 5-year follow up, irrespective of the severity of poisoning at Matsumoto. Psychological symptoms continue in victims of both incidents.

  3. Efficacy of Biperiden and Atropine as Anticonvulsant Treatment for Organophosphorus Nerve Agent Intoxication

    DTIC Science & Technology

    2000-01-01

    3. DATES COVERED (From - To) 4. TITLE AND SUBTITLE Efficacy of biperiden and atropine as anticonvulsant treatment For organophosphorus nerve agent...inhibitors, soman, sarin, tabun, GF, VX, anticonvulsants, atropine, biperiden , anticholinergic compounds, convulsions, EEG activity 16. SECURITY... biperiden and atropine as anticonvulsant treatment for organophosphorus nerve agent intoxication Received: 16 November 1999 /Accepted: 9 February

  4. Novel reversible and selective nerve agent simulant detection in conjunction with superoxide "turn-on" probing.

    PubMed

    Jang, Yoon Jeong; Murale, Dhiraj P; Churchill, David G

    2014-04-07

    Herein, we present fluorescein as a reversible fluorescent sensor for nerve agent simulants diethylchlorophosphate (DCP), diethyl methylphosphonate (DEMP), and diethyl cyanophosphonate (DECP). The superoxide allows for an "off-on" mechanism to regenerate fluorescein. The order of decrease in fluorescence intensity for nerve agent simulants is DCP > DEMP ≫ DECP.

  5. Identification of VX type nerve agents using cryodeposition GC-FTIR

    NASA Astrophysics Data System (ADS)

    Söderström, Martin T.

    1998-06-01

    Analysis of VX type nerve agents with a gas chromatography-Fourier transform infrared spectroscopy (GC-FTIR) system using cryodeposition of the eluents is described. An interpretation system based on comparison of characteristic spectral features to the features in reference spectra, is used to characterize side chains in VX type nerve agents.

  6. Structure-activity relationship for the reactivators of acetylcholinesterase inhibited by nerve agent VX.

    PubMed

    Kuca, Kamil; Musilek, Kamil; Jun, Daniel; Karasova, Jana; Soukup, Ondrej; Pejchal, Jaroslav; Hrabinova, Martina

    2013-08-01

    Nerve agents such as sarin, VX and tabun are organophosphorus compounds able to inhibit an enzyme acetylcholinesterase (AChE). AChE reactivators and anticholinergics are generally used as antidotes in the case of intoxication with these agents. None from the known AChE reactivators is able to reactivate AChE inhibited by all kinds of nerve agents. In this work, reactivation potency of seventeen structurally different AChE reactivators was tested in vitro and subsequently, relationship between their chemical structure and biological activity was outlined. VX was chosen as appropriate member of the nerve agent family.

  7. Evidence of VX nerve agent use from contaminated white mustard plants.

    PubMed

    Gravett, Matthew R; Hopkins, Farrha B; Self, Adam J; Webb, Andrew J; Timperley, Christopher M; Baker, Matthew J

    2014-08-08

    The Chemical Weapons Convention prohibits the development, production, acquisition, stockpiling, retention, transfer or use of chemical weapons by Member States. Verification of compliance and investigations into allegations of use require accurate detection of chemical warfare agents (CWAs) and their degradation products. Detection of CWAs such as organophosphorus nerve agents in the environment relies mainly upon the analysis of soil. We now present a method for the detection of the nerve agent VX and its hydrolysis products by gas chromatography and liquid chromatography mass spectrometry of ethanol extracts of contaminated white mustard plants (Sinapis alba) which retained the compounds of interest for up to 45 days. VX is hydrolysed by the plants to ethyl methylphosphonic acid and then to methylphosphonic acid. The utility of white mustard as a nerve agent detector and remediator of nerve agent-polluted sites is discussed. The work described will help deter the employment of VX in conflict.

  8. Evidence of VX nerve agent use from contaminated white mustard plants

    PubMed Central

    Gravett, Matthew R.; Hopkins, Farrha B.; Self, Adam J.; Webb, Andrew J.; Timperley, Christopher M.; Baker, Matthew J.

    2014-01-01

    The Chemical Weapons Convention prohibits the development, production, acquisition, stockpiling, retention, transfer or use of chemical weapons by Member States. Verification of compliance and investigations into allegations of use require accurate detection of chemical warfare agents (CWAs) and their degradation products. Detection of CWAs such as organophosphorus nerve agents in the environment relies mainly upon the analysis of soil. We now present a method for the detection of the nerve agent VX and its hydrolysis products by gas chromatography and liquid chromatography mass spectrometry of ethanol extracts of contaminated white mustard plants (Sinapis alba) which retained the compounds of interest for up to 45 days. VX is hydrolysed by the plants to ethyl methylphosphonic acid and then to methylphosphonic acid. The utility of white mustard as a nerve agent detector and remediator of nerve agent-polluted sites is discussed. The work described will help deter the employment of VX in conflict. PMID:25104906

  9. Theoretical proton affinity and fluoride affinity of nerve agent VX.

    PubMed

    Bera, Narayan C; Maeda, Satoshi; Morokuma, Keiji; Viggiano, Al A

    2010-12-23

    Proton affinity and fluoride affinity of nerve agent VX at all of its possible sites were calculated at the RI-MP2/cc-pVTZ//B3LYP/6-31G* and RI-MP2/aug-cc-pVTZ//B3LYP/6-31+G* levels, respectively. The protonation leads to various unique structures, with H(+) attached to oxygen, nitrogen, and sulfur atoms; among which the nitrogen site possesses the highest proton affinity of -ΔE ∼ 251 kcal/mol, suggesting that this is likely to be the major product. In addition some H(2), CH(4) dissociation as well as destruction channels have been found, among which the CH(4) + [Et-O-P(═O)(Me)-S-(CH(2))(2)-N(+)(iPr)═CHMe] product and the destruction product forming Et-O-P(═O)(Me)-SMe + CH(2)═N(+)(iPr)(2) are only 9 kcal/mol less stable than the most stable N-protonated product. For fluoridization, the S-P destruction channel to give Et-O-P(═O)(Me)(F) + [S-(CH(2))(2)-N-(iPr)(2)](-) is energetically the most favorable, with a fluoride affinity of -ΔE ∼ 44 kcal. Various F(-) ion-molecule complexes are also found, with the one having F(-) interacting with two hydrogen atoms in different alkyl groups to be only 9 kcal/mol higher than the above destruction product. These results suggest VX behaves quite differently from surrogate systems.

  10. Capillary gas chromatographic analysis of nerve agents using large volume injections.

    PubMed

    Degenhardt-Langelaan, C E; Kientz, C E

    1996-02-02

    The use of large volume injections has been studied for the verification of intact organophosphorus chemical warfare agents in water samples. As the use of ethyl acetate caused severe detection problems new potential solvents were evaluated. With the developed procedure, the nerve agents sarin, tabun, soman, DFP and VX can be determined in freshly prepared water samples at ppt levels. Except for the nerve agent tabun all other agents added to the water samples were still present after 8 days at 20-60% levels, if the pH of the water sample is adjusted to ca. 5 shortly after sampling and adjusted to pH 7 for analysis.

  11. REMOTE BIOSENSOR FOR IN SITU MONITORING OF ORGANOPHOSPHATE NERVE AGENTS. (R823663)

    EPA Science Inventory

    A remote electrochemical biosensor for field monitoring of organophosphate nerve agents is described. The new sensor relies on the coupling of the effective biocatalytic action of organophosphorus hydrolase (OPH) with a submersible amperometric probe design. This combination resu...

  12. Chromogenic and fluorogenic detection of a nerve agent simulant with a rhodamine-deoxylactam based sensor.

    PubMed

    Wu, Xuanjun; Wu, Zhisheng; Han, Shoufa

    2011-11-07

    A chromogenic and fluorogenic detection of a nerve agent simulant was developed based on diethyl chlorophosphate triggered tandem phosphorylation and intramolecular cyclization of N-(rhodamine B)-deoxylactam-2-aminoethanol.

  13. Phosphylated tyrosine in albumin as a biomarker of exposure to organophosphorus nerve agents.

    PubMed

    Williams, Nichola H; Harrison, John M; Read, Robert W; Black, Robin M

    2007-09-01

    The organophosphorus nerve agents sarin, soman, cyclosarin and tabun phosphylate a tyrosine residue on albumin in human blood. These adducts may offer relatively long-lived biological markers of nerve agent exposure that do not 'age' rapidly, and which are not degraded by therapy with oximes. Sensitive methods for the detection of these adducts have been developed using liquid chromatography-tandem mass spectrometry. Adducts of all four nerve agents were detected in the blood of exposed guinea pigs being used in studies to improve medical countermeasures. The tyrosine adducts with soman and tabun were detected in guinea pigs receiving therapy 7 days following subcutaneous administration of five times the LD(50) dose of the respective nerve agent. VX also forms a tyrosine adduct in human blood in vitro but only at high concentrations.

  14. The birth of nerve agent warfare: lessons from Syed Abbas Foroutan.

    PubMed

    Newmark, Jonathan

    2004-05-11

    The author reviewed Farsi-language articles published recently by Dr. Syed Abbas Foroutan, which constitute the only firsthand clinical descriptions of battlefield nerve agent casualties in the world literature, and the author compares his comments with US and North Atlantic Treaty Organization (NATO) chemical casualty care doctrine. Foroutan's lessons learned reassure us that a robust medical evacuation system, coupled with timely and appropriate medical care of nerve agent poisoning, will save many more lives on future battlefields.

  15. Nerve agent detection using networks of single-walled carbon nanotubes

    NASA Astrophysics Data System (ADS)

    Novak, J. P.; Snow, E. S.; Houser, E. J.; Park, D.; Stepnowski, J. L.; McGill, R. A.

    2003-11-01

    We report the use of carbon nanotubes as a sensor for chemical nerve agents. Thin-film transistors constructed from random networks of single-walled carbon nanotubes were used to detect dimethyl methylphosphonate (DMMP), a simulant for the nerve agent sarin. These sensors are reversible and capable of detecting DMMP at sub-ppb concentration levels, and they are intrinsically selective against interferent signals from hydrocarbon vapors and humidity. We provide additional chemical specificity by the use of filters coated with chemoselective polymer films. These results indicate that the electronic detection of sub-ppb concentrations of nerve agents and potentially other chemical warfare agents is possible with simple-to-fabricate carbon nanotube devices.

  16. Analysis of nerve agent metabolites from nail clippings by liquid chromatography tandem mass spectrometry.

    PubMed

    Appel, Amanda S; Logue, Brian A

    2016-09-15

    While several methods for the bioanalysis of nerve agents or their metabolites have been developed for the verification of nerve agent exposure, these methods are generally limited in the amount of time after an exposure that markers of exposure can be detected (due to rapid metabolism from biological matrices). In this study, a method for the analysis of nerve agent hydrolysis products from nail clippings was developed to allow evaluation of nails as a long-term repository of these markers. Pinacolyl methylphosphonic acid (PMPA) and isopropyl methylphosphonic acid (IMPA) were extracted from nail samples with N,N-dimethylformamide and subsequently analyzed by liquid chromatography-tandem mass spectrometry. Limits of detection for PMPA and IMPA were 0.3μg/kg and 7.5μg/kg and linear ranges were 0.75-300μg/kg and 30-1500μg/kg, respectively. Precision was within 10% and 8% for PMPA and IMPA, respectively, and accuracy was 100±12% for both analytes. The approach presented here is complementary to current methods for nerve agent exposure verification, and should allow for long-term determination of nerve agent poisoning.

  17. Nerve agent intoxication: Recent neuropathophysiological findings and subsequent impact on medical management prospects

    SciTech Connect

    Collombet, Jean-Marc

    2011-09-15

    This manuscript provides a survey of research findings catered to the development of effective countermeasures against nerve agent poisoning over the past decade. New neuropathophysiological distinctive features as regards organophosphate (OP) intoxication are presented. Such leading neuropathophysiological features include recent data on nerve agent-induced neuropathology, related peripheral or central nervous system inflammation and subsequent angiogenesis process. Hence, leading countermeasures against OP exposure are down-listed in terms of pre-treatment, protection or decontamination and emergency treatments. The final chapter focuses on the description of the self-repair attempt encountered in lesioned rodent brains, up to 3 months after soman poisoning. Indeed, an increased proliferation of neuronal progenitors was recently observed in injured brains of mice subjected to soman exposure. Subsequently, the latter experienced a neuronal regeneration in damaged brain regions such as the hippocampus and amygdala. The positive effect of a cytokine treatment on the neuronal regeneration and subsequent cognitive behavioral recovery are also discussed in this review. For the first time, brain cell therapy and neuronal regeneration are considered as a valuable contribution towards delayed treatment against OP intoxication. To date, efficient delayed treatment was lacking in the therapeutic resources administered to patients contaminated by nerve agents. - Highlights: > This review focuses on neuropathophysiology following nerve agent poisoning in mice. > Extensive data on long-term neuropathology and related inflammation are provided here. > Delayed self-repair attempts encountered in lesioned rodent brains are also described. > Cell therapy is considered as a valuable treatment against nerve agent intoxication.

  18. [The VR, the Russian version of the nerve agent VX].

    PubMed

    Cuquel, A-C; Dorandeu, F; Ceppa, F; Renard, C; Burnat, P

    2015-05-01

    A product of the arms race during the Cold War, the Russian VX, or VR, is an organophosphorus compound that is a structural isomer of the western VX compound (or A4), with which it shares a very high toxicity. It is much less studied and known than VX because the knowledge of its existence is relatively recent. A very low volatility and high resistance in the environment make it a persistent agent. Poisoning occurs mainly following penetration through skin and mucosa but vapour inhalation is a credible risk in some circumstances. The clinical presentation may be differed by several hours and despite the absence of signs and symptoms, the casualty should not be considered as contamination or intoxication-free. This agent has a long residence time in blood, a characteristics that clearly differentiates it from other compounds such as sarin. The protocols for antidote administration may thus have to be changed accordingly. The fact that VR poisoned individuals will less respond to the current oxime therapy used in France, the 2-PAM and that VR represents a higher threat than VX, being probably possessed by some proliferating states, justify the interest for this toxic product.

  19. Organophosphates/nerve agent poisoning: mechanism of action, diagnosis, prophylaxis, and treatment.

    PubMed

    Bajgar, Jirí

    2004-01-01

    OP/nerve agents are still considered as important chemicals acting on living organisms and are widely used. They are characterized according to their action as compounds influencing cholinergic nerve transmission via inhibition of AChE. Modeling of this action and extrapolation of experimental data from animals to humans is more possible for highly toxic agents than for the OP. The symptoms of intoxication comprise nicotinic, muscarinic, and central symptoms; for some OP/nerve agents, a delayed neurotoxicity is observed. Cholinesterases (AChE and BuChE) are characterized as the main enzymes involved in the toxic effect of these compounds, including molecular forms. The activity of both enzymes (and molecular forms) is influenced by inhibitors (reversible, irreversible, and allosteric) and other factors, such as pathological states. There are different methods for cholinesterase determination; however, the most frequent is the method based on the hydrolysis of thiocholine esters and subsequent detection of free SH-group of the released thiocholine. The diagnosis of OP/nerve agent poisoning is based on anamnesis, the clinical status of the intoxicated organism, and on cholinesterase determination in the blood. For nerve agent intoxication, AChE in the red blood cell is more diagnostically important than BuChE activity in the plasma. This enzyme is a good diagnostic marker for intoxication with OP pesticides. Some other biochemical examinations are recommended, especially arterial blood gas, blood pH, minerals, and some other specialized parameters usually not available in all clinical laboratories. These special examinations are important for prognosis of the intoxication, for effective treatment, and for retrospective analysis of the agent used for exposure. Some principles of prophylaxis against OP/nerve agent poisoning comprising the administration of reversible cholinesterase inhibitors such as pyridostigmine (alone or in combination with other drugs), scavengers

  20. Acetylcholinesterase-based organophosphate nerve agent sensing photonic crystal.

    PubMed

    Walker, Jeremy P; Asher, Sanford A

    2005-03-15

    We developed a polymerized crystalline colloidal array (PCCA) photonic crystal sensing material that senses the organophosphorus compound parathion at ultratrace concentrations in aqueous solutions. A periodic array of colloidal particles is embedded in a hydrogel network with a lattice spacing such that it Bragg diffracts visible light. The molecular recognition agent for the sensor is the enzyme acetylcholinesterase (AChE), which binds organophosphorus compounds irreversibly, creating an anionic phosphonyl species. This charged species creates a Donnan potential, which swells the hydrogel network, which increases the embedded particle array lattice spacing and causes a red-shift in the wavelength of light diffracted. The magnitude of the diffraction red-shift is proportional to the amount of bound parathion. These AChE-PCCAs act as dosimeters for parathion since it irreversibly binds. Parathion concentrations as low as 4.26 fM are easily detected.

  1. Fiber-optic-based surface plasmon resonance (SPR) sensors for the detection of toxic nerve agents

    NASA Astrophysics Data System (ADS)

    Prakash, Anna M. C.; Kim, Yoon-Chang; Banerji, Soame; Masson, Jean-Francois; Booksh, Karl S.

    2004-03-01

    Analytical instruments capable of detecting nerve agents in battlefield conditions where speed, accuracy and ease of operation are a must in today's military. Fast detection and decontamination of nerve agents in very low concentrations is the primary focus of our research. The method presented here focuses on optimizing polymer stabilized sensing elements on the surface of SPR fiber-optic probes. A number of polymers & polymer supported metal complexes capable of reversibly binding to the species of interest & which have robust operation in hostile environments are incorporated with the fiber optic sensing elements. An optical technique, such as Surface Plasmon Resonance (SPR), better suited to rapid data collection without sample pretreatment is employed. The approach using polymer-based optical fibers with off-the-shelf SPR system components has been tested for the detection of Pinacolyl methylphosphonate (PMP), a simulant for nerve agent Soman. Surface initiated polymeric sensors have higher sensitivity toward detecting PMP than bulk-polymerized sensors.

  2. Recent advances in evaluation of oxime efficacy in nerve agent poisoning by in vitro analysis

    SciTech Connect

    Worek, F. . E-mail: FranzWorek@Bundeswehr.org; Eyer, P.; Aurbek, N.; Szinicz, L.; Thiermann, H.

    2007-03-15

    The availability of highly toxic organophosphorus (OP) warfare agents (nerve agents) underlines the necessity for an effective medical treatment. Acute OP toxicity is primarily caused by inhibition of acetylcholinesterase (AChE). Reactivators (oximes) of inhibited AChE are a mainstay of treatment, however, the commercially available compounds, obidoxime and pralidoxime, are considered to be rather ineffective against various nerve agents, e.g. soman and cyclosarin. This led to the synthesis and investigation of numerous oximes in the past decades. Reactivation of OP-inhibited AChE is considered to be the most important reaction of oximes. Clinical data from studies with pesticide-poisoned patients support the assumption that the various reactions between AChE, OP and oxime, i.e. inhibition, reactivation and aging, can be investigated in vitro with human AChE. In contrast to animal experiments such in vitro studies with human tissue enable the evaluation of oxime efficacy without being affected by species differences. In the past few years numerous in vitro studies were performed by different groups with a large number of oximes and methods were developed for extrapolating in vitro data to different scenarios of human nerve agent poisoning. The present status in the evaluation of new oximes as antidotes against nerve agent poisoning will be discussed.

  3. Evaluation of oxime efficacy in nerve agent poisoning: Development of a kinetic-based dynamic model

    SciTech Connect

    Worek, Franz . E-mail: FranzWorek@Bundeswehr.org; Szinicz, Ladislaus; Eyer, Peter; Thiermann, Horst

    2005-12-15

    The widespread use of organophosphorus compounds (OP) as pesticides and the repeated misuse of highly toxic OP as chemical warfare agents (nerve agents) emphasize the necessity for the development of effective medical countermeasures. Standard treatment with atropine and the established acetylcholinesterase (AChE) reactivators, obidoxime and pralidoxime, is considered to be ineffective with certain nerve agents due to low oxime effectiveness. From obvious ethical reasons only animal experiments can be used to evaluate new oximes as nerve agent antidotes. However, the extrapolation of data from animal to humans is hampered by marked species differences. Since reactivation of OP-inhibited AChE is considered to be the main mechanism of action of oximes, human erythrocyte AChE can be exploited to test the efficacy of new oximes. By combining enzyme kinetics (inhibition, reactivation, aging) with OP toxicokinetics and oxime pharmacokinetics a dynamic in vitro model was developed which allows the calculation of AChE activities at different scenarios. This model was validated with data from pesticide-poisoned patients and simulations were performed for intravenous and percutaneous nerve agent exposure and intramuscular oxime treatment using published data. The model presented may serve as a tool for defining effective oxime concentrations and for optimizing oxime treatment. In addition, this model can be useful for the development of meaningful therapeutic animal models.

  4. V-type nerve agent detection using a carbon nanotube-based amperometric enzyme electrode.

    PubMed

    Joshi, Kanchan A; Prouza, Marek; Kum, Maxwell; Wang, Joseph; Tang, Jason; Haddon, Robert; Chen, Wilfred; Mulchandani, Ashok

    2006-01-01

    An enzyme electrode for the detection of V-type nerve agents, VX (O-ethyl-S-2-diisopropylaminoethyl methylphosphonothioate) and R-VX (O-isobutyl-S-2-diethylaminoethyl methylphosphonothioate), is proposed. The principle of the new biosensor is based on the enzyme-catalyzed hydrolysis of the nerve agents and amperometric detection of the thiol-containing hydrolysis products at carbon nanotube-modified screen-printed electrodes. Demeton-S was used as a nerve agent mimic. 2-(Diethylamino)ethanethiol (DEAET) and 2-(dimethylamino)ethanethiol (DMAET), the thiol-containing hydrolysis product and hydrolysis product mimic of R-VX and VX, respectively, were monitored by exploiting the electrocatalytic activity of carbon nanotubes (CNT). As low as 2 microM DMAET and 0.8 microM DEAET were detected selectively at a low applied potential of 0.5 V vs Ag/AgCl at a CNT-modified mediator-free amperometric electrode. Further, the large surface area and the hydrophobicity of CNT was used to immobilize organophosphorus hydrolase mutant with improved catalytic activity for the hydrolysis of the P-S bond of phosphothiolester neurotoxins including VX and R-VX nerve gases to develop a novel, mediator-free, membrane-free biosensor for V-type nerve agents. The applicability of the biosensor was demonstrated for direct, rapid, and selective detection of V-type nerve agents' mimic demeton-S. The selectivity of the sensor against interferences and application to spiked lake water samples was demonstrated.

  5. Estimation of oxime efficacy in nerve agent poisoning: a kinetic approach.

    PubMed

    Worek, Franz; Szinicz, Ladislaus; Thiermann, Horst

    2005-12-15

    Standard treatment of poisoning by organophosphorus compounds (OP) includes the administration of an anti-muscarinic, e.g. atropine, and of an acetylcholinesterase (AChE) reactivator (oxime). Two oximes, obidoxime and pralidoxime (2-PAM), are presently commercially available, yet, these compounds are considered to be of insufficient efficacy against certain nerve agents, e.g. soman and cyclosarin. In the past decades, numerous new oximes were synthesized and tested for their antidotal efficacy. The available data indicate that two Hagedorn oximes, HI 6 and HLö 7, are promising antidotes against various nerve agents. The efficacy of antidotes against nerve agent poisoning cannot be investigated in humans for ethical reasons. Therefore, it is necessary to use surrogate parameters for the evaluation of oxime efficacy. Reactivation of inhibited AChE is considered to be the main mechanism of action of oximes. Clinical data indicate that changes in erythrocyte AChE activity correlate to neuromuscular function indicating that interactions between AChE, inhibitor and oximes can be investigated in vitro with human erythrocyte AChE. Different theoretical models were used for the evaluation of reactivating efficacy of oximes with nerve agent-inhibited human AChE and for estimating effective oxime concentrations. The calculations demonstrate the marked differences between oximes in dependence of the inhibitor and provide a basis for the estimation of the required oxime dose as well as of dosing intervals.

  6. BIOSENSOR FOR DIRECT DETERMINATION OF ORGANOPHOSPHATE NERVE AGENTS. 1. POTENTIOMETRIC ENZYME ELECTRODE. (R823663)

    EPA Science Inventory

    A potentiometric enzyme electrode for the direct measurement of organophosphate (OP)
    nerve agents was developed. The basic element of this enzyme electrode was a pH electrode
    modified with an immobilized organophosphorus hydrolase (OPH) layer formed by cross-linking
    OPH ...

  7. Evaluating of the Anticonvulsant Gabapentin against Nerve Agent-Induced Seizures in a Guinea Pig Model

    DTIC Science & Technology

    2010-07-01

    Neuropharmacological mechanisms of nerve agent-induced seizures and neuropathology. Neuroscience and Biobehavioral Reviews , 1997, 21:559-579...compound soman: pharmacological mechanisms. Neuroscience and Biobehavioral Reviews , 1991, 15:349-362. Shih, T.-M., McDonough, J.H., Koplovitz, I

  8. Control of Nerve Agent-Induced Seizures is Critical for Neuroprotection and Survival

    DTIC Science & Technology

    2002-01-01

    have recently completed a study on the effectiveness of several anticholinergic (atropine sulfate, biperiden HCl, or trihexyphenidyl HCl) and...anticholinergic drug atropine sulfate, biperiden HCl, trihexyphenidyl HCl, or the benzodiazepine drug diazepam or midazolam were given...Behav 64: 147-153. Shih T-M, McDonough JH (2000) Efficacy of biperiden and atropine as anticonvulsant treatment for organophosphorus nerve agent

  9. Polynorbornene derived 8-hydroxyquinoline paper strips for ultrasensitive chemical nerve agent surrogate sensing.

    PubMed

    Sarkar, Santu; Shunmugam, Raja

    2014-08-11

    The detection of nerve agent simulants is achieved by the photoinduced electron transfer (PET) mechanism. A "turn-on" fluorescence response upon phosphorylation at 8-hydroxyquinoline of norbornene-based triazolyl functionalized 8-hydroxyquinoline () followed by intramolecular rearrangement provides very intense green emission. The detection limit of polymer () coated paper strips is 25 ppb with instantaneous response.

  10. Fluorogenic and chromogenic probe for rapid detection of a nerve agent simulant DCP.

    PubMed

    Wu, Wei-hui; Dong, Jun-jun; Wang, Xin; Li, Jian; Sui, Shao-hui; Chen, Gao-yun; Liu, Ji-wei; Zhang, Ming

    2012-07-21

    A fluorogenic and visual probe was devised to detect diethyl chlorophosphate (DCP), a nerve agent simulant. The probe, N-(rhodamine B)-lactam-2-aminoethanol (RB-AE), undergoes oxazoline formation following phosphorylation in the presence of DCP, which gives rapid and clear fluorescence and color change in the assay solutions.

  11. Metal organic frameworks (MOFs) for degradation of nerve agent simulant parathion

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Parathion, a simulant of nerve agent VX, has been studied for degradation on Fe3+, Fe2+ and zerovalent iron supported on chitosan. Chitosan, a naturally occurring biopolymer derivative of chitin, is a very good adsorbent for many chemicals including metals. Chitosan is used as supporting biopolymer ...

  12. FIBER-OPTIC BIOSENSOR FOR DIRECT DETERMINATION OF ORGANOPHOSPHATE NERVE AGENTS. (R823663)

    EPA Science Inventory

    A fiber-optic enzyme biosensor for the direct measurement of organophosphate nerve
    agents
    was developed. The basic element of this biosensor is organophosphorus hydrolase
    immobilized on a nylon membrane and attached to the common end of a bifurcated optical fiber
    bundle....

  13. Metal organic frameworks (MOFs) for degrdation of nerve agent simulant parathion

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Parathion, a simulant of nerve agent VX, has been studied for degradation on Fe3+, Fe2+ and zerovalent iron supported on chitosan. Chitosan, a naturally occurring biopolymer derivative of chitin, is a very good adsorbent for many chemicals including metals. Chitosan is used as supporting biopolymer ...

  14. Engineering of Paraoxonases for Pre- and Post-treatment of Intoxication by a Broad Spectrum of Nerve Agents and Pesticides

    DTIC Science & Technology

    2013-05-01

    and emerging organophosphate -based chemical warfare nerve agents (CWNA). In the first year of the renewal contract we focused on: (a) Design and...weeks. 15. SUBJECT TERMS Directed evolution, X-ray crystallography, organophosphates & bioscavengers 16. SECURITY CLASSIFICATION OF: Unclassified...emerging organophosphate -based chemical warfare nerve agents (CWNA). Enzymes identified in these screens should be capable of catalytically neutralizing

  15. Evaluation of Multiple Blood Matrices for Assessment of Human Exposure to Nerve Agents.

    PubMed

    Schulze, Nicholas D; Hamelin, Elizabeth I; Winkeljohn, W Rucks; Shaner, Rebecca L; Basden, Brian J; deCastro, B Rey; Pantazides, Brooke G; Thomas, Jerry D; Johnson, Rudolph C

    2016-04-01

    Biomedical samples may be used to determine human exposure to nerve agents through the analysis of specific biomarkers. Samples received may include serum, plasma, whole blood, lysed blood and, due to the toxicity of these compounds, postmortem blood. To quantitate metabolites resulting from exposure to sarin (GB), soman (GD), cyclosarin (GF), VX and VR, these blood matrices were evaluated individually for precision, accuracy, sensitivity and specificity. Accuracies for these metabolites ranged from 100 to 113% with coefficients of variation ranging from 2.31 to 13.5% across a reportable range of 1-100 ng/mL meeting FDA recommended guidelines for bioanalytical methods in all five matrices. Limits of detection were calculated to be 0.09-0.043 ng/mL, and no interferences were detected in unexposed matrix samples. The use of serum calibrators was also determined to be a suitable alternative to matrix-matched calibrators. Finally, to provide a comparative value between whole blood and plasma, the ratio of the five nerve agent metabolites measured in whole blood versus plasma was determined. Analysis of individual whole blood samples (n = 40), fortified with nerve agent metabolites across the reportable range, resulted in average nerve agent metabolite blood to plasma ratios ranging from 0.53 to 0.56. This study demonstrates the accurate and precise quantitation of nerve agent metabolites in serum, plasma, whole blood, lysed blood and postmortem blood. It also provides a comparative value between whole blood and plasma samples, which can assist epidemiologists and physicians with interpretation of test results from blood specimens obtained under variable conditions.

  16. Evaluation of Multiple Blood Matrices for Assessment of Human Exposure to Nerve Agents

    PubMed Central

    Schulze, Nicholas D.; Hamelin, Elizabeth I.; Winkeljohn, W. Rucks; Shaner, Rebecca L.; Basden, Brian J.; deCastro, B. Rey; Pantazides, Brooke G.; Thomas, Jerry D.; Johnson, Rudolph C.

    2016-01-01

    Biomedical samples may be used to determine human exposure to nerve agents through the analysis of specific biomarkers. Samples received may include serum, plasma, whole blood, lysed blood and, due to the toxicity of these compounds, postmortem blood. To quantitate metabolites resulting from exposure to sarin (GB), soman (GD), cyclosarin (GF), VX and VR, these blood matrices were evaluated individually for precision, accuracy, sensitivity and specificity. Accuracies for these metabolites ranged from 100 to 113% with coefficients of variation ranging from 2.31 to 13.5% across a reportable range of 1–100 ng/mL meeting FDA recommended guidelines for bioanalytical methods in all five matrices. Limits of detection were calculated to be 0.09–0.043 ng/mL, and no interferences were detected in unexposed matrix samples. The use of serum calibrators was also determined to be a suitable alternative to matrix-matched calibrators. Finally, to provide a comparative value between whole blood and plasma, the ratio of the five nerve agent metabolites measured in whole blood versus plasma was determined. Analysis of individual whole blood samples (n = 40), fortified with nerve agent metabolites across the reportable range, resulted in average nerve agent metabolite blood to plasma ratios ranging from 0.53 to 0.56. This study demonstrates the accurate and precise quantitation of nerve agent metabolites in serum, plasma, whole blood, lysed blood and postmortem blood. It also provides a comparative value between whole blood and plasma samples, which can assist epidemiologists and physicians with interpretation of test results from blood specimens obtained under variable conditions. PMID:26861671

  17. Analogues with fluorescent leaving groups for screening and selection of enzymes that efficiently hydrolyze organophosphorus nerve agents.

    PubMed

    Briseño-Roa, Luis; Hill, Jim; Notman, Stuart; Sellers, David; Smith, Andy P; Timperley, Christopher M; Wetherell, Janet; Williams, Nichola H; Williams, Gareth R; Fersht, Alan R; Griffiths, Andrew D

    2006-01-12

    Enzymes that efficiently hydrolyze highly toxic organophosphorus nerve agents could potentially be used as medical countermeasures. As sufficiently active enzymes are currently unknown, we synthesized twelve fluorogenic analogues of organophosphorus nerve agents with the 3-chloro-7-oxy-4-methylcoumarin leaving group as probes for high-throughput enzyme screening. This set included analogues of the pesticides paraoxon, parathion, and dimefox, and the nerve agents DFP, tabun, sarin, cyclosarin, soman, VX, and Russian-VX. Data from inhibition of acetylcholinesterase, in vivo toxicity tests of a representative analogue (cyclosarin), and kinetic studies with phosphotriesterase (PTE) from Pseudomonas diminuta, and a mammalian serum paraoxonase (PON1), confirmed that the analogues mimic the parent nerve agents effectively. They are suitable tools for high-throughput screens for the directed evolution of efficient nerve agent organophosphatases.

  18. Microfluidic chip with optical sensor for rapid detection of nerve agent Sarin in water samples

    NASA Astrophysics Data System (ADS)

    Tan, Hsih Yin; Nguyen, Nam-Trung; Loke, Weng Keong; Tan, Yong Teng

    2007-12-01

    The chemical warfare agent Sarin is an organophosphate that is highly toxic to humans as they can act as cholinesterase inhibitors, that disrupts neuromuscular transmission. As these nerve agents are colorless, odorless and highly toxic, they can be introduced into drinking water as a means of terrorist sabotage. Hence, numerous innovative devices and methods have been developed for rapid detection of these organophosphates. Microfluidic technology allows the implementation of fast and sensitive detection of Sarin. In this paper, a micro-total analysis systems (TAS), also known as Lab-on-a-chip, fitted with an optical detection system has been developed to analyze the presence of the nerve agent sarin in water samples. In the present set-up, inhibition of co-introduced cholinesterase and water samples containing trace amounts of nerve agent sarin into the microfluidic device was used as the basis for selective detection of sarin. The device was fabricated using polymeric micromachining with PMMA (poly (methymethacrylate)) as the substrate material. A chromophore was utilized to measure the activity of remnant cholinesterase activity, which is inversely related to the amount of sarin present in the water samples. Comparisons were made between two different optical detection techniques and the findings will be presented in this paper. The presented measurement method is simple, fast and as sensitive as Gas Chromatography.

  19. Activity-Based Protein Profiling Reveals Broad Reactivity of the Nerve Agent Sarin.

    PubMed

    Tuin, Adriaan W; Mol, Marijke A E; van den Berg, Roland M; Fidder, A; van der Marel, Gijs A; Overkleeft, Herman S; Noort, Daan

    2009-04-01

    Elucidation of noncholinesterase protein targets of organophosphates, and nerve agents in particular, may reveal additional mechanisms for their high toxicity as well as clues for novel therapeutic approaches toward intoxications with these agents. Within this framework, we here describe the synthesis of the activity-based probe 3, which contains a phosphonofluoridate moiety, a P-Me moiety, and a biotinylated O-alkyl group, and its use in activity-based protein profiling with two relevant biological samples, that is, rhesus monkey liver and cultured human A549 lung cells. In this way, we have unearthed eight serine hydrolases (fatty acid synthase, acylpeptide hydrolase, dipeptidyl peptidase 9, prolyl oligopeptidase, carboxylesterase, long-chain acyl coenzyme A thioesterase, PAF acetylhydrolase 1b, and esterase D/S-formyl glutathione hydrolase) as targets that are modified by the nerve agent sarin. It is also shown that the newly developed probe 3 might find its way into the development of alternative, less laborious purification protocols for human butyrylcholinesterase, a potent bioscavenger currently under clinical investigation as a prophylactic/therapeutic for nerve agent intoxications.

  20. Improvements of the fluoride reactivation method for the verification of nerve agent exposure.

    PubMed

    Degenhardt, Carla E A M; Pleijsier, Kees; van der Schans, Marcel J; Langenberg, Jan P; Preston, Kerry E; Solano, Maria I; Maggio, V L; Barr, John R

    2004-01-01

    One of the most appropriate biomarkers for the verification of organophosphorus nerve agent exposure is the conjugate of the nerve agent to butyrylcholinesterase (BuChE). The phosphyl moiety of the nerve agent can be released from the BuChE enzyme by incubation with fluoride ions, after which the resulting organophosphonofluoridate can be analyzed with gas chromatography-mass spectrometry (GC-MS). This paper describes recent improvements of the fluoride-induced reactivation in human plasma or serum samples by enhancing the sample preparation with new solid-phase extraction cartridges and the MS analysis with large volume injections. Analysis is performed with thermal desorption GC with either mass selective detection with ammonia chemical ionization or high-resolution MS with electron impact ionization. The organophosphorus chemical warfare agents analyzed in this study are O-ethyl S-2-diisopropylaminoethyl methylphosphonothiolate, ethyl methylphosphonofluoridate, isopropyl methylphosphonofluoridate (sarin, GB), O-ethyl N,N-dimethylphosphoramidocyanidate, ethyl N,N-dimethylphosphoramidofluoridate, and cyclohexyl methylphosphonfluoridate. Detection limits of approximately 10 pg/mL plasma were achieved for all analytes, which corresponds to 0.09% inhibition with GB on a sample with normal BuChE levels.

  1. Nerve agent analogues that produce authentic soman, sarin, tabun, and cyclohexyl methylphosphonate-modified human butyrylcholinesterase.

    PubMed

    Gilley, Cynthia; MacDonald, Mary; Nachon, Florian; Schopfer, Lawrence M; Zhang, Jun; Cashman, John R; Lockridge, Oksana

    2009-10-01

    The goal was to test 14 nerve agent model compounds of soman, sarin, tabun, and cyclohexyl methylphosphonofluoridate (GF) for their suitability as substitutes for true nerve agents. We wanted to know whether the model compounds would form the identical covalent adduct with human butyrylcholinesterase that is produced by reaction with true nerve agents. Nerve agent model compounds containing thiocholine or thiomethyl in place of fluorine or cyanide were synthesized as Sp and Rp stereoisomers. Purified human butyrylcholinesterase was treated with a 45-fold molar excess of nerve agent analogue at pH 7.4 for 17 h at 21 degrees C. The protein was denatured by boiling and was digested with trypsin. Aged and nonaged active site peptide adducts were quantified by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry of the tryptic digest mixture. The active site peptides were isolated by HPLC and analyzed by MALDI-TOF-TOF mass spectrometry. Serine 198 of butyrylcholinesterase was covalently modified by all 14 compounds. Thiocholine was the leaving group in all compounds that had thiocholine in place of fluorine or cyanide. Thiomethyl was the leaving group in the GF thiomethyl compounds. However, sarin thiomethyl compounds released either thiomethyl or isopropyl, while soman thiomethyl compounds released either thiomethyl or pinacolyl. Thiocholine compounds reacted more rapidly with butyrylcholinesterase than thiomethyl compounds. Labeling with the model compounds resulted in aged adducts that had lost the O-alkyl group (O-ethyl for tabun, O-cyclohexyl for GF, isopropyl for sarin, and pinacolyl for soman) in addition to the thiocholine or thiomethyl group. The nerve agent model compounds containing thiocholine and the GF thiomethyl analogue were found to be suitable substitutes for true soman, sarin, tabun, and GF in terms of the adduct that they produced with human butyrylcholinesterase. However, the soman and sarin thiomethyl compounds

  2. General guidelines for medically screening mixed population groups potentially exposed to nerve or vesicant agents

    SciTech Connect

    Watson, A.P.; Munro, N.B. ); Sidell, F.R. ); Leffingwell, S.S. . Center for Environmental Health and Injury Control)

    1992-01-01

    A number of state and local planners have requested guidance on screening protocols and have expressed interest in sampling body fluids from exposed or potentially exposed individuals as a means of estimating agent dose. These guidelines have been developed to provide a clear statement that could be used by state and local emergency response personnel in the event of a nerve or vesicant agent incident resulting in off-post contamination; maximum protection from harm is the goal. The assumption is that any population group so exposed would be heterogeneous for age, gender, reproductive status, and state of health.

  3. A structure-activity analysis of the variation in oxime efficacy against nerve agents

    SciTech Connect

    Maxwell, Donald M. Koplovitz, Irwin; Worek, Franz; Sweeney, Richard E.

    2008-09-01

    A structure-activity analysis was used to evaluate the variation in oxime efficacy of 2-PAM, obidoxime, HI-6 and ICD585 against nerve agents. In vivo oxime protection and in vitro oxime reactivation were used as indicators of oxime efficacy against VX, sarin, VR and cyclosarin. Analysis of in vivo oxime protection was conducted with oxime protective ratios (PR) from guinea pigs receiving oxime and atropine therapy after sc administration of nerve agent. Analysis of in vitro reactivation was conducted with second-order rate contants (k{sub r2}) for oxime reactivation of agent-inhibited acetylcholinesterase (AChE) from guinea pig erythrocytes. In vivo oxime PR and in vitro k{sub r2} decreased as the volume of the alkylmethylphosphonate moiety of nerve agents increased from VX to cyclosarin. This effect was greater with 2-PAM and obidoxime (> 14-fold decrease in PR) than with HI-6 and ICD585 (< 3.7-fold decrease in PR). The decrease in oxime PR and k{sub r2} as the volume of the agent moiety conjugated to AChE increased was consistent with a steric hindrance mechanism. Linear regression of log (PR-1) against log (k{sub r2} {center_dot} [oxime dose]) produced two offset parallel regression lines that delineated a significant difference between the coupling of oxime reactivation and oxime protection for HI-6 and ICD585 compared to 2-PAM and obidoxime. HI-6 and ICD585 appeared to be 6.8-fold more effective than 2-PAM and obidoxime at coupling oxime reactivation to oxime protection, which suggested that the isonicotinamide group that is common to both of these oximes, but absent from 2-PAM and obidoxime, is important for oxime efficacy.

  4. Chromogenic and fluorogenic detection and discrimination of nerve agents Tabun and Vx.

    PubMed

    Kumar, Vinod; Rana, Hemlata

    2015-11-28

    Our approach uses squaraine (SQ) as the molecular-receptor as well as an indicator for the chromogenic and fluorogenic detection and discrimination of nerve agents Tabun and Vx. To mimic a real-life scenario, the protocols were implemented in spiked water and soil samples, on surfaces, and in the gas phase. The lower detection limit will be useful to protect human health and national security.

  5. Development of a Broad-Spectrum Oxime for the Treatment of Nerve Agent Toxicity

    DTIC Science & Technology

    2006-11-01

    A. Saxena Division of Biochemistry, Walter Reed Army Institute of Research, Silver Spring, MD 20910 K. Brecht , and D. M. Maxwell US Army Medical...wild-type and mutant AChEs revealed that the peripheral anionic site of AChE plays a critical role in the reactivation of nerve agent-inhibited AChE...reporting burden for the collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching

  6. Selective Real-time Detection of Gaseous Nerve Agent Simulants Using Multiwavelength Photoacoustics

    DTIC Science & Technology

    2012-08-15

    Selective real-time detection of gaseous nerve agent simulants using multiwavelength photoacoustics Kristan P. Gurton,* Melvin Felton, and Richard...concentrations. The technique is based on a modified version of conventional laser photoacoustic (PA) spectroscopy, in which optical absorption is typically...spec- troscopic approach [1–4]. One of the more direct methods to implement in prac- tice (without sacrificing sensitivity) is laser photoacoustic

  7. Highly selective detection of nerve-agent simulants with BODIPY dyes.

    PubMed

    Barba-Bon, Andrea; Costero, Ana M; Gil, Salvador; Harriman, Anthony; Sancenón, Félix

    2014-05-19

    Two chromo-fluorogenic probes, each based on the boron dipyrromethene core, have been developed for the detection of nerve-agent mimics. These chemosensors display both a color change and a significant enhancement of fluorescence in the presence of diethylcyanophosphonate (DCNP) and diisopropylfluorophosphate (DFP). No interference from other organophosphorus compounds or acids has been observed. Two portable chemosensor kits have been developed and tested to demonstrate its practical application in real-time monitoring.

  8. A rhodamine-deoxylactam based sensor for chromo-fluorogenic detection of nerve agent simulant.

    PubMed

    Wu, Zhisheng; Wu, Xuanjun; Yang, Yuhui; Wen, Ting-bin; Han, Shoufa

    2012-10-15

    N-(rhodamine B)-deoxylactam-5-amino-1-pentanol (dRB-APOH) was designed and prepared as the chromo-fluorogenic sensor for detection of a nerve agent simulant via analyte triggered tandem phosphorylation and opening of the intramolecular deoxylactam. The successful detection of diethyl chlorophosphate suggests the utility of rhodamine-deoxylactams as the chromo-fluorogenic signal reporting platform for design of sensors targeting reactive chemical species via various chemistries.

  9. A near infrared colorimetric and fluorometric probe for organophosphorus nerve agent mimics by intramolecular amidation.

    PubMed

    Hu, Xiao-Xiao; Su, Yue-Ting; Ma, Yun-Wei; Zhan, Xin-Qi; Zheng, Hong; Jiang, Yun-Bao

    2015-10-21

    A near infrared probe for sensitive colorimetric and fluorimetric detection of nerve agent mimics, DCP and DCNP, was reported based on the activation of a carboxylic acid group by the mimics to conduct an intramolecular amidation reaction in the heptamethine chromophore, where its absorption or excitation maximum wavelength could be greatly red-shifted by attenuating the electron-donating ability of the amine group in the bridgehead site of heptamethine cyanine.

  10. Comparison of oxime reactivation and aging of nerve agent-inhibited monkey and human acetylcholinesterases.

    PubMed

    Luo, Chunyuan; Tong, Min; Maxwell, Donald M; Saxena, Ashima

    2008-09-25

    Non-human primates are valuable animal models that are used for the evaluation of nerve agent toxicity as well as antidotes and results from animal experiments are extrapolated to humans. It has been demonstrated that the efficacy of an oxime primarily depends on its ability to reactivate nerve agent-inhibited acetylcholinesterase (AChE). If the in vitro oxime reactivation of nerve agent-inhibited animal AChE is similar to that of human AChE, it is likely that the results of an in vivo animal study will reliably extrapolate to humans. Therefore, the goal of this study was to compare the aging and reactivation of human and different monkey (Rhesus, Cynomolgus, and African Green) AChEs inhibited by GF, GD, and VR. The oximes examined include the traditional oxime 2-PAM, two H-oximes HI-6 and HLo-7, and the new candidate oxime MMB4. Results indicate that oxime reactivation of all three monkey AChEs was very similar to human AChE. The maximum difference in the second-order reactivation rate constant between human and three monkey AChEs or between AChEs from different monkey species was 5-fold. Aging rate constants of GF-, GD-, and VR-inhibited monkey AChEs were very similar to human AChE except for GF-inhibited monkey AChEs, which aged 2-3 times faster than the human enzyme. The results of this study suggest that all three monkey species are suitable animal models for nerve agent antidote evaluation since monkey AChEs possess similar biochemical/pharmacological properties to human AChE.

  11. Annual Report 2013-2014: Theoretical Studies of Nerve Agents Adsorbed on Surfaces

    DTIC Science & Technology

    2014-07-08

    L Whitten Professor of Chemistry North Carolina State University Raleigh, NC 27695 Telephone Number: 919-515-7960 Email: whitten@ncsu.edu...electronic states accurately and to identify factors that affect desorption energies and kinetics, solvation of nerve agents by water and the spectral...to describe surface interactions and low energy electronic states at high aaccuracy using theory in order to understand the details of bonding to

  12. Molecular Evolution of Human PON to Design Enhanced Catalytic Efficiency for Hydrolysis of Nerve Agents

    DTIC Science & Technology

    2011-12-01

    Sussman, J.L., Tawfik, D.S. The use of recombinant paraoxonases as bioscavengers for the pretreatment/treatment of organophosphate poisoning , 13th...2006). 10. Bird, S.B., Dawson, A. & Ollis, D. Enzymes and bioscavengers for prophylaxis and treatment of organophosphate poisoning . Front. Biosci...intercepting both existing and emerging organophosphate -based chemical warfare nerve agents (CWNA). The 5 years of performance under this project

  13. Ultraviolet Raman spectra and cross-sections of the G-series nerve agents.

    PubMed

    Christesen, Steven D; Pendell Jones, Jay; Lochner, Joseph M; Hyre, Aaron M

    2008-10-01

    Ultraviolet (UV) Raman spectroscopy is being applied to the detection of chemical agent contamination of natural and man-made surfaces. In support of these efforts, we have measured the UV Raman signatures of the G-series nerve agents GA (tabun), GB (sarin), GD (soman), GF (cyclosarin), and the agent simulant diisopropyl methylphosphonate (DIMP) at 248 nm and 262 nm, as well as taking their UV Raman and UV absorption cross-sections. Of these chemicals, only GA exhibits any significant pre-resonance enhancement. We also show that reduction of the excitation wavelength from 262 nm to 248 nm effectively shifts the Raman spectrum away from a substantial sample fluorescence background, implying a significant improvement in detection capability.

  14. Optimal choice of acetylcholinesterase reactivators for antidotal treatment of nerve agent intoxication.

    PubMed

    Bajgar, Jirí

    2010-01-01

    The studies dealing with mechanism of organophosphates (OP)/nerve agent action, prophylaxis and treatment of intoxications is a very hot topic at present. Though the research is very intensive, unfortunately, up to now, there is not universal or significantly better reactivator sufficiently effective against all nerve agents/OP when compared with presently available oximes (pralidoxime, methoxime, obidoxime, trimedoxime, HI-6). The use of the most effective reactivator (HI-6) using simple type of autoinjector (e.g. ComboPen) is strictly limited because of decomposition of HI-6 in solution. Thanks to better solubility it is clear that another salt of HI-6 (dimethanesulfonate, HI-6 DMS) is more convenient for the use as antidote against nerve agents in the autoinjector than HI-6 chloride (Cl). It was clearly demonstrated that reactivation potency of HI-6 DMS in comparison with HI-6 Cl in vivo was the same and bioavailability of HI-6 DMS is better than that of HI-6 Cl. Three chambered autoinjector allows administration of all three antidotes (atropine, reactivator, diazepam) simultaneously. Moreover, the content of chambers can be changed according to proposed requirements. Possible way to solve the problem of universal reactivator could be the use of two reactivators. Three chambered autoinjector is an ideal device for this purpose.

  15. A HTS assay for the detection of organophosphorus nerve agent scavengers.

    PubMed

    Louise-Leriche, Ludivine; Paunescu, Emilia; Saint-André, Géraldine; Baati, Rachid; Romieu, Anthony; Wagner, Alain; Renard, Pierre-Yves

    2010-03-15

    A new pro-fluorescent probe aimed at a HTS assay of scavengers is able to selectively and efficiently cleave the P-S bond of organophosphorus nerve agents and by this provides non-toxic phosphonic acid has been designed and synthesised. The previously described pro-fluorescent probes were based on a conventional activated P-Oaryl bond cleavage, whereas our approach uses a self-immolative linker strategy that allows the detection of phosphonothioase activity with respect to a non-activated P-Salkyl bond. Further, we have also developed and optimised a high-throughput screening assay for the selection of decontaminants (chemical or biochemical scavengers) that could efficiently hydrolyse highly toxic V-type nerve agents. A preliminary screening, realised on a small alpha-nucleophile library, allowed us to identify some preliminary "hits", among which pyridinealdoximes, alpha-oxo oximes, hydroxamic acids and, less active but more original, amidoximes were the most promising. Their selective phosphonothioase activity has been further confirmed by using PhX as the substrate, and thus they offer new perspectives for the synthesis of more potent V nerve agent scavengers.

  16. Screening organophosphorus nerve agent degradation products in pesticide mixtures by GC-ICPMS.

    PubMed

    Richardson, Douglas D; Caruso, Joseph A

    2007-10-01

    Gas chromatography inductively coupled plasma mass spectrometry (GC-ICPMS) was utilized for the analysis of four organophosphorus nerve agent degradation products in the presence of mixtures of common organophosphorus pesticides. The first degradation products of sarin (isopropyl methylphosphonic acid, GB acid), cyclosarin (cyclohexyl methylphosphonic acid, GF acid), and soman (pinacolyl methylphosphonic acid) as well as their common final hydrolysis product methyl phosphonic acid were utilized throughout these experiments. Due to the non-volatile nature of these alkyl phosphonic acid degradation products, derivatization was performed to generate the volatile tert-butyl dimethylsilyl species. Degraded organophosphorus pesticide standards were obtained for acephate, chlorpyrifos, dichlorvos, ethion, and parathion ethyl. Mixtures consisting of three pesticides in the presence of a single nerve agent degradation product were prepared. GC-ICPMS allowed for the separation and detection of all four degradation products in the presence of pesticide mixtures in just over 12 minutes. This is the first study analyzing pesticides as interfering species for analysis of nerve agent degradation products by GC-ICPMS.

  17. Fully integrated ready-to-use paper-based electrochemical biosensor to detect nerve agents.

    PubMed

    Cinti, Stefano; Minotti, Clarissa; Moscone, Danila; Palleschi, Giuseppe; Arduini, Fabiana

    2017-07-15

    Paper-based microfluidic devices are gaining large popularity because of their uncontested advantages of simplicity, cost-effectiveness, limited necessity of laboratory infrastructure and skilled personnel. Moreover, these devices require only small volumes of reagents and samples, provide rapid analysis, and are portable and disposable. Their combination with electrochemical detection offers additional benefits of high sensitivity, selectivity, simplicity of instrumentation, portability, and low cost of the total system. Herein, we present the first example of an integrated paper-based screen-printed electrochemical biosensor device able to quantify nerve agents. The principle of this approach is based on dual electrochemical measurements, in parallel, of butyrylcholinesterase (BChE) enzyme activity towards butyrylthiocholine with and without exposure to contaminated samples. The sensitivity of this device is largely improved using a carbon black/Prussian Blue nanocomposite as a working electrode modifier. The proposed device allows an entirely reagent-free analysis. A strip of a nitrocellulose membrane, that contains the substrate, is integrated with a paper-based test area that holds a screen-printed electrode and BChE. Paraoxon, chosen as nerve agent simulant, is linearly detected down to 3µg/L. The use of extremely affordable manufacturing techniques provides a rapid, sensitive, reproducible, and inexpensive tool for in situ assessment of nerve agent contamination. This represents a powerful approach for use by non-specialists, that can be easily broadened to other (bio)systems.

  18. Colorimetric dipstick for assay of organophosphate pesticides and nerve agents represented by paraoxon, sarin and VX.

    PubMed

    Pohanka, Miroslav; Karasova, Jana Zdarova; Kuca, Kamil; Pikula, Jiri; Holas, Ondrej; Korabecny, Jan; Cabal, Jiri

    2010-04-15

    A dipstick for fast assay of nerve agents and organophosphate pesticides was developed. Indicator pH papers were used as detectors. The principle of the assay is based on enzymatic hydrolysis of acetylcholine into acetic acid and choline by acetylcholinesterase. Acidification of the reaction medium due to accumulation of acetic acid was visible. The colour changed from dark red to yellow as the pH indicator recognized pH shift. Presence of an organophosphate pesticide or a nerve agent results in irreversible inhibition of acetylcholinesterase intercepted on the dipstick. The inhibition stops the enzymatic reaction. The inhibition appears as no change of the medium pH. Three compounds were assayed: paraoxon-ethyl as representative organophosphate pesticides and nerve agents sarin and VX. The achieved limit of detection was 5 x 10(-8)M for paraoxon-ethyl and 5 x 10(-9)M for sarin and VX. Dipsticks were found stable for at least one month. Suitability of these dipsticks for routine assay is discussed.

  19. Choice of approaches in developing novel medical countermeasures for nerve agent poisoning.

    PubMed

    Myhrer, Trond; Aas, Pål

    2014-09-01

    During the establishment of a research branch, all relevant matters encountered will be of interest to study. After having acquired a body of basal knowledge, it becomes possible to derive ideas or hypotheses for further elaboration of information. The purpose of the present study was to show that therapies for nerve agent poisoning based on specific neuropharmacological approaches can have greater probability for being successful than treatment regimens based on fragmental research or serendipitous discoveries. By following the guidelines for research in experimental epilepsy, neuronal target areas for nerve agents have been identified through lesion studies, and critical receptors for pharmacological treatment have been specified through microinfusion studies of rats. Subsequent experimentations have shown that the results achieved from microinfusion studies are transferable to systemic administration. It is demonstrated that a treatment regimen developed through the novel approach is more efficacious than regimens derived from conventional research on countermeasures. A therapy consisting of HI-6, levetiracetam, and procyclidine that has been worked out along the new lines, exerts powerful anticonvulsant capacity and appears to have universal utility as a stand-alone therapy against soman intoxication in rats. It would be of great interest to examine whether the latter findings can be expanded to other animal species than rats and other classical nerve agents than soman.

  20. Directed evolution of hydrolases for prevention of G-type nerve agent intoxication.

    PubMed

    Gupta, Rinkoo D; Goldsmith, Moshe; Ashani, Yacov; Simo, Yair; Mullokandov, Gavriel; Bar, Hagit; Ben-David, Moshe; Leader, Haim; Margalit, Raanan; Silman, Israel; Sussman, Joel L; Tawfik, Dan S

    2011-02-01

    Organophosphate nerve agents are extremely lethal compounds. Rapid in vivo organophosphate clearance requires bioscavenging enzymes with catalytic efficiencies of >10(7) (M(-1) min(-1)). Although serum paraoxonase (PON1) is a leading candidate for such a treatment, it hydrolyzes the toxic S(p) isomers of G-agents with very slow rates. We improved PON1's catalytic efficiency by combining random and targeted mutagenesis with high-throughput screening using fluorogenic analogs in emulsion compartments. We thereby enhanced PON1's activity toward the coumarin analog of S(p)-cyclosarin by ∼10(5)-fold. We also developed a direct screen for protection of acetylcholinesterase from inactivation by nerve agents and used it to isolate variants that degrade the toxic isomer of the coumarin analog and cyclosarin itself with k(cat)/K(M) ∼ 10(7) M(-1) min(-1). We then demonstrated the in vivo prophylactic activity of an evolved variant. These evolved variants and the newly developed screens provide the basis for engineering PON1 for prophylaxis against other G-type agents.

  1. SERS-based ultrasensitive detection of organophosphorus nerve agents via substrate's surface modification.

    PubMed

    Zhao, Qian; Liu, Guangqiang; Zhang, Hongwen; Zhou, Fei; Li, Yue; Cai, Weiping

    2017-02-15

    Highly efficient detection of the organicphosphor nerve agents such as sarin and soman, based on surface enhanced Raman scattering (SERS) effect, has been in challenge due to their weak adsorption property on coin metals. In this paper, a new strategy is presented to achieve the SERS-based ultrasensitive detection of sarin-simulated agent methanephosphonic acid (MPA) via the surface modification of SERS-substrates. The Au-coated Si nanocone array is surface-modified with 2-aminoethanethiol and used as SERS-substrate for detection of MPA. It has been shown that the modified substrate could preferentially capture MPA molecules in the solution with coupling agent and induce amidation reaction. The reaction products are still bound or anchor on the substrate's surface. The MPA molecules can thus be detected by Raman spectral measurement of the solution-soaked SERS-substrate. The minimum detection level is down to ∼1ppb. The Raman peak intensity versus the MPA concentration is subject to a linear double logarithmic relation from ∼1ppb to ∼1000ppm, which is attributed to Freundlich adsorption of MPA on the surface-modified SERS substrate. This study provides a new way for the highly efficient SERS-based detection of the organophosphorus nerve agents and some other target molecules weakly interacted with metal substrates.

  2. Chemical synthesis of two series of nerve agent model compounds and their stereoselective interaction with human acetylcholinesterase and human butyrylcholinesterase.

    PubMed

    Barakat, Nora H; Zheng, Xueying; Gilley, Cynthia B; MacDonald, Mary; Okolotowicz, Karl; Cashman, John R; Vyas, Shubham; Beck, Jeremy M; Hadad, Christopher M; Zhang, Jun

    2009-10-01

    Both G and V type nerve agents possess a center of chirality about phosphorus. The S(p) enantiomers are generally more potent inhibitors than their R(p) counterparts toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). To develop model compounds with defined centers of chirality that mimic the target nerve agent structures, we synthesized both the S(p) and the R(p) stereoisomers of two series of G type nerve agent model compounds in enantiomerically enriched form. The two series of model compounds contained identical substituents on the phosphorus as the G type agents, except that thiomethyl (CH(3)-S-) and thiocholine [(CH(3))(3)NCH(2)CH(2)-S-] groups were used to replace the traditional nerve agent leaving groups (i.e., fluoro for GB, GF, and GD and cyano for GA). Inhibition kinetic studies of the thiomethyl- and thiocholine-substituted series of nerve agent model compounds revealed that the S(p) enantiomers of both series of compounds showed greater inhibition potency toward AChE and BChE. The level of stereoselectivity, as indicated by the ratio of the bimolecular inhibition rate constants between S(p) and R(p) enantiomers, was greatest for the GF model compounds in both series. The thiocholine analogues were much more potent than the corresponding thiomethyl analogues. With the exception of the GA model compounds, both series showed greater potency against AChE than BChE. The stereoselectivity (i.e., S(p) > R(p)), enzyme selectivity, and dynamic range of inhibition potency contributed from these two series of compounds suggest that the combined application of these model compounds will provide useful research tools for understanding interactions of nerve agents with cholinesterase and other enzymes involved in nerve agent and organophosphate pharmacology. The potential of and limitations for using these model compounds in the development of biological therapeutics against nerve agent toxicity are also discussed.

  3. Nanoparticle-Based Electrochemical Immunosensor for the Detection of Phosphorylated Acetylcholinesterase: An Exposure Biomarker of Organophosphate Pesticides and Nerve AgentsOrganophosphate Pesticides and Nerve Agents

    SciTech Connect

    Liu, Guodong; Wang, Jun; Barry, Richard C.; Petersen, Catherine E.; Timchalk, Charles; Gassman, Paul L.; Lin, Yuehe

    2008-11-01

    A nanoparticle-based electrochemical immunosensor has been developed for the detection of phosphorylated acetylcholinesterase (AChE) adducts, which is a potential exposure biomarker for organophosphate pesticides (OP) and chemical warfare nerve agent exposures. Zirconia nanoparticles (ZrO2 NPs) were used as selective sorbents to capture the phosphorylated AChE adduct, and quantum dots (ZnS@CdS, QDs) were used as tags to label monoclonal anti-AChE antibody to track the immunorecognition events. The sandwich-like immunoreactions were performed among the ZrO2 NPs, which were pre-coated on a screen printed electrode (SPE) by electrodeposition, phosphorylated AChE and QD-anti-AChE. The captured QD tags were determined on the SPE by electrochemical stripping analysis of its metallic component (cadmium) after an acid-dissolution step. Paraoxon was used as a model OP insecticide to prepare the phosphorylated AChE adduct to demonstrate the proof of principle for this sensor technology. The paraoxon-AChE adduct was characterized by Fourier Transform Infrared Spectrum, and the binding affinity of anti-AChE to the paraoxon-AChE was validated with an enzyme-linked immunosorbent assay. The parameters (e.g., amount of ZrO2 NP, QD-anti-AChE concentration,) that govern the electrochemical response of immunosensors were optimized. The voltammetric response of the immunosensor is highly linear over the range of 10 pM to 4 nM paraoxon-AChE, and the limit of detection is estimated to be 8 pM. This new nanoparticle-based electrochemical immunosensor thus provides a sensitive and quantitative tool for biomonitoring exposure to OP pesticides and nerve agents.

  4. A lab-on-a-chip for detection of nerve agent sarin in blood.

    PubMed

    Tan, Hsih Yin; Loke, Weng Keong; Tan, Yong Teng; Nguyen, Nam-Trung

    2008-06-01

    Sarin (C(4)H(10)FO(2)P,O-isopropyl methylphosphonofluoridate) is a colourless, odourless and highly toxic phosphonate that acts as a cholinesterase inhibitor and disrupts neuromuscular transmission. Sarin and related phosphonates are chemical warfare agents, and there is a possibility of their application in a military or terrorist attack. This paper reports a lab-on-a-chip device for detecting a trace amount of sarin in a small volume of blood. The device should allow early detection of sarin exposure during medical triage to differentiate between those requiring medical treatment from mass psychogenic illness cases. The device is based on continuous-flow microfluidics with sequential stages for lysis of whole blood, regeneration of free nerve agent from its complex with blood cholinesterase, protein precipitation, filtration, enzyme-assisted reaction and optical detection. Whole blood was first mixed with a nerve gas regeneration agent, followed by a protein precipitation step. Subsequently, the lysed product was filtered on the chip in two steps to remove particulates and fluoride ions. The filtered blood sample was then tested for trace levels of regenerated sarin using immobilised cholinesterase on the chip. Activity of immobilised cholinesterase was monitored by the enzyme-assisted reaction of a substrate and reaction of the end-product with a chromophore. Resultant changes in chromophore-induced absorbance were recorded on the chip using a Z-shaped optical window. Loss of enzyme activity obtained prior and after passage of the treated blood sample, as shown by a decrease in recorded absorbance values, indicates the presence of either free or regenerated sarin in the blood sample. The device was fabricated in PMMA (polymethylmethacrylate) using CO(2)-laser micromachining. This paper reports the testing results of the different stages, as well as the whole device with all stages in the required assay sequence. The results demonstrate the potential use of a

  5. Visual and fluorogenic detection of a nerve agent simulant via a Lossen rearrangement of rhodamine-hydroxamate.

    PubMed

    Han, Shoufa; Xue, Zhongwei; Wang, Zhen; Wen, Ting Bin

    2010-11-28

    A visual and fluorogenic detection method for a nerve agent simulant was developed based on a Lossen rearrangement of rhodamine-hydroxamate, in the presence of diethyl chlorophosphate, under alkaline conditions.

  6. Selective opening of nanoscopic capped mesoporous inorganic materials with nerve agent simulants; an application to design chromo-fluorogenic probes.

    PubMed

    Candel, Inmaculada; Bernardos, Andrea; Climent, Estela; Marcos, M Dolores; Martínez-Máñez, Ramón; Sancenón, Félix; Soto, Juan; Costero, Ana; Gil, Salvador; Parra, Margarita

    2011-08-07

    A hybrid nanoscopic capped mesoporous material, that is selectively opened in the presence of nerve agent simulants, has been prepared and used as a probe for the chromo-fluorogenic detection of these chemicals.

  7. Development of pretreatment compounds against nerve-gas agents. Annual report (Final), 16 May 88-30 Sep 90

    SciTech Connect

    Carroll, F.I.; Abraham, P.

    1990-09-30

    The U. S. Army Medical Research and Development Command is interested in research directed toward the development of countermeasures to chemical warfare (CW) agents such as the nerve gas poison soman. Soman and other nerve gas poisons are extremely potent cholinesterase inhibitors. This inhibition leads to a buildup of excess acetylcholine resulting in over-stimulation of both the peripheral and central nervous system and can lead to death. Standard therapy for organophosphate nerve agent poisoning is based on co-administration of an anticholinergic agent such as atropine to antagonize the effects of accumulated acetylcholine and a cholinesterase reactivator such as 2-PAM to dephosphorylate the inhibited enzyme. However, since many problems remain in the treatment of organophosphate nerve agent poisoning, there is considerable interest and need to develop new pretreatment and treatment drugs, particularly for soman poisoning.

  8. Detection of nerve agents using proton transfer reaction mass spectrometry with ammonia as reagent gas.

    PubMed

    Ringer, Joachim M

    2013-01-01

    The chemical warfare agents (CWA) Sarin, Soman, Cyclosarin and Tabun were characterised by proton transfer mass spectrometry (PTRMS). It was found that PTRMS is a suitable technique to detect nerve agents highly sensitively, highly selectively and in near real-time. Methods were found to suppress molecule fragmentation which is significant under PTRMS hollow cathode ionisation conditions. In this context, the drift voltage (as one of the most important system parameters) was varied and ammonia was introduced as an additional chemical reagent gas. Auxiliary chemicals such as ammonia affect ionisation processes and are quite common in context with detectors for CWAs based on ion mobility spectrometry (IMS). With both, variation of drift voltage and ammonia as the reagent gas, fragmentation can be suppressed effectively. Suppression of fragmentation is crucial particularly concerning the implementation of an algorithm for automated agent identification in field applications. On the other hand, appearance of particular fragments might deliver additional information. Degradation and rearrangement products of nerve agents are not distinctive for the particular agent but for the chemical class they belong to. It was found that switching between ammonia doped and ordinary water ionisation chemistry can easily be performed within a few seconds. Making use of this effect it is possible to switch between fragment and molecular ion peak spectra. Thus, targeted fragmentation can be used to confirm identification based only on single peak detection. PTRMS turned out to be a promising technique for future CWA detectors. In terms of sensitivity, response time and selectivity (or confidence of identification, respectively) PTRMS performs as a bridging technique between IMS and GC-MS.

  9. Application of Hydrogen Bond Acidic Polycarbosilane Polymers and Solid-Phase Microextraction for the Collection of Nerve Agent Simulant

    DTIC Science & Technology

    2006-01-01

    and analyzed on a GC/MS with a SPME injection port. 20 3. Methodolgy This chapter describes the methods used to answer the research questions...can be improved by using a SPME polymer coating that is selective for nerve agents in place of current commercial polymers. This research focuses on...three hydrogen bond acidic polymers developed by the Naval Research Laboratory that have an increased affinity for nerve agents. These polymers

  10. A FRET-based ratiometric fluorescent and colorimetric probe for the facile detection of organophosphonate nerve agent mimic DCP.

    PubMed

    Xuan, Weimin; Cao, Yanting; Zhou, Jiahong; Wang, Wei

    2013-11-18

    A FRET ratiometric fluorescent probe enabling a fast and highly sensitive response to OP nerve agent mimic DCP within 1 min and with as low as 0.17 ppm concentration detection limit has been developed. Moreover, the probe exhibits noticeable color changes under UV light and even with the naked eye. It is also demonstrated that it can detect both liquid and gas nerve agents.

  11. Detrimental influences of intraluminally-administered sclerotic agents on surrounding tissues and peripheral nerves: An experimental study

    PubMed Central

    Fujiki, Masahide; Kurita, Masakazu; Ozaki, Mine; Kawakami, Hayato; Kaji, Nobuyuki; Takushima, Akihiko; Harii, Kiyonori

    2012-01-01

    The minimally-invasive nature of sclerotherapy makes it one of the first treatment options for venous malformations, although treatment-related complications, such as peripheral nerve paralysis, have been reported in some clinical cases. However, no studies of the aetiology of the detrimental effects of intraluminally-administered sclerotic agents on the surrounding tissues, including the peripheral nerves, have yet been published. This study therefore investigated the influences of intraluminally-administered sclerotic agents on the tissues surrounding the injection site using a newly-developed rat femoral vein model. Using this model, the effects of absolute ethanol, 5% ethanolamine oleate, and 1% polidocanol were compared histologically with those of normal saline controls. Fluorescein isothiocyanate-conjugated agents were administered and the leakage of sclerotic agents through the venous wall was evaluated by fluorescence microscopy. Damage to the adjacent femoral nerve was quantitatively evaluated by counting the numbers of axons in cross-sections. All the sclerotic agents caused vascular wall injuries and leakage into the surrounding tissues. The number of axons in the femoral nerve was significantly reduced following administration of absolute ethanol or 5% ethanolamine oleate, compared with normal saline. The results of this study suggest that sclerotic agents commonly leak out the vascular lumen, and some agents can cause adjacent nerve injury. It is important to be aware of this type of complication of sclerotherapy for venous malformations when selecting appropriate therapeutic interventions. PMID:22686430

  12. RSDL decontamination of human skin contaminated with the nerve agent VX.

    PubMed

    Thors, L; Lindberg, S; Johansson, S; Koch, B; Koch, M; Hägglund, L; Bucht, A

    2017-03-05

    Dermal exposure to low volatile organophosphorus compounds (OPC) may lead to penetration through the skin and uptake in the blood circulation. Skin decontamination of toxic OPCs, such as pesticides and chemical warfare nerve agents, might therefore be crucial for mitigating the systemic toxicity following dermal exposure. Reactive skin decontamination lotion (RSDL) has been shown to reduce toxic effects in animals dermally exposed to the nerve agent VX. In the present study, an in vitro flow-through diffusion cell was utilized to evaluate the efficacy of RSDL for decontamination of VX exposed to human epidermis. In particular, the impact of timing in the initiation of decontamination and agent dilution in water was studied. The impact of the lipophilic properties of VX in the RSDL decontamination was additionally addressed by comparing chemical degradation in RSDL and decontamination efficacy between the VX and the hydrophilic OPC triethyl phosphonoacetate (TEPA). The epidermal membrane was exposed to 20, 75 or 90% OPC diluted in deionized water and the decontamination was initiated 5, 10, 30, 60 or 120min post-exposure. Early decontamination of VX with RSDL, initiated 5-10min after skin exposure, was very effective. Delayed decontamination initiated 30-60min post-exposure was less effective but still the amount of penetrated agent was significantly reduced, while further delayed start of decontamination to 120min resulted in very low efficacy. Comparing RSDL decontamination of VX with that of TEPA showed that the decontamination efficacy at high agent concentrations was higher for VX. The degradation mechanism of VX and TEPA during decontamination was dissected by (31)P NMR spectroscopy of the OPCs following reactions with RSDL and its three nucleophile components. The degradation rate was clearly associated with the high pH of the specific solution investigated; i.e. increased pH resulted in a more rapid degradation. In addition, the solubility of the OPC in RSDL

  13. SAR study to find optimal cholinesterase reactivator against organophosphorous nerve agents and pesticides.

    PubMed

    Gorecki, Lukas; Korabecny, Jan; Musilek, Kamil; Malinak, David; Nepovimova, Eugenie; Dolezal, Rafael; Jun, Daniel; Soukup, Ondrej; Kuca, Kamil

    2016-12-01

    Irreversible inhibition of acetylcholinesterase (AChE) by organophosphates leads to many failures in living organism and ultimately in death. Organophosphorus compounds developed as nerve agents such as tabun, sarin, soman, VX and others belong to the most toxic chemical warfare agents and are one of the biggest threats to the modern civilization. Moreover, misuse of nerve agents together with organophosphorus pesticides (e.g. malathion, paraoxon, chlorpyrifos, etc.) which are annually implicated in millions of intoxications and hundreds of thousand deaths reminds us of insufficient protection against these compounds. Basic treatments for these intoxications are based on immediate administration of atropine and acetylcholinesterase reactivators which are currently represented by mono- or bis-pyridinium aldoximes. However, these antidotes are not sufficient to ensure 100 % treatment efficacy even they are administered immediately after intoxication, and in general, they possess several drawbacks. Herein, we have reviewed new efforts leading to the development of novel reactivators and proposition of new promising strategies to design novel and effective antidotes. Structure-activity relationships and biological activities of recently proposed acetylcholinesterase reactivators are discussed and summarized. Among further modifications of known oximes, the main attention has been paid to dual binding site ligands of AChE as the current mainstream strategy. We have also discussed new chemical entities as potential replacement of oxime functional group.

  14. Lab-on-a-chip for rapid electrochemical detection of nerve agent Sarin.

    PubMed

    Tan, Hsih Yin; Loke, Weng Keong; Nguyen, Nam-Trung; Tan, Swee Ngin; Tay, Nam Beng; Wang, Wei; Ng, Sum Huan

    2014-04-01

    This paper reports a lab-on-a-chip for the detection of Sarin nerve agent based on rapid electrochemical detection. The chemical warfare agent Sarin (C₄H₁₀FO₂P, O-isopropyl methylphosphonofluoridate) is a highly toxic organophosphate that induces rapid respiratory depression, seizures and death within minutes of inhalation. As purified Sarin is colourless, odourless, water soluble and a easily disseminated nerve agent, it has been used as a weapon in terrorist or military attacks. To ascertain whether potable water supplies have been adulterated with this extremely potent poison, an inexpensive, sensitive and easy to use portable test kit would be of interest to first responders investigating such attacks. We report here an amperometric-based approach for detecting trace amounts of Sarin in water samples using a screen-printed electrode (SPE) integrated in a microfluidic chip. Enzymatic inhibition was obtained by exposing the immobilised biosensor in the microfluidic platform to Sarin in water samples. With the aid of cobalt phthalocyanine modified SPE, the device could detect Sarin at part-per-billion levels with concentration as low as 1 nM. The detection method reported here represents a significant improvement over the authors'previous optical-based detection method.

  15. Catalytic degradation of the nerve agent VX by water-swelled polystyrene-supported ammonium fluorides.

    PubMed

    Marciano, Daniele; Goldvaser, Michael; Columbus, Ishay; Zafrani, Yossi

    2011-10-21

    The catalytic degradation of the nerve agent VX (O-ethyl S-2-(diisopropylamino)ethyl methylphosphonothioate) by water-swelled polymer-supported ammonium fluorides is described. VX (0.06-0.53 mol/mol F(-)) is rapidly degraded (t(1/2) ∼ 10-30 min) to form the "G-analogue" (O-ethyl methylphosphonofluoridate), which hydrolyzes (t(1/2) ∼ 1-1.5 h) to the nontoxic EMPA (ethyl methylphosphonic acid). The toxic desethyl-VX is not formed. The catalytic effect of fluoride is maintained even when 6 equiv of VX are loaded. GB (O-isopropyl methylphosphonofluoridate) and desethyl-VX agents are also degraded under these conditions.

  16. Portable Analytical Systems for On-Site Diagnosis of Exposure to Pesticides and Nerve Agents

    SciTech Connect

    Lin, Yuehe; Wang, Jun; Liu, Guodong; Timchalk, Chuck

    2009-12-01

    In this chapter, we summarize recent work in our laboratory on the development of sensitive portable analytical systems for use in on-site detection of exposure to organophosphate (OP) pesticides and chemical nerve agents. These systems are based on various nanomaterials functioning as transducers; recognition agents or labels and various elelectrochemical/immunoassay techniques. The studied nanomaterials included functionalized carbon nanotubes (CNT), zirconia nanoparticles (NPs) and quantum dots (QDs). Three biomarkers e.g. the free OPs, metabolites of OPs and protein-OP adducts in biological matrices have been employed for biomonitoring of OP exposure with our developed system. It has been found that the nanomaterial-based portable analytical systems have high sensitivity for the detection of the biomarkers, which suggest that these technologies offer great promise for the rapid and on-site detection and evaluation of OP exposure.

  17. Efficacy of biperiden and atropine as anticonvulsant treatment for organophosphorus nerve agent intoxication.

    PubMed

    Shih, T M; McDonough, J H

    2000-05-01

    The ability of the nerve agents tabun, sarin, soman, GF, VR, and VX to produce brain seizures and the effectiveness of the anticholinergics biperiden HCl or atropine SO4 as an anticonvulsant treatment were studied in a guinea-pig model. All animals were implanted a week prior to the experiment with cortical electrodes for electroencephalogram (EEG) recordings. On the day of exposure, the animals were pretreated with pyridostigmine (0.026 mg/kg, i.m.) 30 min prior to challenge with a 2 x LD50 dose (s.c.) of a given agent. In separate experiments, animals were challenged with 5 x LD50 (s.c.) of soman. One minute after agent challenge, the animals were treated intramuscularly (i.m.) with 2 mg/kg atropine SO4 admixed with 25 mg/kg 2-PAM Cl and then observed for the onset of seizure activity. Five minutes after the start of nerve agent-induced EEG seizures, animals were treated i.m. with different doses of biperiden HCl or atropine SO4 and observed for seizure termination. The anticonvulsant ED50 of biperiden HCl and atropine SO4 for termination of seizures induced by each nerve agent was calculated and compared. With equally toxic doses (2 x LD50) of these agents, continuous EEG seizures (status epilepticus) developed in all animals challenged with soman, tabun, or VR, and in more than 90% of the animals challenged with GF or sarin. In contrast, only 50% of the animals developed seizures when challenged with VX. The times to onset of seizures for soman, tabun, GF, and sarin were very similar (5-8 min) while for VR, it was about 10 min. In the case of VX, not only was the time to seizure development longer (20.7 min), but the seizure activity in 19% of the animals terminated spontaneously within 5 min after onset and did not return. Under these conditions, the anticonvulsant ED50s of biperiden HCl for soman, GF, VR, tabun, sarin, and VX were 0.57, 0.51, 0.41, 0.2, 0.1, and 0.09 mg/kg, respectively, while those of atropine SO4 for soman, VR, tabun, GF, sarin, and VX were

  18. Detection of nerve agents and biological molecules using embedded piezoresistive microcantilever sensors.

    NASA Astrophysics Data System (ADS)

    Porter, Timothy; Vail, Tim; Wooley, Amanda

    2008-03-01

    Embedded piezoresistive microcantilever (EPM) sensors have been used in the detection of a variety of analyte species. EPM sensors utilize a tiny piezoresistive microcantilever partially embedded into a sensing material to produce a sensing element that is compact, simple, resistant to movement and shock, and suitable for remote sensing applications. In the current project, we have used sensing materials comprised of an immobilizing polymer functionalized with either target enzymes or antibodies to detect two biological agents, bacillus globigi (BG) and Diisopropyl fluorophosphate (DFP). DFP is an organophosphate used as a simulant for organophosphate nerve agents, while BG is a large bacterial spore used as a simulant for other bacterial spores such as bacillus anthracis. Sensing results are presented for both types of EPM sensors.

  19. Molecular Dynamics of Organophosphorous Hydrolases Bound to the Nerve Agent Soman

    SciTech Connect

    Soares, Thereza A.; Osman, Mohamed A.; Straatsma, TP

    2007-07-01

    The organophosphorous hydrolase (OPH) from Pseudomonas diminuta is capable of degrading extremely toxic organophosphorous compounds with a high catalytic turnover and broad substrate specificity. The potential use of this enzyme for the detection and detoxification of warfare nerve agents has spurred efforts to engineer mutants of enhanced catalytic activity and modified stereospecificity towards the most toxic forms of organophosphate nerve agents. Molecular dynamics simulations of the wild-type OPH and the complexes between the wild-type and the triple-mutant H254G/H257W/L303R forms and the substrate SpSc-soman have been carried out to enhance our molecular level understanding of its reaction mechanism. Comparison of the three simulations indicate that substrate binding induces conformational changes of the loops near the active site, suggesting an induced-fit mechanism. Likewise, the coordination of the zinc cations in the active site of the enzyme differs between the free enzyme and the complexes. In the absence of the substrate, the more exposed b-zinc is hexa-coordinated and the less exposed a-zinc is penta-coordinated. In the presence of the substrate, the b- zinc atom can be both penta- or hexa-coordinated while the a-zinc atom is tetra-coordinated. In addition, binding energies were calculated from electrostatic properties obtained by solution of the Poisson-Boltzmann equation combined with a surface area-dependent apolar contribution. The calculations indicate that the binding of SpSc-soman to OPH is driven by nonpolar interactions while electrostatic interactions determine binding specificity. These results provide a qualitative, molecular-level explanation for 2 the three-fold increase in catalytic efficiency of the triple-mutant towards SpSc-soman. Keywords: organophosphorous hydrolase, phosphotriesterase, nerve agents, soman, molecular dynamics, Poisson-Boltzmann equation, continuum electrostatics, metalloprotein.

  20. Novel dual-mode immunomagnetic method for studying reactivation of nerve agent-inhibited butyrylcholinesterase.

    PubMed

    Abney, Carter W; Knaack, Jennifer L S; Ali, Ahmed A I; Johnson, Rudolph C

    2013-05-20

    A novel immunomagnetic method has been developed for the simultaneous measurement of organophosphorus nerve agent (OPNA) adducts to butyrylcholinesterase (BuChE) and free OPNAs in serum. This new approach, deemed dual-mode immunomagnetic analysis (Dual-Mode IMA), combines immunomagnetic separation (IMS) and immunomagnetic scavenging (IMSc) and has been used to measure the effectiveness of cholinesterase reactivators on OPNA-inhibited BuChE in serum. BuChE inhibited by the nerve agent VX, uninhibited BuChE, and unbound VX were measured up to 1 h after the addition of oxime reactivators pralidoxime (2-PAM) and obidoxime. IMS experiments consisted of extracting BuChE and VX-BuChE serum adducts using antibutyrylcholinesterase monoclonal antibodies conjugated to protein-G ferromagnetic particles. In a parallel set of experiments using IMSc, BuChE-coated magnetic beads were used to extract free VX from protein-depleted serum. Adducts from both IMS and IMSc were analyzed using a published IMS liquid chromatography tandem mass spectrometry (IMS-LC-MS/MS) protocol, which has also been demonstrated with other OPNAs. By applying this Dual-Mode IMA approach, 2-PAM was observed to be more potent than obidoxime in reactivating VX-adducted BuChE. VX-BuChE peptide concentrations initially measured at 19.7 ± 0.7 ng/mL decreased over 1 h to 10.6 ± 0.6 ng/mL when reactivated with 2-PAM and 14.4 ± 1.2 ng/mL when reactivated with obidoxime. These experiments also show that previously published IMS-LC-MS/MS analyses are compatible with serum treated with oximes. Dual-Mode IMA is the first immunoaffinity method developed for the simultaneous measurement of OPNA adducted BuChE, unadducted BuChE, and free nerve agent in serum and is a promising new tool for studying reactivator effectiveness on cholinesterases inhibited by nerve agents.

  1. Human Paraoxonase Double Mutants Hydrolyze V and G Class Organophosphorus Nerve Agents

    DTIC Science & Technology

    2013-01-01

    serum paraoxonase 1 (EC 3.1.8.1) is a calcium - dependent enzyme secreted by the liver into the bloodstream. It is associated with high-density...H115W/F347W. The green sphere is one of two coordinated calcium ions. 182 S.D. Kirby et al. / Chemico-Biological Interactions 203 (2013) 181–185...internal standard. The majority of the organic layer containing the unbound nerve agent was removed and passed over type 4A (grade 514) alumina- silicate

  2. Integration of metal oxide nanobelts with microsystems for nerve agent detection

    NASA Astrophysics Data System (ADS)

    Yu, Choongho; Hao, Qing; Saha, Sanjoy; Shi, Li; Kong, Xiangyang; Wang, Z. L.

    2005-02-01

    We have assembled tin dioxide nanobelts with low-power microheaters for detecting dimethyl methylphosphonate (DMMP), a nerve agent simulant. The electrical conductance of a heated nanobelt increased for 5% upon exposure to 78 parts per billion DMMP in air. The nanobelt conductance recovered fully quickly after the DMMP was shut off, suggesting that the single-crystal nanobelt was not subject to poisoning often observed in polycrystalline metal oxide sensors. While the sensitivity can be improved via doping nanobelts with catalytic additives, directed assembly or growth of nanobelts on microsystems will potentially allow for the large-scale fabrication of nanosensor arrays.

  3. Reactivation of Brain Acetylcholinesterase by Monoisonitrosoacetone Increases the Therapeutic Efficacy Against Nerve Agents in Guinea Pigs

    DTIC Science & Technology

    2010-01-01

    reactivated ChE in the brain, educed toxic signs, improved survival, and prevented or termi- ated seizures following GB intoxication in guinea pigs [15,16...nerve agent intox - cation more effectively than peripherally acting reversible ChE nhibitors, such as pyridostigmine [17–19]. The present study was...cumulative score was categorized as mild intoxication [0–3.0], moderate intoxication [3.1–6.0] and severe intoxication [6.1–9.0]. 2.3.2. ChE activity

  4. Efficacy of antidotes (midazolam, atropine and HI-6) on nerve agent induced molecular and neuropathological changes

    PubMed Central

    2014-01-01

    Background Recent alleged attacks with nerve agent sarin on civilians in Syria indicate their potential threat to both civilian and military population. Acute nerve agent exposure can cause rapid death or leads to multiple and long term neurological effects. The biochemical changes that occur following nerve agent exposure needs to be elucidated to understand the mechanisms behind their long term neurological effects and to design better therapeutic drugs to block their multiple neurotoxic effects. In the present study, we intend to study the efficacy of antidotes comprising of HI-6 (1-[[[4-(aminocarbonyl)-pyridinio]-methoxy]-methyl]-2-[(hydroxyimino) methyl] pyridinium dichloride), atropine and midazolam on soman induced neurodegeneration and the expression of c-Fos, Calpain, and Bax levels in discrete rat brain areas. Results Therapeutic regime consisting of HI-6 (50 mg/kg, i.m), atropine (10 mg/kg, i.m) and midazolam (5 mg/kg, i.m) protected animals against soman (2 × LD50, s.c) lethality completely at 2 h and 80% at 24 h. HI-6 treatment reactivated soman inhibited plasma and RBC cholinesterase up to 40%. Fluoro-Jade B (FJ-B) staining of neurodegenerative neurons showed that soman induced significant necrotic neuronal cell death, which was reduced by this antidotal treatment. Soman increased the expression of neuronal proteins including c-Fos, Bax and Calpain levels in the hippocampus, cerebral cortex and cerebellum regions of the brain. This therapeutic regime also reduced the soman induced Bax, Calpain expression levels to near control levels in the different brain regions studied, except a mild induction of c-Fos expression in the hippocampus. Conclusion Rats that received antidotal treatment after soman exposure were protected from mortality and showed reduction in the soman induced expression of c-Fos, Bax and Calpain and necrosis. Results highlight the need for timely administration of better antidotes than standard therapy in order to prevent the

  5. An evaluation of the spectral properties of nerve agents for laser ionization mass spectrometry.

    PubMed

    Imasaka, Tomoko; Imasaka, Totaro

    2014-01-01

    Excitation energies, oscillator strengths, and vacuum-ultraviolet/deep-ultraviolet absorption spectra were calculated for nerve agents, such as sarin, soman, VX, tabun, mustard gas, and analogs. We used time-dependent density functional theory (TD-DFT) methods that included B3LYP combined with basis sets of cc-pVDZ and cc-pVTZ, and ωB97XD with cc-pVTZ. The vertical ionization energies were also calculated for these compounds, in order to collect additional information relative to the optimal pathways for multiphoton ionization in mass spectrometry.

  6. Carboxylic Acid-Functionalized Conducting-Polymer Nanotubes as Highly Sensitive Nerve-Agent Chemiresistors

    NASA Astrophysics Data System (ADS)

    Kwon, Oh Seok; Park, Chul Soon; Park, Seon Joo; Noh, Seonmyeong; Kim, Saerona; Kong, Hye Jeong; Bae, Joonwon; Lee, Chang-Soo; Yoon, Hyeonseok

    2016-09-01

    Organophosphates are powerful inhibitors of acetylcholinesterase, which is critical to nerve function. Despite continuous research for detecting the highly toxic organophosphates, a new and improved methodology is still needed. Herein we demonstrate simple-to-fabricate chemiresistive gas sensors using conducting-polymer polypyrrole (PPy) nanotube transducers, which are chemically specific and capable of recognizing sub-ppb concentrations (ca. 0.5 ppb) of dimethyl methylphosphonate (DMMP), a simulant of nerve agent sarin. Interestingly, the introduction of carboxylic groups on the surface of PPy nanotube transistors resulted in enhanced sensitivity to DMMP via intermolecular hydrogen bonding. Furthermore, it was found that the sensitivity of the nanotube transducer depended on the degree of the carboxylic group introduced. Finally, a sensor array composed of 5 different transducers including the carboxylated nanotubes exhibited excellent selectivity to DMMP in 16 vapor species.

  7. Carboxylic Acid-Functionalized Conducting-Polymer Nanotubes as Highly Sensitive Nerve-Agent Chemiresistors

    PubMed Central

    Kwon, Oh Seok; Park, Chul Soon; Park, Seon Joo; Noh, Seonmyeong; Kim, Saerona; Kong, Hye Jeong; Bae, Joonwon; Lee, Chang-Soo; Yoon, Hyeonseok

    2016-01-01

    Organophosphates are powerful inhibitors of acetylcholinesterase, which is critical to nerve function. Despite continuous research for detecting the highly toxic organophosphates, a new and improved methodology is still needed. Herein we demonstrate simple-to-fabricate chemiresistive gas sensors using conducting-polymer polypyrrole (PPy) nanotube transducers, which are chemically specific and capable of recognizing sub-ppb concentrations (ca. 0.5 ppb) of dimethyl methylphosphonate (DMMP), a simulant of nerve agent sarin. Interestingly, the introduction of carboxylic groups on the surface of PPy nanotube transistors resulted in enhanced sensitivity to DMMP via intermolecular hydrogen bonding. Furthermore, it was found that the sensitivity of the nanotube transducer depended on the degree of the carboxylic group introduced. Finally, a sensor array composed of 5 different transducers including the carboxylated nanotubes exhibited excellent selectivity to DMMP in 16 vapor species. PMID:27650635

  8. Reactivation of nerve agent-inhibited human acetylcholinesterase by obidoxime, HI-6 and obidoxime+HI-6: Kinetic in vitro study with simulated nerve agent toxicokinetics and oxime pharmacokinetics.

    PubMed

    Worek, Franz; Koller, Marianne; Thiermann, Horst; Wille, Timo

    2016-03-28

    Despite extensive research for decades no effective broad-spectrum oxime for the treatment of poisoning by a broad range of nerve agents is available. Previous in vitro and in vivo data indicate that the combination of in service oximes could be beneficial. To investigate the ability of obidoxime, HI-6 and the combination of both oximes to reactivate inhibited human AChE in the presence of sarin, cyclosarin or tabun we adopted a dynamic in vitro model with real-time and continuous determination of AChE activity to simulate inhalation nerve agent exposure and intramuscular oxime administration. The major findings of this kinetic study are that the extent and velocity of reactivation is dependent on the nerve agent and the oxime-specific reactivating potency. The oxime-induced reactivation of inhibited human AChE in the presence of nerve agents is markedly impaired and the combination of obidoxime and HI-6 had no additive effect but could broaden the spectrum. In conclusion, these data indicate that a combination of obidoxime and HI-6 would be beneficial for the treatment of poisoning by a broad spectrum of nerve agents and could present an interim solution until more effective and broad-spectrum reactivators are available.

  9. Favorable pendant-amino metal chelation in VX nerve agent model systems.

    PubMed

    Bandyopadhyay, Indrajit; Kim, Min Jeong; Lee, Yoon Sup; Churchill, David G

    2006-03-16

    We have performed DFT computational studies [B3LYP, 6-31+G] to obtain metal ion coordination isomers of VX-Me [MeP(O)(OMe)(SCH2CH2NMe2)], a model of two of the most lethal nerve agents: VX [MeP(O)(OEt)(SCH2CH2N(iPr)2)] and Russian-VX [MeP(O)(OCH2CHMe2)(SCH2CH2N(Et)2)]. Our calculations involved geometry optimizations of the neutral VX-Me model as well as complexes with H+, Li+, Na+, K+, Be2+, Mg2+, and Ca2+ that yielded 2-8 different stable chelation modes for each ion that involved mainly mono- and bidentate binding. Importantly, our studies revealed that the [O(P),N] bidentate binding mode, long thought to be the active mode in differentiating the hydrolytic path of VX from other nerve agents, was the most stable for all ions studied here. Binding energy depended mainly on ionic size as well as charge, with binding energies ranging from 364 kcal mol(-1) for Be2+ to 33 kcal mol(-1) for K+. Furthermore, calculated NMR shifts for VX-Me correlate to experimental values of VX.

  10. Isotope dilution LC/MS/MS for the detection of nerve agent exposure in urine.

    PubMed

    Ciner, Frederic L; McCord, Carla E; Plunkett, Roy W; Martin, Michael F; Croley, Timothy R

    2007-02-01

    Organophosphorus nerve agents (OPNA), chemically related to and derived from organophosphate insecticides, constitute a clear and present threat to both military and civilian targets. Military regimes and terrorist organizations have demonstrated the will and ability to produce mass casualties by dispersing organophosphorus nerve agents, which, in turn could terrorize populations and overwhelm healthcare systems. A high throughput, robust and sensitive analytical protocol has been developed for the quantitation of the urinary metabolites of sarin (GB), soman (GD), VX, Russian VX (RVX) and cyclohexylsarin (GF) utilizing solid phase extraction (SPE) followed by High Performance Liquid Chromatography (HPLC)-isotope dilution tandem mass spectrometry (LC/MS/MS). The method has demonstrated linearity and reproducibility (1-200 ng/mL) for all analytes and has a Limit of Quantitation (LOQ)< or =0.5 ng/mL for all analytes (S/N> or =10/1). The method was validated by performing 20 individual analyses over 10 days by five scientists with all values falling within two standard deviations of the mean.

  11. An Acetylcholinesterase-Based Chronoamperometric Biosensor for Fast and Reliable Assay of Nerve Agents

    PubMed Central

    Pohanka, Miroslav; Adam, Vojtech; Kizek, Rene

    2013-01-01

    The enzyme acetylcholinesterase (AChE) is an important part of cholinergic nervous system, where it stops neurotransmission by hydrolysis of the neurotransmitter acetylcholine. It is sensitive to inhibition by organophosphate and carbamate insecticides, some Alzheimer disease drugs, secondary metabolites such as aflatoxins and nerve agents used in chemical warfare. When immobilized on a sensor (physico-chemical transducer), it can be used for assay of these inhibitors. In the experiments described herein, an AChE- based electrochemical biosensor using screen printed electrode systems was prepared. The biosensor was used for assay of nerve agents such as sarin, soman, tabun and VX. The limits of detection achieved in a measuring protocol lasting ten minutes were 7.41 × 10−12 mol/L for sarin, 6.31 × 10−12 mol/L for soman, 6.17 × 10−11 mol/L for tabun, and 2.19 × 10−11 mol/L for VX, respectively. The assay was reliable, with minor interferences caused by the organic solvents ethanol, methanol, isopropanol and acetonitrile. Isopropanol was chosen as suitable medium for processing lipophilic samples. PMID:23999806

  12. Chiral Separation of G-type Chemical Warfare Nerve Agents via Analytical Supercritical Fluid Chromatography

    PubMed Central

    Kasten, Shane A; Zulli, Steven; Jones, Jonathan L; Dephillipo, Thomas; Cerasoli, Douglas M

    2014-01-01

    Chemical warfare nerve agents (CWNAs) are extremely toxic organophosphorus compounds that contain a chiral phosphorus center. Undirected synthesis of G-type CWNAs produces stereoisomers of tabun, sarin, soman, and cyclosarin (GA, GB, GD, and GF, respectively). Analytical-scale methods were developed using a supercritical fluid chromatography (SFC) system in tandem with a mass spectrometer for the separation, quantitation, and isolation of individual stereoisomers of GA, GB, GD, and GF. Screening various chiral stationary phases (CSPs) for the capacity to provide full baseline separation of the CWNAs revealed that a Regis WhelkO1 (SS) column was capable of separating the enantiomers of GA, GB, and GF, with elution of the P(+) enantiomer preceding elution of the corresponding P(–) enantiomer; two WhelkO1 (SS) columns had to be connected in series to achieve complete baseline resolution. The four diastereomers of GD were also resolved using two tandem WhelkO1 (SS) columns, with complete baseline separation of the two P(+) epimers. A single WhelkO1 (RR) column with inverse stereochemistry resulted in baseline separation of the GD P(–) epimers. The analytical methods described can be scaled to allow isolation of individual stereoisomers to assist in screening and development of countermeasures to organophosphorus nerve agents. Chirality 26:817–824, 2014. © 2014 The Authors. Chirality published by John Wiley Periodicals, Inc. PMID:25298066

  13. Chiral separation of G-type chemical warfare nerve agents via analytical supercritical fluid chromatography.

    PubMed

    Kasten, Shane A; Zulli, Steven; Jones, Jonathan L; Dephillipo, Thomas; Cerasoli, Douglas M

    2014-12-01

    Chemical warfare nerve agents (CWNAs) are extremely toxic organophosphorus compounds that contain a chiral phosphorus center. Undirected synthesis of G-type CWNAs produces stereoisomers of tabun, sarin, soman, and cyclosarin (GA, GB, GD, and GF, respectively). Analytical-scale methods were developed using a supercritical fluid chromatography (SFC) system in tandem with a mass spectrometer for the separation, quantitation, and isolation of individual stereoisomers of GA, GB, GD, and GF. Screening various chiral stationary phases (CSPs) for the capacity to provide full baseline separation of the CWNAs revealed that a Regis WhelkO1 (SS) column was capable of separating the enantiomers of GA, GB, and GF, with elution of the P(+) enantiomer preceding elution of the corresponding P(-) enantiomer; two WhelkO1 (SS) columns had to be connected in series to achieve complete baseline resolution. The four diastereomers of GD were also resolved using two tandem WhelkO1 (SS) columns, with complete baseline separation of the two P(+) epimers. A single WhelkO1 (RR) column with inverse stereochemistry resulted in baseline separation of the GD P(-) epimers. The analytical methods described can be scaled to allow isolation of individual stereoisomers to assist in screening and development of countermeasures to organophosphorus nerve agents.

  14. Quantification of nerve agent VX-butyrylcholinesterase adduct biomarker from an accidental exposure.

    PubMed

    Solano, Maria I; Thomas, Jerry D; Taylor, James T; McGuire, Jeffrey M; Jakubowski, Edward M; Thomson, Sandra A; Maggio, Vincent L; Holland, Kerry E; Smith, J Richard; Capacio, Benedict; Woolfitt, Adrian R; Ashley, David L; Barr, John R

    2008-01-01

    The lack of data in the open literature on human exposure to the nerve agent O-ethyl-S-(2-diisopropylaminoethyl) methylphosphonothioate (VX) gives a special relevance to the data presented in this study in which we report the quantification of VX-butyrylcholinesterase adduct from a relatively low-level accidental human exposure. The samples were analyzed by gas chromatography-high resolution mass spectrometry using the fluoride ion regeneration method for the quantification of multiple nerve agents including VX. Six human plasma samples from the same individual were collected after the patient had been treated once with oxime immediately after exhibiting signs of exposure. Detection limits of approximately 5.5 pg/mL plasma were achieved for the G-analogue of VX (G-VX). Levels of the G-VX ranged from 81.4 pg/mL on the first day after the exposure to 6.9 pg/mL in the sample taken 27 days after the exposure. Based on the reported concentration of human butyrylcholinesterase in plasma of approximately 80 nM, it can be calculated that inhibition levels of >or= 0.05% of BuChE can be accurately quantified. These data further indicate that the fluoride ion regeneration method is a potentially powerful tool that can be used to assess low-level exposure to VX.

  15. The noncontact detection of nerve agent simulants on U.S. military CARC

    NASA Astrophysics Data System (ADS)

    Petryk, Michael W. P.

    2009-05-01

    The non-contact detection of chemical warfare agent simulants is achieved in the condensed phase using polarization modulation infrared reflection-absorption spectroscopy (PMIRRAS). The G-series nerve agent simulants, trimethyl phosphate (TMP) and triethyl phosphate (TEP), are detected on US military chemical agent resistant coating (CARC) using PMIRRAS. Optimal detector angles for PMIRRAS are determined, as are absorption features which can be used to distinguish between the spectral contributions of the substrate (CARC) and the analyte (TMP or TEP). Ab initio calculations carried out at the B3LYP / 6-31G(d,p) level of theory and basis set are used to predict the most stable simulant conformations, and their harmonic (unscaled) vibrational frequencies. Ab initio vibrational frequency data is used to explain the existence of both upward-oriented and downward-oriented PMIRRAS absorption features in terms of molecular orientation at a surface and the orientation of the dipole derivative vector of a given vibrational mode.

  16. Characterizing biological variability in livestock blood cholinesterase activity for biomonitoring organophosphate nerve agent exposure

    SciTech Connect

    Halbrook, R.S.; Shugart, L.R.; Watson, A.P.; Munro, N.B.; Linnabary, R.D. )

    1992-09-01

    A biomonitoring protocol, using blood cholinesterase (ChE) activity in livestock as a monitor of potential organophosphate nerve agent exposure during the planned destruction of US unitary chemical warfare agent stockpiles, is described. The experimental design included analysis of blood ChE activity in individual healthy sheep, horses, and dairy and beef cattle during a 10- to 12-month period. Castrated and sexually intact males, pregnant and lactating females, and adult and immature animals were examined through at least one reproductive cycle. The same animals were used throughout the period of observation and were not exposed to ChE-inhibiting organophosphate or carbamate compounds. A framework for an effective biomonitoring protocol within a monitoring area includes establishing individual baseline blood ChE activity for a sentinel group of 6 animals on the bases of blood samples collected over a 6-month period, monthly collection of blood samples for ChE-activity determination during monitoring, and selection of adult animals as sentinels. Exposure to ChE-inhibiting compounds would be suspected when all blood ChE activity of all animals within the sentinel group are decreased greater than 20% from their own baseline value. Sentinel species selection is primarily a logistical and operational concern; however, sheep appear to be the species of choice because within-individual baseline ChE activity and among age and gender group ChE activity in sheep had the least variability, compared with data from other species. This protocol provides an effective and efficient means for detecting abnormal depressions in blood ChE activity in livestock and can serve as a valuable indicator of the extent of actual plume movement and/or deposition in the event of organophosphate nerve agent release.

  17. Agent Orange

    MedlinePlus

    ... Index Agent Orange Agent Orange Home Facts about Herbicides Veterans' Diseases Birth Defects Benefits Exposure Locations Provider ... Orange Parkinson’s Awareness Month Were you exposed to herbicides during service and have Parkinson’s disease? You may ...

  18. Chemical warfare agents.

    PubMed

    Kuca, Kamil; Pohanka, Miroslav

    2010-01-01

    Chemical warfare agents are compounds of different chemical structures. Simple molecules such as chlorine as well as complex structures such as ricin belong to this group. Nerve agents, vesicants, incapacitating agents, blood agents, lung-damaging agents, riot-control agents and several toxins are among chemical warfare agents. Although the use of these compounds is strictly prohibited, the possible misuse by terrorist groups is a reality nowadays. Owing to this fact, knowledge of the basic properties of these substances is of a high importance. This chapter briefly introduces the separate groups of chemical warfare agents together with their members and the potential therapy that should be applied in case someone is intoxicated by these agents.

  19. Development of a surface acoustic wave gas sensor for organophosphorus nerve agents employing lanthanide compounds as the chemical interface.

    PubMed

    Nieuwenhuizen, M S; Harteveld, J L

    1994-03-01

    The results of a study dealing with surface acoustic wave gas sensors for organophosphorus compounds such as nerve agents are described. Several lanthanum coordination compounds were applied as the chemical interface. The various sensors prepared were challenged with both the nerve agent sarin and the simulant dimethyl methylphosphonate. Many aspects were studied, such as sensitivity, selectivity, reversibility and response rate as well as the effect of temperature and structural features. Detection limits down to 0.1 ppm were found. Response rates require further improvement. Degradation phenomena were observed which in some cases yielded irreversible responses. The selectivity for organophosphorus compounds was found to be promising.

  20. Impurity Profiling to Match a Nerve Agent to Its Precursor Source for Chemical Forensics Applications

    SciTech Connect

    Fraga, Carlos G.; Perez Acosta, Gabriel A.; Crenshaw, Michael D.; Wallace, Krys; Mong, Gary M.; Colburn, Heather A.

    2011-10-31

    Chemical forensics is an emerging field in homeland security that aims to attribute a weaponized toxic chemical or related material to its source. Herein, for the first time, trace impurities originating from a chemical precursor were used to match a synthesized nerve agent to its precursor source. Specifically, multiple batches of sarin and its intermediate were synthesized from two commercial stocks of methylphosphonic dichloride (DC) and were then matched by impurity profiling to their DC stocks from out of five possible stocks. This was possible because each DC stock had a unique impurity profile that, for the tested stocks, persisted through synthesis, decontamination, and sample preparation. This work may form a basis for using impurity profiling to help find and prosecute perpetrators of chemical attacks.

  1. Comparison of the lethal effects of chemical warfare nerve agents across multiple ages.

    PubMed

    Wright, Linnzi K M; Lee, Robyn B; Vincelli, Nicole M; Whalley, Christopher E; Lumley, Lucille A

    2016-01-22

    Children may be inherently more vulnerable than adults to the lethal effects associated with chemical warfare nerve agent (CWNA) exposure because of their closer proximity to the ground, smaller body mass, higher respiratory rate, increased skin permeability and immature metabolic systems. Unfortunately, there have only been a handful of studies on the effects of CWNA in pediatric animal models, and more research is needed to confirm this hypothesis. Using a stagewise, adaptive dose design, we estimated the 24h median lethal dose for subcutaneous exposure to seven CWNA in both male and female Sprague-Dawley rats at six different developmental times. Perinatal (postnatal day [PND] 7, 14 and 21) and adult (PND 70) rats were more susceptible than pubertal (PND 28 and 42) rats to the lethal effects associated with exposure to tabun, sarin, soman and cyclosarin. Age-related differences in susceptibility were not observed in rats exposed to VM, Russian VX or VX.

  2. A Comparative Toxidrome Analysis of Human Organophosphate and Nerve Agent Poisonings Using Social Media.

    PubMed

    Reddy, D S; Colman, E

    2017-02-26

    Here we utilized social media to compare the toxidrome of three lethal chemical exposures worldwide. YouTube videos were the main source from which the data were collected, but published reports and news were also utilized to fill in some gaps. All videos were organized in a database detailing symptoms and severity of each victim, along with demographics such as approximate age and gender. Each symptom was rated as mild, moderate, or severe and corresponding pie graphs for each incident were compared. The videos displayed symptoms ranging from mild to severe cholinergic toxicity and life-threatening convulsions. Social media may represent an important resource in developing a viable approach to the early detection and identification of chemical exposure, reinforce our preparedness for better antidotes, long-term follow up, and training about deadly chemical nerve agent attacks.

  3. Gas sensor based on nano ZSM-5 zeolite films for the nerve agent simulant dimethylmethylphosphonate detection

    NASA Astrophysics Data System (ADS)

    Xie, Haifen; Ting, Yu; Sun, Xiaoxiang; Jia, Zhou; Huang, Yiping

    2004-12-01

    The piezoelectric sensor device coated with nanosize ZSM-5 zeolite films has beem fabricated. The Nerve agent simulant Dimethylmethylphosphonate has been tested with this piezoelectric sensor devices. The frequency shifts to time at 1 ppm, 5ppm and 20ppm DMMP are examined respectively. The minimum detection concentration of 1ppm DMMP has been obtained in the N2 at 293K. 1 ppm is lower than the EC50 concentration value (where EC50 is the airborne concentration sufficient to induce severe effects in 50% of those exposed for 30 min). The frequency sensitivity was found to be about 60HZ / ppm. The effect of acetone on the ZSM-5 zeolite film was also investigated for the selectivity test. Using principle component analysis (PCA), we can qualify and quantify these testing gases.

  4. Direct derivatization and rapid GC-MS screening of nerve agent markers in aqueous samples.

    PubMed

    Subramaniam, Raja; Astot, Crister; Juhlin, Lars; Nilsson, Calle; Ostin, Anders

    2010-09-01

    A rapid screening and identification method based on derivatization and gas chromatography mass spectrometry (GC-MS) has been developed for the detection of alkylphosphonic acids (APAs), the degradation products of organophosphorus nerve agents. The novel method described involves rapid (5 min) and direct derivatization of 25 microL aqueous sample using highly fluorinated phenyldiazomethane reagents (e.g., 1-(diazomethyl)-3,5-bis(trifluoromethyl)benzene). The APA derivatives are then screened by GC-MS negative ion chemical ionization (NICI) and identified by electron ionization (EI) mode. The conditions for the derivatization were optimized using statistical experimental design and multivariate data analysis. Method robustness was evaluated using aqueous samples from an official OPCW Proficiency Test and all APAs present in the sample were conclusively identified. Limits of detection for rapid screening using SIM NICI were between 5 and 10 ng/mL APA in aqueous sample, and for identification using full scan EI 100 ng/mL.

  5. Detoxification of organophosphorus pesticides and nerve agents through RSDL: efficacy evaluation by (31)P NMR spectroscopy.

    PubMed

    Elsinghorst, Paul W; Worek, Franz; Koller, Marianne

    2015-03-04

    Intoxication by organophosphorus compounds, especially by pesticides, poses a considerable risk to the affected individual. Countermeasures involve both medical intervention by means of antidotes as well as external decontamination to reduce the risk of dermal absorption. One of the few decontamination options available is Reactive Skin Decontamination Lotion (RSDL), which was originally developed for military use. Here, we present a (31)P NMR spectroscopy based methodology to evaluate the detoxification efficacy of RSDL with respect to a series of organophosphorus pesticides and nerve agents. Kinetic analysis of the obtained NMR data provided degradation half-lives proving that RSDL is also reasonably effective against organophosphorus pesticides. Unexpected observations of different RSDL degradation patterns are presented in view of its reported oximate-catalyzed mechanism of action.

  6. [Terror in Japan: mass-intoxication with the nerve-agent sarin].

    PubMed

    Solberg, Y; Nachtomi-Shick, O; Shemer, Y; Alcalay, M

    1998-10-01

    During 1994/5 the Japanese civilian population suffered 2 terror attacks by the organophosphorus nerve-agent sarin. In these 2 episodes it is estimated that more than 6000 people were injured, of whom 19 died. The quick and efficient response of the civilian emergency systems to these unforeseen, attacks has to be analyzed by local authorities to determine the best solutions in case of another attack. We summarize the events, and note the emergency system's response, the need for rapid and accurate chemical identification of the toxin, the necessity for decontaminating the casualties and for providing protective gear for rescue units in the contaminated area. We also describe the clinical status of the casualties and outline the mode of therapy applied.

  7. Trapping of organophosphorus chemical nerve agents in water with amino acid functionalized baskets.

    PubMed

    Ruan, Yian; Dalkiliç, Erdin; Peterson, Paul W; Pandit, Aroh; Dastan, Arif; Brown, Jason D; Polen, Shane M; Hadad, Christopher M; Badjić, Jovica D

    2014-04-07

    We prepared eleven amino-acid functionalized baskets and used (1) H NMR spectroscopy to quantify their affinity for entrapping dimethyl methylphosphonate (DMMP, 118 Å(3) ) in aqueous phosphate buffer at pH=7.0±0.1; note that DMMP guest is akin in size to chemical nerve agent sarin (132 Å(3) ). The binding interaction (Ka ) was found to vary with the size of substituent groups at the basket's rim. In particular, the degree of branching at the first carbon of each substituent had the greatest effect on the host-guest interaction, as described with the Verloop's B1 steric parameter. The branching at the remote carbons, however, did not perturb the encapsulation, which is important for guiding the design of more effective hosts and catalysts in future.

  8. Showering effectiveness for human hair decontamination of the nerve agent VX.

    PubMed

    Josse, Denis; Wartelle, Julien; Cruz, Catherine

    2015-05-05

    In this work, our goals were to establish whether hair decontamination by showering one hour post-exposure to the highly toxic organophosphate nerve agent VX was effective, whether it required the addition of a detergent to water and, if it could be improved by using the adsorbent Fuller's Earth (FE) or the Reactive Skin Decontamination Lotion (RSDL) 30 min prior to showering. Hair exposure to VX and decontamination was performed by using an in vitro model. Hair showering led to 72% reduction of contamination. Addition of detergent to water slightly increased the decontamination effectiveness. Hair treatment with FE or RSDL improved the decontamination rate. Combination of FE use and showering, which yielded a decontamination factor of 41, was demonstrated to be the most effective hair decontamination procedure. Hair wiping after showering was shown to contribute to hair decontamination. Altogether, our results highlighted the importance of considering hair decontamination as an important part of body surface decontamination protocols.

  9. Nerve Agent Exposure Elicits Site-Specific Changes in Protein Phosphorylation in Mouse Brain

    PubMed Central

    Zhu, Hongwen; O’Brien, Jennifer J.; O’Callaghan, James P.; Miller, Diane B.; Zhang, Qiang; Rana, Minal; Tsui, Tiffany; Peng, Youyi; Tomesch, John; Hendrick, Joseph P.; Wennogle, Lawrence P; Snyder, Gretchen L.

    2010-01-01

    Organophosphorus (OP) compounds cause toxic symptoms, including convulsions, coma, and death, as the result of irreversible inhibition of acetylcholinesterase (AChE). The development of effective treatments to block these effects and attenuate long-term cognitive and motor disabilities that result from OP intoxication is hampered by a limited understanding of the CNS pathways responsible for these actions. We employed a candidate method (called CNSProfile™) to identify changes in the phosphorylation state of key neuronal phosphoproteins evoked by the OP compound, diisopropyl fluorophosphate (DFP). Focused microwave fixation was used to preserve the phosphorylation state of phosphoproteins in brains of DFP-treated mice; hippocampus and striatum were analyzed by immunoblotting with a panel of phospho-specific antibodies. DFP exposure elicited comparable effects on phosphorylation of brain phosphoproteins in both C57BL/6 and FVB mice. DFP treatment significantly altered phosphorylation at regulatory residues on glutamate receptors, including Serine897 (S897) of the NR1 NMDA receptor. NR1 phosphorylation was bi-directionally regulated after DFP in striatum versus hippocampus. NR1 phosphorylation was reduced in striatum, but elevated in hippocampus, compared with controls. DARPP-32 phosphorylation in striatum was selectively increased at the Cdk5 kinase substrate, Threonine75 (T75). Phencynonate hydrochloride, a muscarinic cholinergic antagonist, prevented seizure-like behaviors and the observed changes in phosphorylation induced by DFP. The data reveal region-specific effects of nerve agent exposure on intracellular signaling pathways that correlate with seizure-like behavior and which are reversed by the muscarinic receptor blockade. This approach identifies specific targets for nerve agents, including substrates for Cdk5 kinase, which may be the basis for new anti-convulsant therapies. PMID:20423708

  10. CATALYTIC DETOXIFICATION OF NERVE AGENT AND PESTICIDE ORGANOPHOSPHATES BY BUTYRYLCHOLINESTERASE ASSISTED WITH NON-PYRIDINIUM OXIMES

    PubMed Central

    Radić, Zoran; Dale, Trevor; Kovarik, Zrinka; Berend, Suzana; Garcia, Edzna; Zhang, Limin; Amitai, Gabriel; Green, Carol; Radić, Božica; Duggan, Brendan M.; Ajami, Dariush; Rebek, Julius; Taylor, Palmer

    2016-01-01

    SYNOPSIS We present here a comprehensive in vitro, ex vivo and in vivo study on hydrolytic detoxification of nerve agent and pesticide organophosphates (OPs) catalyzed by purified human butyrylcholinesterase (hBChE) in combination with novel non-pyridinium oxime reactivators. We identified 2-trimethylammonio-6-hydroxybenzaldehyde oxime (TAB2OH) as an efficient reactivator of OP-hBChE conjugates formed by the nerve agents, VX and cyclosarin, and the pesticide, paraoxon. It was also functional in reactivation of sarin and tabun inhibited hBChE. A three to five-fold enhancement of in vitro reactivation of VX, cyclosarin and paraoxon inhibited hBChE was observed, when compared to the commonly used N-methylpyridinium aldoxime reactivator, 2PAM. Kinetic analysis showed the enhancement resulted from improved molecular recognition of corresponding OP-hBChE conjugates by TAB2OH. The unique features of TAB2OH stem from an exocyclic quaternary nitrogen and a hydroxyl, both ortho to an oxime group on a benzene ring. pH dependences reveal participation of the hydroxyl (pKa=7.6) forming an additional ionizing nucleophile to potentiate the oxime (pKa=10) at physiological pH. The TAB2OH protective indices in therapy of sarin and paraoxon exposed mice were enhanced by 30% – 60% when they were treated with a combination of TAB2OH and sub-stoichiometric hBChE. These results establish that oxime-assisted catalysis is feasible for OP bioscavenging. PMID:23216060

  11. Good manufacturing practice: manufacturing of a nerve agent antidote nanoparticle suspension.

    PubMed

    Clark, Andrew P-Z; Dixon, Hong; Cantu, Norma L; Cabell, Larry A; McDonough, Joe A

    2013-01-01

    We have established a current good manufacturing practice (GMP) manufacturing process to produce a nanoparticle suspension of 1,1'-methylenebis-4-[(hydroxyimino)methyl]pyridinium dimethanesulfonate (MMB4 DMS) in cottonseed oil (CSO) as a nerve agent antidote for a Phase 1 clinical trial. Bis-pyridinium oximes such as MMB4 were previously developed for emergency treatment of organophosphate nerve agent intoxication. Many of these compounds offer efficacy superior to monopyridinium oximes, but they have poor thermal stability due to hydrolytic cleavage in aqueous solution. We previously developed a nonaqueous nanoparticle suspension to improve the hydrothermal stability, termed Enhanced Formulation (EF). An example of this formulation technology is a suspension of MMB4 DMS nanoparticles in CSO. Due to the profound effect of particle size distribution on product quality and performance, particle size must be controlled during the manufacturing process. Therefore, a particle size analysis method for MMB4 DMS in CSO was developed and validated to use in support of good laboratory practice/GMP development and production activities. Manufacturing of EF was accomplished by milling MMB4 DMS with CSO and zirconia beads in an agitator bead mill. The resulting bulk material was filled into 5-mL glass vials at a sterile fill facility and terminally sterilized by gamma irradiation. The clinical lot was tested and released, a Certificate of Analysis was issued, and a 3-year International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) stability study started. The drug product was placed in storage for Phase 1 clinical trial distribution. A dose delivery uniformity study was undertaken to ensure that the correct doses were delivered to the patients in the clinic.

  12. Antiparkinson drugs used as prophylactics for nerve agents: studies of cognitive side effects in rats.

    PubMed

    Myhrer, Trond; Enger, Siri; Aas, Pål

    2008-06-01

    Antiparkinson agents possess excellent anticonvulsant properties against nerve agent-induced seizures by exerting both cholinergic and glutamatergic antagonisms. It is important, however, that drugs used as prophylactics not by themselves cause impairment of cognitive capability. The purpose of the present study was to make a comparative assessment of potential cognitive effects of benactyzine (0.3 mg/kg), biperiden (0.11 mg/kg), caramiphen (10 mg/kg), procyclidine (3 mg/kg), and trihexyphenidyl (0.12 mg/kg) separately and each in combination with physostigmine (0.1 mg/kg). The results showed that benactyzine, caramiphen, and trihexyphenidyl reduced rats' innate preference for novelty, whereas biperiden and procyclidine did not. When benactyzine, caramiphen, and trihexyphenidyl were combined with physostigmine the cognitive impairment disappeared. This counteracting effect, however, caused changes in locomotor and rearing activities not seen by each drug alone. Acetylcholinesterase inhibitors and anticholinergics used as prophylactics can offset each other, but exceptions are observed in a previous study when a very potent anticholinergic (scopolamine) or a high dose of procyclidine still results in cognitive deficits in spite of coadministration with physostigmine. Among the present drugs tested, procyclidine appears to be a robust anticonvulsant with few cognitive side effects.

  13. Detection and classification of organophosphate nerve agent simulants using support vector machines with multiarray sensors.

    PubMed

    Sadik, Omowunmi; Land, Walker H; Wanekaya, Adam K; Uematsu, Michiko; Embrechts, Mark J; Wong, Lut; Leibensperger, Dale; Volykin, Alex

    2004-01-01

    The need for rapid and accurate detection systems is expanding and the utilization of cross-reactive sensor arrays to detect chemical warfare agents in conjunction with novel computational techniques may prove to be a potential solution to this challenge. We have investigated the detection, prediction, and classification of various organophosphate (OP) nerve agent simulants using sensor arrays with a novel learning scheme known as support vector machines (SVMs). The OPs tested include parathion, malathion, dichlorvos, trichlorfon, paraoxon, and diazinon. A new data reduction software program was written in MATLAB V. 6.1 to extract steady-state and kinetic data from the sensor arrays. The program also creates training sets by mixing and randomly sorting any combination of data categories into both positive and negative cases. The resulting signals were fed into SVM software for "pairwise" and "one" vs all classification. Experimental results for this new paradigm show a significant increase in classification accuracy when compared to artificial neural networks (ANNs). Three kernels, the S2000, the polynomial, and the Gaussian radial basis function (RBF), were tested and compared to the ANN. The following measures of performance were considered in the pairwise classification: receiver operating curve (ROC) Az indices, specificities, and positive predictive values (PPVs). The ROC Az) values, specifities, and PPVs increases ranged from 5% to 25%, 108% to 204%, and 13% to 54%, respectively, in all OP pairs studied when compared to the ANN baseline. Dichlorvos, trichlorfon, and paraoxon were perfectly predicted. Positive prediction for malathion was 95%.

  14. In vivo decontamination of the nerve agent VX using the domestic swine model.

    PubMed

    Misik, Jan; Pavlik, Michal; Novotny, Ladislav; Pavlikova, Ruzena; Chilcott, Robert P; Cabal, Jiri; Kuca, Kamil

    2012-11-01

    The purpose of this in vivo study was to assess a new, putatively optimised method for mass casualty decontamination ("ORCHIDS protocol") for effectiveness in removing the chemical warfare agent VX from the skin of anaesthetised, domestic white pigs. ORCHIDS protocol consists of a 1.5-minute shower with a mild detergent (Argos™) supplemented by physical removal. A standard method of wet decontamination was used for comparison. Experimental animals were divided into four groups (A-D). Two groups were exposed to a supra-lethal percutaneous dose (5 × LD(50); 300 μg kg(-1)) of VX for 1 h prior to decontamination with either the ORCHIDS (C) or standard protocol (D). A third (B, positive control) group was exposed but not subject to decontamination. Blank controls (A) received anaesthesia and the corresponding dose of normal saline instead of VX. Observations of the clinical signs of intoxication were supplemented by measurements of whole blood cholinesterase (ChE) performed on samples of arterial blood acquired at 30-minute intervals for the duration of the study (up to 6 h). Untreated (B) animals displayed typical cholinergic signs consistent with VX intoxication (local fasciculation, mastication, salivation, pilo-erection and motor convulsions) and died 165-240 min post exposure. All animals in both decontamination treatment groups (C, D) survived the duration of the study and exhibited less severe signs of cholinergic poisoning. Thus, both the standard and ORCHIDS protocol were demonstrably effective against exposure to the potent nerve agent VX, even after a delay of 1 h. A critical advantage of the ORCHIDS protocol is the relatively short shower duration (1½ min compared to 3 min). In practice, this could substantially improve the rate at which individuals could be decontaminated by emergency responders following exposure to toxic materials such as chemical warfare agents.

  15. Fragmentation pathways and structural characterization of 14 nerve agent compounds by electrospray ionization tandem mass spectrometry.

    PubMed

    Housman, Kathleen J; Swift, Austin T; Oyler, Jonathan M

    2015-03-01

    Organophosphate nerve agents (OPNAs) are some of the most widely used and proliferated chemical warfare agents. As evidenced by recent events in Syria, these compounds remain a serious military and terrorist threat to human health because of their toxicity and the ease with which they can be used, produced and stored. There are over 2,000 known, scheduled compounds derived from common parent structures with many more possible. To address medical, forensic, attribution, remediation and other requirements, laboratory systems have been established to provide the capability to analyze 'unknown' samples for the presence of these compounds. Liquid chromatography/mass spectrometric methods have been validated and are routinely used in the analysis of samples for a very limited number of these compounds, but limited data exist characterizing the electrospray ionization (ESI) and mass spectrometric fragmentation pathways of the compound families. This report describes results from direct infusion ESI/MS, ESI/MS(2) and ESI/MS(3) analysis of 14 G and V agents, the major OPNA families, using an AB Sciex 4000 QTrap. Using a range of conditions, spectra were acquired and characteristic fragments identified. The results demonstrated that the reproducible and predictable fragmentation of these compounds by ESI/MS, ESI/MS(2) and ESI/MS(3) can be used to describe systematic fragmentation pathways specific to compound structural class. These fragmentation pathways, in turn, may be useful as a predictive tool in the analysis of samples by screening and confirmatory laboratories to identify related compounds for which authentic standards are not readily available.

  16. Advances in toxicology and medical treatment of chemical warfare nerve agents

    PubMed Central

    2012-01-01

    Organophosphorous (OP) Nerve agents (NAs) are known as the deadliest chemical warfare agents. They are divided into two classes of G and V agents. Most of them are liquid at room temperature. NAs chemical structures and mechanisms of actions are similar to OP pesticides, but their toxicities are higher than these compounds. The main mechanism of action is irreversible inhibition of Acetyl Choline Esterase (AChE) resulting in accumulation of toxic levels of acetylcholine (ACh) at the synaptic junctions and thus induces muscarinic and nicotinic receptors stimulation. However, other mechanisms have recently been described. Central nervous system (CNS) depression particularly on respiratory and vasomotor centers may induce respiratory failure and cardiac arrest. Intermediate syndrome after NAs exposure is less common than OP pesticides poisoning. There are four approaches to detect exposure to NAs in biological samples: (I) AChE activity measurement, (II) Determination of hydrolysis products in plasma and urine, (III) Fluoride reactivation of phosphylated binding sites and (IV) Mass spectrometric determination of cholinesterase adducts. The clinical manifestations are similar to OP pesticides poisoning, but with more severity and fatalities. The management should be started as soon as possible. The victims should immediately be removed from the field and treatment is commenced with auto-injector antidotes (atropine and oximes) such as MARK I kit. A 0.5% hypochlorite solution as well as novel products like M291 Resin kit, G117H and Phosphotriesterase isolated from soil bacterias, are now available for decontamination of NAs. Atropine and oximes are the well known antidotes that should be infused as clinically indicated. However, some new adjuvant and additional treatment such as magnesium sulfate, sodium bicarbonate, gacyclidine, benactyzine, tezampanel, hemoperfusion, antioxidants and bioscavengers have recently been used for OP NAs poisoning. PMID:23351280

  17. Radioactive diagnostic agent

    SciTech Connect

    Shigematsu, A.; Aihara, M.; Matsuda, M.; Suzuki, A.; Tsuya, A.

    1984-02-07

    A radioactive diagnostic agent for renal cortex, adrenal cortex, myocardium, brain stem, spinal nerve, etc., which comprises as an essential component monoiodoacetic acid wherein the iodine atom is radioactive.

  18. Comparison of High Resolution and Tandem Mass Spectrometry for the Analysis of Nerve Agent Metabolites in Urine

    PubMed Central

    Hamelin, Elizabeth I.; Bragg, William; Shaner, Rebecca L.; Swaim, Leigh L.; Johnson, Rudolph C.

    2015-01-01

    Rationale Although use is prohibited, concerns remain for human exposure to nerve agents during decommissioning, research, and warfare. High-resolution mass spectrometry (HRMS) was compared to tandem mass spectrometry (MS/MS) analysis for the quantitation of five urinary metabolites specific to VX, Russian VX, soman, sarin and cyclosarin nerve agents. The HRMS method was further evaluated for qualitative screening of metabolites not included in the test panel. Methods Nerve agent metabolites were extracted from urine using solid phase extraction, separated using hydrophilic interaction chromatography and analyzed using both tandem and high resolution mass spectrometry. MS/MS results were obtained using selected reaction monitoring with unit resolution; HRMS results were obtained using a mass extraction window of 10 ppm at a mass resolution of 50,000. The benchtop Orbitrap HRMS instrument was operated in full scan mode, to measure the presence of unexpected agents. Results The assessment of two quality control samples demonstrated high accuracy (99.5-104%) and high precision (2-9%) for both HRMS and MS/MS. Sensitivity, as described by the limit of detection, was overlapping for both detectors (0.2-0.7 ng/mL). Additionally, the HRMS method positively confirmed the presence of a nerve agent metabolite, not included in the test panel, using the accurate mass and relative retention time. Conclusions The precision, accuracy, and sensitivity were comparable between the current MS/MS method and this newly developed HRMS analysis for five nerve agent metabolites. HRMS showed additional capabilities beyond the current method by confirming the presence of a metabolite not included in the test panel. PMID:23821563

  19. Improving the promiscuous nerve agent hydrolase activity of a thermostable archaeal lactonase.

    PubMed

    Merone, Luigia; Mandrich, Luigi; Porzio, Elena; Rossi, Mosé; Müller, Susanne; Reiter, Georg; Worek, Franz; Manco, Giuseppe

    2010-12-01

    The thermostable Phosphotriesterase-Like Lactonase from Sulfolobus solfataricus (SsoPox) hydrolyzes lactones and, at a lower rate, neurotoxic organophosphorus compounds. The persistent demand of detoxification tools in the field of agricultural wastes and restoring of conditions after terrorist acts prompted us to exploit SsoPox as a "starter" to evolve its ancillary nerve agents hydrolytic capability. A directed evolution strategy yielded, among several variants, the single mutant W263F with k(cat) and specificity constant against paraoxon 16- and 6-fold enhanced, respectively, compared to the wild type. Furthermore, a phenomenon of enzyme activation by SDS has been observed, which allowed to increase those values 150- and 28-fold, respectively. The activity of SsoPox against the deadly nerve gas Cyclosarin has been reported for the first time and proved to be substantially unaffected for variant W263F. Finally, outperforming efficiency of W263F was demonstrated, under severe stressing conditions, with respect to the best known phosphotriesterase PTE from Brevundimonas diminuta.

  20. AMPEROMETRIC THICK-FILM STRIP ELECTRODES FOR MONITORING ORGANOPHOSPHATE NERVE AGENTS BASED ON IMMOBILIZED ORGANOPHOSPHORUS HYDROLASE. (R823663)

    EPA Science Inventory

    An amperometric biosensor based on the immobilization of organophosphorus hydrolase
    (OPH) onto screen-printed carbon electrodes is shown useful for the rapid, sensitive, and low-cost
    detection of organophosphate (OP) nerve agents. The sensor relies upon the sensitive and ra...

  1. Quantitation of five organophosphorus nerve agent metabolites in serum using hydrophilic interaction liquid chromatography and tandem mass spectrometry.

    PubMed

    Hamelin, Elizabeth I; Schulze, Nicholas D; Shaner, Rebecca L; Coleman, Rebecca M; Lawrence, Richard J; Crow, Brian S; Jakubowski, E M; Johnson, Rudolph C

    2014-08-01

    Although nerve agent use is prohibited, concerns remain for human exposure to nerve agents during decommissioning, research, and warfare. Exposure can be detected through the analysis of hydrolysis products in urine as well as blood. An analytical method to detect exposure to five nerve agents, including VX, VR (Russian VX), GB (sarin), GD (soman), and GF (cyclosarin), through the analysis of the hydrolysis products, which are the primary metabolites, in serum has been developed and characterized. This method uses solid-phase extraction coupled with high-performance liquid chromatography for separation and isotopic dilution tandem mass spectrometry for detection. An uncommon buffer of ammonium fluoride was used to enhance ionization and improve sensitivity when coupled with hydrophilic interaction liquid chromatography resulting in detection limits from 0.3 to 0.5 ng/mL. The assessment of two quality control samples demonstrated high accuracy (101-105%) and high precision (5-8%) for the detection of these five nerve agent hydrolysis products in serum.

  2. Direct derivatization and gas chromatography-tandem mass spectrometry identification of nerve agent biomarkers in urine samples.

    PubMed

    Subramaniam, Raja; Östin, Anders; Nilsson, Calle; Åstot, Crister

    2013-06-01

    Rapid determination of nerve agent biomarkers at low-ppb levels in urine samples was achieved by direct derivatization and sample analysis using gas chromatography-tandem mass spectrometry. The studied biomarkers were alkylphosphonic acids (APAs), as they are specific hydrolysis products of organophosphorus nerve agents that can be used to verify nerve agent exposure. The sample preparation technique employed involves rapid direct derivatization (5min) of acidified urine samples (25μL) using a highly fluorinated phenyldiazomethane reagent [1-(diazomethyl)-3,5-bis(trifluoromethyl)benzene]. The derivatization conditions were optimized using statistical experimental design and multivariate data analysis. The APA derivatives were analyzed by GC-MS and MS/MS using negative ion chemical ionization. The selectivity and sensitivity of analyses performed by low and high resolution single ion monitoring MS-mode were compared with those performed by multiple reaction monitoring MS/MS-mode. The MS/MS technique offered the greatest sensitivity and selectivity of the tested mass spectrometric techniques, with limits of detection ranging from 0.5 to 1ng APAs/mL of urine. The method's robustness was evaluated using urine samples from the OPCW 2nd biomedical confidence building exercise and all APAs present in the samples were conclusively identified. The method thus offers excellent performance and is viable for the simultaneous trace determination of a wide range of nerve agent markers.

  3. Supralethal poisoning by any of the classical nerve agents is effectively counteracted by procyclidine regimens in rats.

    PubMed

    Myhrer, Trond; Mariussen, Espen; Enger, Siri; Aas, Pål

    2015-09-01

    A treatment regimen consisting of HI-6, levetiracetam, and procyclidine (termed the triple regimen) has previously been shown to work as a universal therapy against soman poisoning in rats, since it has capacities to function as both prophylactic and therapeutic measure. The purpose of the present study was to examine whether the triple regimen may have antidotal efficacy against intoxication by other classical nerve agents than soman. The treatment was given 1 and 5 min after exposure to a supralethal dose of nerve agents, and the results showed that the triple regimen successfully prevented or terminated seizures and preserved the lives of rats exposed to 5×LD50 of soman, sarin, cyclosarin, or VX, but solely 3×LD50 of tabun was managed by this regimen. To meet the particular antidotal requirements of tabun, the triple regimen was reinforced with obidoxime and was made to a quadruple regimen that effectively treated rats intoxicated by 5×LD50 of tabun. The rats recovered very well and the majority gained pre-exposure body weight within 7 days. Neuropathology was seen in all groups regardless of whether the rats seized or not. The most extensive damage was produced by sarin and cyclosarin. Differentiation between the nerve agents' potency to cause lesions was probably seen because the efficacious treatments ensured survival of supralethal poisoning. A combination of 2 oximes and 2 anticonvulsants may be a prerequisite to counteract effectively high levels of poisoning by any classical nerve agent.

  4. Quantitation of five organophosphorus nerve agent metabolites in serum using hydrophilic interaction liquid chromatography and tandem mass spectrometry

    PubMed Central

    Hamelin, Elizabeth I.; Schulze, Nicholas D.; Shaner, Rebecca L.; Coleman, Rebecca M.; Lawrence, Richard J.; Crow, Brian S.; Jakubowski, E. M.; Johnson, Rudolph C.

    2015-01-01

    Although nerve agent use is prohibited, concerns remain for human exposure to nerve agents during decommissioning, research, and warfare. Exposure can be detected through the analysis of the hydrolysis products in urine as well as blood. An analytical method to detect exposure to five nerve agents, including VX, VR (Russian VX), GB (sarin), GD (soman) and GF (cyclosarin), through the analysis of the hydrolysis products, which are the primary metabolites, in serum has been developed and characterized. This method uses solid phase extraction coupled with high performance liquid chromatography for separation and isotopic dilution tandem mass spectrometry for detection. An uncommon buffer of ammonium fluoride was used to enhance ionization and improve sensitivity when coupled with hydrophilic interaction liquid chromatography resulting in detection limits from 0.3–0.5 ng/mL. The assessment of two quality control samples demonstrated high accuracy (101–105%) and high precision (5–8%) for the detection of these five nerve agent hydrolysis products in serum. PMID:24633507

  5. Bis(dialkylamide)hydrogen dibromobromate precursors of hypobromite ion in reactions with nerve and blister agent simulants.

    PubMed

    Simanenko, Yuri S; Savelova, Vera A; Prokop'eva, Tatyana M; Mikhailov, Vasily A; Turovskaya, Marya K; Karpichev, Eugen A; Popov, Anatolii F; Gillitt, Nicholas D; Bunton, Clifford A

    2004-12-24

    Hypobromite ion, BrO(-), is an effective alpha-nucleophile that reacts rapidly with activated phosphorus(V) and sulfonate esters. The parent acid rapidly oxidizes organic sulfides and aryloxide ions. At pH 10-11 BrO(-) and HOBr coexist in water and are potentially useful as decontaminants of chlorosulfide blister agents and the phosphonyl nerve agents. Bis(dialkylamide)hydrogen dibromobromates are well characterized, stable, solids which rapidly form HOBr-BrO(-) in mildly alkaline water. Reactions of 4-nitrophenyl diethyl phosphate and phosphonate, which are simulants of the phosphonofluoridate nerve agents, and of 4-nitrophenyl tosylate, with BrO(-) are rapid (t(1/2) = 60-700 s) with 0.1 M BrO(-), under conditions in which oxidations of organic sulfides are too fast to be followed by conventional methods.

  6. Acute lung injury following inhalation exposure to nerve agent VX in guinea pigs.

    PubMed

    Wright, Benjamin S; Rezk, Peter E; Graham, Jacob R; Steele, Keith E; Gordon, Richard K; Sciuto, Alfred M; Nambiar, Madhusoodana P

    2006-05-01

    A microinstillation technique of inhalation exposure was utilized to assess lung injury following chemical warfare nerve agent VX [methylphosphonothioic acid S-(2-[bis(1-methylethyl)amino]ethyl) O-ethyl ester] exposure in guinea pigs. Animals were anesthetized using Telazol-meditomidine, gently intubated, and VX was aerosolized using a microcatheter placed 2 cm above the bifurcation of the trachea. Different doses (50.4 microg/m3, 70.4 micro g/m(m3), 90.4 microg/m(m3)) of VX were administered at 40 pulses/min for 5 min. Dosing of VX was calculated by the volume of aerosol produced per 200 pulses and diluting the agent accordingly. Although the survival rate of animals exposed to different doses of VX was similar to the controls, nearly a 20% weight reduction was observed in exposed animals. After 24 h of recovery, the animals were euthanized and bronchoalveolar lavage (BAL) was performed with oxygen free saline. BAL was centrifuged and separated into BAL fluid (BALF) and BAL cells (BALC) and analyzed for indication of lung injury. The edema by dry/wet weight ratio of the accessory lobe increased 11% in VX-treated animals. BAL cell number was increased in VX-treated animals compared to controls, independent of dosage. Trypan blue viability assay indicated an increase in BAL cell death in 70.4 microg/m(m3) and 90.4 microg/m(m3) VX-exposed animals. Differential cell counting of BALC indicated a decrease in macrophage/monocytes in VX-exposed animals. The total amount of BAL protein increased gradually with the exposed dose of VX and was highest in animals exposed to 90.4 microg/m(m3), indicating that this dose of VX caused lung injury that persisted at 24 h. In addition, histopathology results also suggest that inhalation exposure to VX induces acute lung injury.

  7. Intrinsic optical fiber sensor for sensing organophosphate nerve agent using the modified cladding approach

    NASA Astrophysics Data System (ADS)

    Bansal, Lalitkumar; El-Sherif, Mahmoud

    2004-03-01

    The concept of modified cladding based sensors represents the largest class of intrinsic fiber optic chemical sensors. In this design, the passive cladding of the optical fiber is replaced by an active coating, called modified cladding. The analyte in this case diffuses into the coating and induces changes in the absorbance, fluorescence, or some other spectroscopic property of the modified cladding, the coating acts as a chemo-chromic transducer and sensing takes place by intensity modulation. This design i.e. of the coating based sensors, has found enormous applicability in the realm of chemical and biochemical sensing which also includes environmental monitoring and detection of chemical warfare agents. In this paper, the development of an intrinsic fiber optic sensor for detection of organophosphate dimethyl-methyl phoshopnate (DMMP) is presented. DMMP is a chemical precursor to the nerve agent sarin. The chemo-chromic transducer material used as a modified coating on the fiber core is NDSA (Naphthalene disulphonic acid) doped polypyrrole. This coating material shows conductivity and absorbance change when exposed to DMMP. The fabrication of the sensor device is a three step process which involves (a) etching a small section of the optical fiber to expose the core, (b) coating the etched section of the optical fiber with the polymer, (c) integration of sensor components and testing. Thin film characterization is done using the UV-Vis spectrophotometer on in-situ coated films of polypyrrole on a glass substrate to check for absorbance change upon exposure to DMMP. The development procedure is presented next and encouraging results are discussed.

  8. A high-throughput diagnostic method for measuring human exposure to organophosphorus nerve agents.

    PubMed

    Knaack, Jennifer S; Zhou, Yingtao; Abney, Carter W; Jacob, Justin T; Prezioso, Samantha M; Hardy, Katelyn; Lemire, Sharon W; Thomas, Jerry; Johnson, Rudolph C

    2012-11-06

    An automated high-throughput immunomagnetic separation (IMS) method for diagnosing exposure to the organophosphorus nerve agents (OPNAs) sarin (GB), cyclohexylsarin (GF), VX, and Russian VX (RVX) was developed to increase sample processing capacity for emergency response applications. Diagnosis of exposure to OPNAs was based on the formation of OPNA adducts to butyrylcholinesterase (BuChE). Data reported with this method represent a ratio of the agent-specific BuChE adduct concentration, relative to the total BuChE peptide concentration that provides a nonactivity measurement expressed as percent adducted. All magnetic bead transfer steps and washes were performed using instrumentation in a 96-well format allowing for simultaneous extraction of 86 clinical samples plus reference materials. Automating extractions increased sample throughput 50-fold, as compared to a previously reported manual method. The limits of detection, determined using synthetic peptides, were 1 ng/mL for unadducted BuChE and GB-, GF-, VX-, and RVX-adducted BuChE. The automated method was characterized using unexposed serum and serum pools exposed to GB, GF, VX, or RVX. Variation for the measurement of percent adducted was <12% for all characterized quality control serum pools. Twenty-six (26) serum samples from individuals asymptomatic for cholinesterase inhibitor exposure were analyzed using this method, and no background levels of OPNA exposure were observed. Unexposed BuChE serum concentrations measured using this method ranged from 2.8 μg/mL to 10.6 μg/mL, with an average concentration of 6.4 μg/mL.

  9. Evaluation of potency of known oximes (pralidoxime, trimedoxime, HI-6, methoxime, obidoxime) to in vitro reactivate acetylcholinesterase inhibited by pesticides (chlorpyrifos and methylchlorpyrifos) and nerve agent (Russian VX).

    PubMed

    Musílek, Kamil; Kuca, Kamil; Jun, Daniel

    2007-01-01

    Nerve agents and pesticides belong to the group of organophosphates. They are able to inhibit irreversibly the enzyme acetylcholinesterase (AChE). Acetylcholinesterase reactivators were designed for the treatment of nerve agent intoxications. Their potency to reactivate pesticide-inhibited AChE was many times evaluated. In this study, five commonly used AChE reactivators (pralidoxime, methoxime, HI-6, obidoxime, trimedoxime) for the reactivation of AChE inhibited by two pesticides (chlorpyrifos and methylchlorpyrifos) were used. Russian VX (nerve agent) as a member of nerve agents' family was taken for comparison. Obtained results show that oximes developed against nerve agent intoxication are less effective for intoxication with organophosphorus pesticides. Especially, methylchlorpyrifos-inhibited AChE was found to be poorly reactivated by the compounds used.

  10. Reaction of nerve agents with phosphate buffer at pH 7.

    PubMed

    Creasy, William R; Fry, Roderick A; McGarvey, David J

    2012-07-12

    Chemical weapon nerve agents, including isopropyl methylphosphonofluoridate (GB or Sarin), pinacolyl methylphosphonofluoridate (GD or Soman), and S-(2-diisopropylaminoethyl) O-ethyl methylphosphonothioate (VX), are slow to react in aqueous solutions at midrange pH levels. The nerve agent reactivity increases in phosphate buffer at pH 7, relative to distilled water or acetate buffer. Reactions were studied using (31)P NMR. Phosphate causes faster reaction to the corresponding alkyl methylphosphonic acids, and produces a mixed phosphate/phosphonate compound as an intermediate reaction product. GB has the fastest reaction rate, with a bimolecular rate constant of 4.6 × 10(-3) M(-1)s(-1)[PO(4)(3-)]. The molar product branching ratio of GB acid to the pyro product (isopropyl methylphosphonate phosphate anhydride) is 1:1.4, independent of phosphate concentration, and the pyro product continues to react much slower to form GB acid. The pyro product has two doublets in the (31)P NMR spectrum. The rate of reaction for GD is slower than GB, with a rate constant of 1.26 × 10(-3) M(-1)s(-1) [PO(4)(3-)]. The rate for VX is considerably slower, with a rate constant of 1.39 × 10(-5) M(-1)s(-1) [PO(4)(3-)], about 2 orders of magnitude slower than the rate for GD. The rate constant of the reaction of GD with pyrophosphate at pH 8 is 2.04 × 10(-3) min(-1) at a concentration of 0.0145 M. The rate of reaction for diisopropyl fluorophosphate is 2.84 × 10(-3) min(-1) at a concentration of 0.153 M phosphate, a factor of 4 slower than GD and a factor of 15 slower than GB, and there is no detectable pyro product. The half-lives of secondary reaction of the GB pyro product in 0.153 and 0.046 M solution of phosphate are 23.8 and 28.0 h, respectively, which indicates little or no dependence on phosphate.

  11. Bio-inspired Supramolecular Assemblies and Porous Materials for the Degradation of Organophosphate Nerve Agents

    NASA Astrophysics Data System (ADS)

    Totten, Ryan K.

    This thesis reports the synthesis of bio-inspired supramolecular assemblies and porous materials that are catalytically active in the degradation of organophosphate nerve agents. The first catalysts described are a series of cofacial metalloporphyrin dimers modeled after the active site of phosphotriesterase that were modularly prepared from a single porphyrin building block and shown to catalyze the methanolysis of p-nitrophenyl diphenyl phosphate (PNPDPP), a simulant for nerve agents. Notably, tuning the active sites inside the cavities of these dimers, from ZnII metal centers to Al-OMe moieties, affords an enhanced nucleophilic environment where a high concentration of methoxy ligands becomes available for reaction with encapsulated phosphate triesters. Up to a 1300-fold rate acceleration over the uncatalyzed reaction can be achieved via a combination of cavity-localized Lewis-acid activation and methoxide-induced methanolysis. Based on the design principles learned from the aforementioned solution-phase Al(porphyrin) dimers, a heterogeneous porous organic polymer (POP) catalyst was synthesized by incorporating an Al(porphyrin) functionalized with a large axial ligand into a POP using a cobalt-catalyzed acetylene trimerization strategy. Removal of the axial ligand afforded a microporous material that is capable of encapsulating and solvolytically degrading PNPDPP. Supercritical CO 2 processing of the Al(porphyrin)-based POP dramatically increased the pore size and volume, allowing for significantly higher catalytic activities. The syntheses of porphyrin-based POPs with tunable pore diameters and volumes have also been attempted. SnIV(porphyrins) functionalized with bulky trans-diaxial ligands can be incorporated into POPs. Post-synthesis removal of the ligands reveal POPs with a tunable range of micro- and mesopores as well as tunable pore volumes. Expanding upon the idea that active sites that can both bind substrates and deliver nucleophiles should be active

  12. Respiratory Complications of Organophosphorus Nerve Agent and Insecticide Poisoning. Implications for Respiratory and Critical Care

    PubMed Central

    Hulse, Elspeth J.; Davies, James O. J.; Simpson, A. John; Sciuto, Alfred M.

    2014-01-01

    Organophosphorus (OP) compound poisoning is a major global public health problem. Acute OP insecticide self-poisoning kills over 200,000 people every year, the majority from self-harm in rural Asia. Highly toxic OP nerve agents (e.g., sarin) are a significant current terrorist threat, as shown by attacks in Damascus during 2013. These anticholinesterase compounds are classically considered to cause an acute cholinergic syndrome with decreased consciousness, respiratory failure, and, in the case of insecticides, a delayed intermediate syndrome that requires prolonged ventilation. Acute respiratory failure, by central and peripheral mechanisms, is the primary cause of death in most cases. However, preclinical and clinical research over the last two decades has indicated a more complex picture of respiratory complications after OP insecticide poisoning, including onset of delayed neuromuscular junction dysfunction during the cholinergic syndrome, aspiration causing pneumonia and acute respiratory distress syndrome, and the involvement of solvents in OP toxicity. The treatment of OP poisoning has not changed over the last 50 years. However, a better understanding of the multiple respiratory complications of OP poisoning offers additional therapeutic opportunities. PMID:25419614

  13. In vitro release of organophosphorus acid anhydrolase from functionalized mesoporous silica against nerve agents.

    SciTech Connect

    Chen, Baowei; Shah, Saumil S.; Shin, Yongsoon; Lei, Chenghong; Liu, Jun

    2011-10-02

    We report here that under different physiological conditions, biomolecular drugs can be stockpiled in a nanoporous support and afterward can be instantly released when needed for acute responses, and the biomolecular drug molecules can also be gradually released from the nanoporous support over a long time for a complete recovery. Organophosphorus acid anhydrolase (OPAA) was spontaneously and largely entrapped in functionalized mesoporous silica (FMS) due to the dominant electrostatic interaction. The OPAA-FMS composite exhibited a burst release in a pH 9.0 NaHCO(3)-Na(2)CO(3) buffer system and a gradual release in pH 7.4 simulated body fluid. The binding of OPAA to NH(2)-FMS can result in less tyrosinyl and tryptophanyl exposure OPAA molecules to aqueous environment. The bound OPAA in FMS displayed lower activity than the free OPAA in solution prior to the enzyme entrapment. However, the released enzyme maintained the native conformational structure and the same high enzymatic activity as that prior to the enzyme entrapment. The in vitro results in the rabbit serum demonstrate that both OPAA-FMS and the released OPAA may be used as a medical countermeasure against the organophosphorus nerve agents.

  14. In vitro release of organophosphorus acid anhydrolase from functionalized mesoporous silica against nerve agents

    PubMed Central

    Chen, Baowei; Shah, Saumil S.; Shin, Yongsoon; Lei, Chenghong; Liu, Jun

    2011-01-01

    We report here that under different physiological conditions, biomolecular drugs can be stockpiled in a nanoporous support and afterwards can be instantly released when needed for acute responses, and the biomolecular drug molecules can also be gradually released from the nanoporous support over a long time for a complete recovery. Organophosphorus acid anhydrolase (OPAA) was spontaneously and largely entrapped in functionalized mesoporous silica (FMS) due to the dominant electrostatic interaction. The OPAA-FMS composite exhibited a burst release in pH 9.0, NaHCO3-Na2CO3 buffer system and a gradual release in pH 7.4, simulated body fluid. The binding of OPAA to NH2-FMS can result in less Trp exposure of OPAA molecules to aqueous environment. The bound OPAA in FMS displayed lower activity than the free OPAA in solution prior to the enzyme entrapment. However, the released enzyme still displayed the native conformational structure and the same high enzymatic activity as that prior to the enzyme entrapment. The in vitro results in the rabbit serum demonstrate that both OPAA-FMS and the released OPAA may be used as the medical measures against the organophosphorus nerve agents. PMID:22019765

  15. Investigating the Affinities and Persistence of VX Nerve Agent in Environmental Matrices

    SciTech Connect

    Love, A H; Vance, A L; Reynolds, J G; Davisson, M L

    2004-03-09

    Laboratory experiments were conducted to determine environmental variables that affect the affinities and persistence of the nerve agent O-ethyl S-(2-diisopropylaminoethyl) methylphosphonothiolate (VX) at dilute concentrations in environmental matrices. Quantitative analyses of VX and its degradation products were performed using LC-MS. Batch hydrolysis experiments demonstrated an increasing hydrolysis rate as pH increased, as shown in previous studies, but also indicated that dissolved aqueous constituents can cause significant differences in the absolute hydrolysis rate. Adsorption isotherms from batch aqueous experiments revealed that VX has a high affinity for hydrophobic organics, a moderate affinity for montmorillonite clay, and a very low affinity for an iron-oxyhydroxide soil mineral, goethite. The adsorption on goethite was increased with the presence of dissolved organic matter in solution. VX degraded rapidly when dried onto goethite, when an inner-sphere complex was forced. No enhanced degradation occurred with goethite in small amounts water. These results suggest that aqueous conditions have important controls on VX adsorption and degradation in the environment and a more mechanistic understanding of these controls is needed in order to enable accurate predictions of its long-term fate and persistence.

  16. Electrochemical Sensor for Organophosphate Pesticides and Nerve Agents Using Zirconia Nanoparticles as Selective Sorbents

    SciTech Connect

    Liu, Guodong; Lin, Yuehe

    2005-09-15

    Electrochemical sensor for detection of organophosphate (OP) pesticides and nerve agents using zirconia (ZrO₂) nanoparticles as selective sorbents is presented. Zirconia nanoparticles were electrodynamically deposited onto the polycrystalline gold electrode by cyclic voltammetry. Because of a strong affinity of zirconia to the phosphoric group, nitroaromatic OPs strongly bind to the ZrO₂ nanoparticle surface. The electrochemical characterization and anodic stripping voltammetric performance of bound OPs were evaluated using cyclic voltammetric and square-wave voltammetric (SWV) analysis. SWV was used to monitor the amount of bound OPs and provide simple, fast, and facile quantitative methods for nitroaromatic OP compounds. The sensor surface can be regenerated by successively running SWV scanning. Operational parameters, including the amount of nanoparticles, adsorption time, and the pH of the reaction medium have been optimized. The stripping voltammetric response is highly linear over the 5–200 ng/mL (ppb) methyl parathion range examined (2-min adsorption), with a detection limit of 1 ng/mL (10 min accumulation), and good precision (RSD=5.3 %, n = 10). The promising stripping voltammetric performances open new opportunities for fast, simple, and sensitive analyzing of OPs in environmental and biological samples. These findings can lead to a widespread use of electrochemical sensors to detect OP contaminates.

  17. Determination of Nerve Agent Metabolites by Ultraviolet Femtosecond Laser Ionization Mass Spectrometry.

    PubMed

    Hamachi, Akifumi; Imasaka, Tomoko; Nakamura, Hiroshi; Li, Adan; Imasaka, Totaro

    2017-04-04

    Nerve agent metabolites, i.e., isopropyl methylphosphonic acid (IMPA) and pinacolyl methylphosphonic acid (PMPA), were derivatized by reacting them with 2,3,4,5,6-pentafluorobenzyl bromide (PFBBr) and were determined by mass spectrometry using an ultraviolet femtosecond laser emitting at 267 and 200 nm as the ionization source. The analytes of the derivatized compounds, i.e., IMPA-PFB and PMPA-PFB, contain a large side-chain, and molecular ions are very weak or absent in electron ionization mass spectrometry. The use of ultraviolet femtosecond laser ionization mass spectrometry, however, resulted in the formation of a molecular ion, even for compounds such as these that contain a highly-bulky functional group. The signal intensity was larger at 200 nm due to resonance-enhanced two-photon ionization. In contrast, fragmentation was suppressed at 267 nm (non-resonant two-photon ionization) especially for PMPA-PFB, thus resulting in a lower background signal. This favorable result can be explained by the small excess energy in ionization at 267 nm and by the low-frequency vibrational mode of a bulky trimethylpropyl group in PMPA.

  18. Phosphoproteomic analysis reveals compensatory effects in the piriform cortex of VX nerve agent exposed rats.

    PubMed

    Nirujogi, Raja Sekhar; Wright, James D; Manda, Srikanth S; Zhong, Jun; Na, Chan Hyun; Meyerhoff, James; Benton, Bernard; Jabbour, Rabih; Willis, Kristen; Kim, Min-Sik; Pandey, Akhilesh; Sekowski, Jennifer W

    2015-01-01

    To gain insights into the toxicity induced by the nerve agent VX, an MS-based phosphoproteomic analysis was carried out on the piriform cortex region of brains from VX-treated rats. Using isobaric tag based TMT labeling followed by titanium dioxide enrichment strategy, we identified 9975 unique phosphosites derived from 3287 phosphoproteins. Temporal changes in the phosphorylation status of peptides were observed over a time period of 24 h in rats exposed to a 1× LD50, intravenous (i.v.) dose with the most notable changes occurring at the 1 h postexposure time point. Five major functional classes of proteins exhibited changes in their phosphorylation status: (i) ion channels/transporters, including ATPases, (ii) kinases/phosphatases, (iii) GTPases, (iv) structural proteins, and (v) transcriptional regulatory proteins. This study is the first quantitative phosphoproteomic analysis of VX toxicity in the brain. Understanding the toxicity and compensatory signaling mechanisms will improve the understanding of the complex toxicity of VX in the brain and aid in the elucidation of novel molecular targets that would be important for development of improved countermeasures. All MS data have been deposited in the ProteomeXchange with identifier PXD001184 (http://proteomecentral.proteomexchange.org/dataset/PXD001184).

  19. In vitro selection and efficacy of topical skin protectants against the nerve agent VX.

    PubMed

    Millerioux, J; Cruz, C; Bazire, A; Lallement, G; Lefeuvre, L; Josse, D

    2009-04-01

    Against highly toxic chemicals that are quickly absorbed in the skin, topical formulations could adequately complement specific protective suits and equipments. In this work, we evaluated in vitro and compared the skin protection efficacy against the nerve agent VX of four different topical formulations: oil-in-water and water-in-oil emulsions, a perfluorinated-based cream and a hydrogel. Semi-permeable silicone membrane, pig-ear and human abdominal split-thickness skin samples mounted in diffusion cells were compared as in vitro permeation tests. The results showed that silicone membrane could be used instead of skin samples to screen for potentially effective formulations. However, the results indicated that due to potentially significant interactions between formulations and skin, relevant ranking of formulations according to their protective efficacy could require tests with skin samples. The main phase of emulsions, water or oil, was not found to be critical for skin protective efficacy against VX. Instead, specific film-forming ingredients such as perfluorinated-based polymers and silicones could significantly affect the skin protective efficacy of formulations. We showed that a hydrogel containing specific hydrophilic polymers was by far the most effective of the formulations evaluated against VX skin permeation in vitro.

  20. Investigating the affinities and persistence of VX nerve agent in environmental matrices.

    PubMed

    Love, Adam H; Vance, Andrew L; Reynolds, John G; Davisson, M Lee

    2004-12-01

    Laboratory experiments were conducted to determine environmental variables that affect the affinities and persistence of the nerve agent O-ethyl S-(2-diisopropylaminoethyl) methylphosphonothiolate (VX) at dilute concentrations in environmental matrices. Quantitative analyses of VX and its degradation products were performed using LC-MS. Batch hydrolysis experiments demonstrated an increasing hydrolysis rate as pH increased, as shown in previous studies, but also indicated that dissolved aqueous constituents can cause significant differences in the absolute hydrolysis rate. Adsorption isotherms from batch aqueous experiments revealed that VX has a high affinity for hydrophobic organics, a moderate affinity for montmorillonite clay, and a very low affinity for an iron-oxyhydroxide soil mineral, goethite. The adsorption on goethite was increased with the presence of dissolved organic matter in solution. VX degraded rapidly when dried onto goethite, when specific adsorption was forced. No enhanced degradation occurred with goethite in small amounts of water. These results suggest that aqueous conditions have important controls on VX adsorption and degradation in the environment and a more mechanistic understanding of these controls is needed in order to enable accurate predictions of its long-term fate and persistence.

  1. Toxicogenomic studies of human neural cells following exposure to organophosphorus chemical warfare nerve agent VX.

    PubMed

    Gao, Xiugong; Lin, Hsiuling; Ray, Radharaman; Ray, Prabhati

    2013-05-01

    Organophosphorus (OP) compounds represent an important group of chemical warfare nerve agents that remains a significant and constant military and civilian threat. OP compounds are considered acting primarily via cholinergic pathways by binding irreversibly to acetylcholinesterase, an important regulator of the neurotransmitter acetylcholine. Many studies over the past years have suggested that other mechanisms of OP toxicity exist, which need to be unraveled by a comprehensive and systematic approach such as genome-wide gene expression analysis. Here we performed a microarray study in which cultured human neural cells were exposed to 0.1 or 10 μM of VX for 1 h. Global gene expression changes were analyzed 6, 24, and 72 h post exposure. Functional annotation and pathway analysis of the differentially expressed genes has revealed many genes, networks and canonical pathways that are related to nervous system development and function, or to neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, and Parkinson's disease. In particular, the neuregulin pathway impacted by VX exposure has important implications in many nervous system diseases including schizophrenia. These results provide useful information valuable in developing suitable antidotes for more effective prevention and treatment of, as well as in developing biomarkers for, VX-induced chronic neurotoxicity.

  2. Competitive FRET-aptamer-based detection of methylphosphonic acid, a common nerve agent metabolite.

    PubMed

    Bruno, John G; Carrillo, Maria P; Phillips, Taylor; Vail, Neal K; Hanson, Douglas

    2008-09-01

    Competitive fluorescence resonance energy transfer (FRET)-aptamer-based assay formats are described for one-step detection of methylphosphonic acid (MPA; a metabolite of several organophosphorus (OP) nerve agents). AminoMPA was attached to tosyl-magnetic beads and used for DNA aptamer selection from which one dominant aptamer sequence emerged. Two different FRET approaches were attempted. In one approach, the complementary DNA sequence was used as a template for labeling the aptamer with Alexa Fluor 546 (AF 546)-14-dUTP by asymmetric PCR. Following 3-dimensional (3-D), molecular modeling of the aptamer-MPA complex, a series of three fluoresceinated aptamers labeled at positions 50, 51, and 52 in the putative optimal binding pocket were synthesized. In both FRET formats, aminoMPA was linked to Black Hole Quencher (BHQ-1 or BHQ-2)-succinimides and allowed to bind the fluorescein or AF 546-labeled MPA aptamer. Following gel filtration to purify the labeled MPA aptamer-BHQ-aminoMPA FRET complexes, the complexes were competed against various concentrations of unlabeled MPA, MPA derivatives, and unrelated compounds in titration and cross-reactivity studies. Both approaches yielded low microgram per milliliter detection limits for MPA with generally low levels of cross-reactivity for unrelated compounds. However, the data suggest a pattern of traits that may effect the direction (lights on or off) and intensity of the FRET.

  3. Selective real-time detection of gaseous nerve agent simulants using multiwavelength photoacoustics.

    PubMed

    Gurton, Kristan P; Felton, Melvin; Tober, Richard

    2012-08-15

    An optical detection method is presented that is designed to detect and identify the presence of macromolecular gas species (e.g., organophosphate-based nerve agent simulants) at trace level concentrations. The technique is based on a modified version of conventional laser photoacoustic (PA) spectroscopy, in which optical absorption is typically measured using a single laser source. We demonstrate the ability to simultaneously measure multiple absorption-related parameters that serve as a concentration-independent identifier. Three continuous wave mid-infrared laser sources, operating at 8.68, 9.29, and 10.35 μm, are combined and propagated axially through a specially designed flow through PA cell. Each laser is modulated at a different frequency and the resultant acoustic signal(s) are detected and deconvolved using a PC-based 24 bit dynamic signal acquisition device. Species detection and identification is achieved by tabulating independent ratios of the acoustic response for each laser source. Quantitative absorption measured is verified using a Fourier transform infrared spectrometer. Results show good detection and species separation/identification at moderately low ppm concentrations.

  4. An Enhanced Butyrylcholinesterase Method to Measure Organophosphorus Nerve Agent Exposure in Humans

    PubMed Central

    Pantazides, Brooke G.; Watson, Caroline M.; Carter, Melissa D.; Crow, Brian S.; Perez, Jonas W.; Blake, Thomas A.; Thomas, Jerry D.; Johnson, Rudolph C.

    2016-01-01

    Organophosphorus nerve agent (OPNA) adducts to butyrylcholinesterase (BChE) can be used to confirm exposure in humans. A highly accurate method to detect G-series and V-series OPNA adducts to BChE in 75 μL of filtered blood, serum, or plasma has been developed using immunomagnetic separation (IMS) coupled with liquid chromatography tandem mass spectrometry (LC-MS/MS). The reported IMS method captures > 88% of the BChE in a specimen and corrects for matrix effects on peptide calibrators. The optimized method has been used to quantify baseline BChE levels (unadducted and OPNA-adducted) in a matched set of serum, plasma and whole blood (later processed in-house for plasma content) from 192 unexposed individuals to determine the interchangeability of the tested matrices. The results of these measurements demonstrate the ability to accurately measure BChE regardless of the format of the blood specimen received. Criteria for accepting or denying specimens were established through a series of sample stability and processing experiments. The results of these efforts are an optimized and rugged method that is transferrable to other laboratories and an increased understanding of the BChE biomarker in matrix. PMID:24604326

  5. Detection of the organophosphorus nerve agent sarin by a competitive inhibition enzyme immunoassay.

    PubMed

    Zhou, Y X; Yan, Q J; Ci, Y X; Guo, Z Q; Rong, K T; Chang, W B; Zhao, Y F

    1995-01-01

    Two artificial antigens, NalphaNepsilon-di(O,O-diisopropyl) phosphoryl L-lysine (DIP)- bovine serum albumin (BSA) conjugate (DIP-BSA) and DIP-KLH (keyhole limpet hemocyanin), were synthesized. Antibodies against sarin (O-isopropyl methylphosphonofluoridate) were obtained after immunization of rabbits with DIP-KLH conjugate. A competitive inhibition enzyme immunoassay (CIEIA) was developed to detect the organophosphorus nerve agent sarin. The antibody solutions could be inhibited by sarin as low as 10(-6) mol/l, and the standard curve was linear over 3 orders of magnitude. The coefficients of intraassay and interassay variation of this method were 5.4-6.2% (n = 11) and 8.0-9.5% (n = 6) at a sarin concentration range of 10(-3)-10(-6) mol/l, respectively. The recovery of sarin in water samples at the concentration of 5 x 10(-5) mol/l was in the range of 96.8-102.5%. The specificity of the antiserum was assessed by comparing the inhibition induced by sarin with soman, Vx, isopropyl alcohol and isopropyl methyl phosphonic acid. The results showed that less than 5 mmol/l soman, 2 mmol/l Vx, 16 mmol/l isopropyl alcohol and 8 mmol/l isopropyl methyl phosphonic acid did not influence the determination of sarin in water samples.

  6. Inactivation of organophosphorus nerve agents by the phosphotriesterase from Pseudomonas diminuta.

    PubMed

    Dumas, D P; Durst, H D; Landis, W G; Raushel, F M; Wild, J R

    1990-02-15

    The phosphotriesterase from Pseudomonas diminuta was tested as a catalyst for the hydrolysis of phosphofluoridates. The purified enzyme has been shown to hydrolyze the phosphorus-fluorine bond of diisopropyl fluorophosphate, isopropyl methylphosphonofluoridate, and 1,2,2-trimethylpropylmethylphosphonofluoridate at pH 7.0, 25 degrees C, with turnover numbers of 41, 56, and 5 s-1, respectively. The enzymatic rate enhancement for the hydrolysis of sarin at pH 7.0 is 2.2 X 10(7). The turnover number for paraoxon hydrolysis is 2100 s-1. The enzyme does not hydrolyze methanesulfonyl fluoride, phenylmethylsulfonyl fluoride, or O-p-nitrophenyl phenylsulfonate nor do these compounds inactivate or inhibit the ability of the enzyme to hydrolyze diethyl p-nitrophenyl phosphate. The breadth of substrate utility and the efficiency of the hydrolytic reaction exceed the more limited abilities of other prokaryotic and eukaryotic enzymes that catalyze similar reactions. The substantial rate enhancement exhibited by this enzyme for the hydrolysis of a wide variety of organophosphorus nerve agents make this enzyme the prime candidate for the biological detoxification of insecticide and mammalian acetylcholinesterase inhibitors.

  7. Cholinergic modulation of periaqueductal grey neurons: does it contribute to epileptogenesis after organophosphorus nerve agent intoxication?

    PubMed

    Sanada, Mitsuru; Zheng, Fang; Huth, Tobias; Alzheimer, Christian

    2007-04-20

    Previous work has shown that a single focal microinjection of the unselective cholinergic agonist, carbachol, into the periaqueductal grey (PAG) of the midbrain is sufficient to induce forebrain seizures in rats. In order to determine the cholinergic mechanisms underlying epileptogenesis at the cellular and network level of the PAG, we performed whole-cell recordings from rat PAG neurons in vitro and examined how the activation of muscarinic and nicotinic receptors modulates cellular excitability and synaptic responses. Stimulation of muscarinic receptors produced either a pirenzepine-sensitive depolarization (40% of PAG neurons), or a gallamine-sensitive hyperpolarization (20%), suggesting the involvement of M1 and M2 receptors, respectively. In the remaining neurons (40%), no change was observed. Voltage-clamp recordings showed that muscarinic depolarization resulted from the inhibition of a resting K(+) current, in part accompanied by simultaneous activation of a presumed non-selective cation current. Muscarinic hyperpolarization was caused by the activation of a G protein-coupled, inwardly rectifying K(+) current. Stimulation of muscarinic receptors enhanced the frequency of spontaneous inhibitory postsynaptic currents (IPSCs), but strongly suppressed evoked IPSCs. In addition, nicotine almost doubled the frequency of miniature IPSCs. Based on our findings and the network properties of the PAG, we advance a scenario in which excessive stimulation of cholinergic receptors would substantially contribute to generalized seizures after organophosphorus nerve agent poisoning.

  8. Percutaneous exposure to the nerve agent VX: Efficacy of combined atropine, obidoxime and diazepam treatment.

    PubMed

    Joosen, Marloes J A; van der Schans, Marcel J; van Helden, Herman P M

    2010-10-06

    The nerve agent VX is most likely to enter the body via liquid contamination of the skin. After percutaneous exposure, the slow uptake into the blood, and its slow elimination result in toxic levels in plasma for a period of several hours. Consequently, this has implications for the development of toxic signs and for treatment onset. In the present study, clinical signs, toxicokinetics and effects on respiration, electroencephalogram and heart rate were investigated in hairless guinea pigs after percutaneous exposure to 500 microg/kg VX. We found that full inhibition of AChE and partial inhibition of BuChE in blood were accompanied by the onset of clinical signs, reflected by a decline in respiratory minute volume, bronchoconstriction and a decrease in heart rate. Furthermore, we investigated the therapeutic efficacy of a single dose of atropine, obidoxime and diazepam, administered at appearance of first clinical signs, versus that of repetitive dosing of these drugs on the reappearance of signs. A single shot treatment extended the period to detrimental physiological decline and death for several hours, whereas repetitive administration remained effective as long as treatment was continued. In conclusion, percutaneous VX poisoning showed to be effectively treatable when diagnosed on time and when continued over the entire period of time during which VX, in case of ineffective decontamination, penetrates the skin.

  9. Antibiotic Agents

    MedlinePlus

    ... producing ). Examples of this type are the alcohols, chlorine, peroxides, and aldehydes. The second group consists mostly ... viruses have some kind of antibacterial agent. Alcohols, chlorine and peroxides have been used for many decades ...

  10. Agent Orange

    MedlinePlus

    ... Z) Hepatitis HIV Mental Health Mental Health Home Suicide Prevention Substance Abuse Military Sexual Trauma PTSD Research ( ... eligible Veterans a free Agent Orange Registry health exam for possible long-term health problems related to ...

  11. Crystal structures of human group-VIIA phospholipase A2 inhibited by organophosphorus nerve agents exhibit non-aged complexes

    SciTech Connect

    Samanta, Uttamkumar; Kirby, Stephen D.; Srinivasan, Prabhavathi; Cerasoli, Douglas M.; Bahnson, Brian J.

    2009-09-02

    The enzyme group-VIIA phospholipase A2 (gVIIA-PLA2) is bound to lipoproteins in human blood and hydrolyzes the ester bond at the sn-2 position of phospholipid substrates with a short sn-2 chain. The enzyme belongs to a serine hydrolase superfamily of enzymes, which react with organophosphorus (OP) nerve agents. OPs ultimately exert their toxicity by inhibiting human acetycholinesterase at nerve synapses, but may additionally have detrimental effects through inhibition of other serine hydrolases. We have solved the crystal structures of gVIIA-PLA2 following inhibition with the OPs diisopropylfluorophosphate, sarin, soman and tabun. The sarin and soman complexes displayed a racemic mix of P{sub R} and P{sub S} stereoisomers at the P-chiral center. The tabun complex displayed only the P{sub R} stereoisomer in the crystal. In all cases, the crystal structures contained intact OP adducts that had not aged. Aging refers to a secondary process OP complexes can go through, which dealkylates the nerve agent adduct and results in a form that is highly resistant to either spontaneous or oxime-mediated reactivation. Non-aged OP complexes of the enzyme were corroborated by trypsin digest and matrix-assisted laser desorption ionization mass spectrometry of OP-enzyme complexes. The lack of stereoselectivity of sarin reaction was confirmed by gas chromatography/mass spectrometry using a chiral column to separate and quantitate the unbound stereoisomers of sarin following incubation with enzyme. The structural details and characterization of nascent reactivity of several toxic nerve agents is discussed with a long-term goal of developing gVIIA-PLA2 as a catalytic bioscavenger of OP nerve agents.

  12. High-separation efficiency micro-fabricated multi-capillary gas chromatographic columns for simulants of the nerve agents and blister agents

    NASA Astrophysics Data System (ADS)

    Li, Yi; Du, Xiaosong; Wang, Yang; Tai, Huiling; Qiu, Dong; Lin, Qinghao; Jiang, Yadong

    2014-05-01

    To achieve both high speed and separation efficiency in the separation of a mixture of nerve and blister agent simulants, a high-aspect-ratio micro-fabricated multi-capillary column (MCC, a 50-cm-long, 450-μm-deep, and 60-μm-wide four-capillary column) was fabricated by the application of the microelectromechanical system (MEMS) techniques. Mixtures of chemical warfare agent (CWA) simulants - dimethyl methylphosphonate (DMMP), triethyl phosphate (TEP), and methyl salicylate - were used as samples. The fabricated MCC allowed for the separation of all the components of the gaseous mixture within 24 s, even when the difference in boiling point was 4°C, as in the case of TEP and methyl salicylate. Furthermore, interfering agents - dichloromethane, ethanol, and toluene - were also included in the subsequent gaseous mixture samples. The boiling point of these six components ranged from 78°C to 219°C. All six components were clearly separated within 70 s. This study is the first to report the clear separation of gas mixtures of components with close boiling points. The column efficiency was experimentally determined to be 12,810 plates/m.

  13. High-separation efficiency micro-fabricated multi-capillary gas chromatographic columns for simulants of the nerve agents and blister agents

    PubMed Central

    2014-01-01

    To achieve both high speed and separation efficiency in the separation of a mixture of nerve and blister agent simulants, a high-aspect-ratio micro-fabricated multi-capillary column (MCC, a 50-cm-long, 450-μm-deep, and 60-μm-wide four-capillary column) was fabricated by the application of the microelectromechanical system (MEMS) techniques. Mixtures of chemical warfare agent (CWA) simulants - dimethyl methylphosphonate (DMMP), triethyl phosphate (TEP), and methyl salicylate - were used as samples. The fabricated MCC allowed for the separation of all the components of the gaseous mixture within 24 s, even when the difference in boiling point was 4°C, as in the case of TEP and methyl salicylate. Furthermore, interfering agents - dichloromethane, ethanol, and toluene - were also included in the subsequent gaseous mixture samples. The boiling point of these six components ranged from 78°C to 219°C. All six components were clearly separated within 70 s. This study is the first to report the clear separation of gas mixtures of components with close boiling points. The column efficiency was experimentally determined to be 12,810 plates/m. PMID:24899869

  14. Conjugated poly(fluorene-quinoxaline) for fluorescence imaging and chemical detection of nerve agents with its paper-based strip.

    PubMed

    Jo, Seonyoung; Kim, Daigeun; Son, Sang-Ho; Kim, Yongkyun; Lee, Taek Seung

    2014-01-22

    Conjugated polymer of poly(fluorene-co-quinoxaline) was synthesized via Suzuki coupling polymerization. The emission color of the polymer can be tuned depending on the concentration of the polymer in solution. A low-energy bandgap is observed both in the concentrated solution and in the solid state, caused by aggregation of the polymer chains, resulting in long wavelength emission from the quinoxaline moiety, while short wavelength emission can be seen in diluted, well-dissolved solution. The presence of quinoxaline units enables us to demonstrate fluorescence switching and imaging. Paper-based strips containing the polymer are prepared via simple immersion of filter paper in the polymer solution for practical use in the detection of nerve agents. The emission of the paper-based strip is quenched upon exposure to diethyl chlorophosphate (DCP), a nerve agent simulant, and the initial emission intensity can be almost restored by treatment with aqueous sodium hydroxide solution, making a possible reversible paper-based sensor.

  15. A fluorescent sensing of nerve agent simulant with dual emissions at wide pH range in aqueous solution.

    PubMed

    Kim, Youngsam; Jang, Yoon Jeong; Mulay, Sandip V; Nguyen, Thuy-Tien T; Churchill, David G

    2017-03-23

    A new 1,8-naphthalimide-based fluorescent probe for the detection of diethyl cyanophosphonate, a very common nerve agent simulant, was designed, synthesized and characterized fully. The probe showed around 50-fold enhancement of fluorescence intensity over other nerve agent simulants. Importantly, the probe is able to work under aqueous conditions at wide pH range. Two reactive groups, the oxime and phenol, allowed a dual emission with different kinetic reaction. The reaction of diethyl cyanophosphonate with the oxime group occurred in advance; the resulting time-response of fluorescence enhancement was observed within ~30 s. After the oxime underwent reaction, then phenol also underwent substitution reaction with diethyl cyanophosphate resulting blue emission. To show real application of this new probe, silica plate assays for the detection of diethyl cyanophosphonate in gas and liquid phase through dual emissions channel were carried out.

  16. Selective enrichment of the degradation products of organophosphorus nerve agents by zirconia based solid-phase extraction.

    PubMed

    Kanaujia, Pankaj K; Pardasani, Deepak; Tak, Vijay; Purohit, Ajay K; Dubey, D K

    2011-09-23

    Selective extraction and enrichment of nerve agent degradation products has been achieved using zirconia based commercial solid-phase extraction cartridges. Target analytes were O-alkyl alkylphosphonic acids and alkylphosphonic acids, the environmental markers of nerve agents such as sarin, soman and VX. Critical extraction parameters such as modifier concentration, nature and volume of washing and eluting solvents were investigated. Amongst other anionic compounds, selectivity in extraction was observed for organophosphorus compounds. Recoveries of analytes were determined by GC-MS which ranged from 80% to 115%. Comparison of zirconia based solid-phase extraction method with anion-exchange solid-phase extraction revealed its selectivity towards phosphonic acids. The limits of detection (LOD) and limit of quantification (LOQ) with selected analytes were achieved down to 4.3 and 8.5 ng mL(-1), respectively, in selected ion monitoring mode.

  17. Sunscreening Agents

    PubMed Central

    Martis, Jacintha; Shobha, V; Sham Shinde, Rutuja; Bangera, Sudhakar; Krishnankutty, Binny; Bellary, Shantala; Varughese, Sunoj; Rao, Prabhakar; Naveen Kumar, B.R.

    2013-01-01

    The increasing incidence of skin cancers and photodamaging effects caused by ultraviolet radiation has increased the use of sunscreening agents, which have shown beneficial effects in reducing the symptoms and reoccurrence of these problems. Many sunscreen compounds are in use, but their safety and efficacy are still in question. Efficacy is measured through indices, such as sun protection factor, persistent pigment darkening protection factor, and COLIPA guidelines. The United States Food and Drug Administration and European Union have incorporated changes in their guidelines to help consumers select products based on their sun protection factor and protection against ultraviolet radiation, whereas the Indian regulatory agency has not yet issued any special guidance on sunscreening agents, as they are classified under cosmetics. In this article, the authors discuss the pharmacological actions of sunscreening agents as well as the available formulations, their benefits, possible health hazards, safety, challenges, and proper application technique. New technologies and scope for the development of sunscreening agents are also discussed as well as the role of the physician in patient education about the use of these agents. PMID:23320122

  18. Multiscale modeling of nerve agent hydrolysis mechanisms: a tale of two Nobel Prizes

    NASA Astrophysics Data System (ADS)

    Field, Martin J.; Wymore, Troy W.

    2014-10-01

    The 2013 Nobel Prize in Chemistry was awarded for the development of multiscale models for complex chemical systems, whereas the 2013 Peace Prize was given to the Organisation for the Prohibition of Chemical Weapons for their efforts to eliminate chemical warfare agents. This review relates the two by introducing the field of multiscale modeling and highlighting its application to the study of the biological mechanisms by which selected chemical weapon agents exert their effects at an atomic level.

  19. Chromo-fluorogenic detection of nerve-agent mimics using triggered cyclization reactions in push-pull dyes.

    PubMed

    Costero, Ana M; Parra, Margarita; Gil, Salvador; Gotor, Raúl; Mancini, Pedro M E; Martínez-Máñez, Ramón; Sancenón, Félix; Royo, Santiago

    2010-07-05

    A family of azo and stilbene derivatives (1-9) are synthesized, and their chromo-fluorogenic behavior in the presence of nerve-agent simulants, diethylchlorophosphate (DCP), diisopropylfluorophosphate (DFP), and diethylcyanophosphate (DCNP) in acetonitrile and mixed solution of water/acetonitrile (3:1 v/v) buffered at pH 5.6 with MES, is investigated. The prepared compounds contain 2-(2-N,N-dimethylaminophenyl)ethanol or 2-[(2-N,N-dimethylamino)phenoxy]ethanol reactive groups, which are part of the conjugated pi-system of the dyes and are able to give acylation reactions with phosphonate substrates followed by a rapid intramolecular N-alkylation. The nerve-agent mimic-triggered cyclization reaction transforms a dimethylamino group into a quaternary ammonium, inducing a change of the electronic properties of the delocalized systems that results in a hypsochromic shift of the absorption band of the dyes. Similar reactivity studies are also carried out with other "non-toxic" organophosphorus compounds, but no changes in the UV/Vis spectra were observed. The emission behaviour of the reagents in acetonitrile and water-acetonitrile 3:1 v/v mixtures is also studied in the presence of nerve-agent simulants and other organophosphorous derivatives. The reactivity between 1-9 and DCP, DCNP, or DFP in buffered water-acetonitrile 3:1 v/v solutions under pseudo first-order kinetic conditions, using an excess of the corresponding simulant, are studied in order to determine the rate constants (k) and the half-life times (t(1/2)=ln2/k) for the reaction. The detection limits in water/acetonitrile 3:1 v/v are also determined for 1-9 and DCP, DCNP, and DFP. Finally, the chromogenic detection of nerve agent simulants both in solution and in gas phase are tested using silica gel containing adsorbed compounds 1, 2, 3, 4, or 5 with fine results.

  20. Perspectives on the Use of Scopolamine as an Adjunct Treatment to Enhance Survival Following Organophosphorus Nerve Agent Poisoning

    DTIC Science & Technology

    2010-11-01

    MILITARY MEDICINE, 175, 11:878,2010 Perspectives on the Use of Scopolamine as an Adjunct Treatment to Enhance Survival Following Organophosphorus...Nerve Agent Poisoning Irwin Koplovitz, RhD; Susan Schulz ABSTRACT Scopolamine (SCP) is an anticholinergic drug used clinically for decades to treat...PB is currently EDA approved only for use against soman. Scopolamine (SCP) is a well known anticholinergic drug that has been used clinically for

  1. Structural Analysis and Bioengineering of Thermostable Pyrococcus furiosus Prolidase for the Optimization of Organophosphorus Nerve Agent Detoxification

    DTIC Science & Technology

    2012-04-26

    findings contained in this report are those of the author(s) and should not contrued as an official Department of the Army position, policy or decision...used in this project to design a prolidase mutant with two integral metal sites, which will relieve the requirement for exogenous metal and improve...its efficacy in OP nerve agent detoxification. In addition, a Ph prolidase homolog has been identified and has been biochemically characterized to

  2. The application of the fluoride reactivation process to the detection of sarin and soman nerve agent exposures in biological samples.

    PubMed

    Adams, T K; Capacio, B R; Smith, J R; Whalley, C E; Korte, W D

    2004-02-01

    The fluoride reactivation process was evaluated for measuring the level of sarin or soman nerve agents reactivated from substrates in plasma and tissue from in vivo exposed guinea pigs (Cava porcellus), in blood from in vivo exposed rhesus monkeys (Macaca mulatta), and in spiked human plasma and purified human albumin. Guinea pig exposures ranged from 0.05 to 44 LD50, and reactivated nerve agent levels ranged from 1.0 ng/mL in plasma obtained from 0.05 LD50 sarin-exposed guinea pigs to an average of 147 ng/g in kidney tissue obtained from two 2.0 LD50 soman-exposed guinea pigs. Positive dose-response relationships were observed in all low-level, 0.05 to 0.4 LD50, exposure studies. An average value of 2.4 ng/mL for reactivated soman was determined in plasma obtained from two rhesus monkeys three days after a 2 LD50 exposure. Of the five types of guinea pig tissue studied, plasma, heart, liver, kidney and lung, the lung and kidney tissue yielded the highest amounts of reactivated agent. In similar tissue and with similar exposure procedures, reactivated soman levels were greater than reactivated sarin levels. Levels of reactivated agents decreased rapidly with time while the guinea pig was alive, but decreased much more slowly after death. This latter chemical stability should facilitate forensic retrospective identification. The high level of reactivated agents in guinea pig samples led to the hypothesis that the principal source of reactivated agent came from the agent-carboxylesterase adduct. However, there could be contributions from adducts of the cholinesterases, albumin and fibrous tissue, as well. Quantitative analysis was performed with a GC-MS system using selected ion monitoring of the 99 and 125 ions for sarin and the 99 and 126 ions for soman. Detection levels were as low as 0.5 ng/mL. The assay was precise and easy to perform, and has potential for exposure analysis from organophosphate nerve agents and pesticides in other animal species.

  3. Cholinesterase reactivators: the fate and effects in the organism poisoned with organophosphates/nerve agents.

    PubMed

    Bajgar, J; Kuca, K; Jun, D; Bartosova, L; Fusek, J

    2007-12-01

    Understanding the mechanism of action of organophosphates (OP)/nerve agents -- irreversible acetylcholinesterase (AChE, EC 3.1.1.7) inhibition at the cholinergic synapses followed by metabolic dysbalance of the organism -- two therapeutic principles for antidotal treatment are derived. The main drugs are anticholinergics that antagonize the effects of accumulated acetylcholine at the cholinergic synapses and cholinesterase reactivators (oximes) reactivating inhibited AChE. Anticonvulsants such as diazepam are also used to treat convulsions. Though there are experimental data on a good therapeutic effects of reactivators, some attempts to underestimate the role of reactivators as effective antidotes against OP poisoning have been made. Some arguments on the necessity of their administration following OP poisoning are discussed. Their distribution patterns and some metabolic and pharmacological effects are described with the aim to resolve the question on their effective use, possible repeated administration in the treatment of OP poisoning, their peripheral and central effects including questions on their penetration through the blood brain barrier as well as a possibility to achieve their effective concentration for AChE reactivation in the brain. Reactivation of cholinesterases in the peripheral and central nervous system is described and it is underlined its importance for the survival or death of the organism poisoned with OP. Metabolization and some other effects of oximes (not connected with AChE reactivation) are discussed (e.g. forming of the phosphonylated oxime, parasympatholytic action, hepatotoxicity, behavioral changes etc.). An universality of oximes able to reactivate AChE inhibited by all OP is questioned and therefore, needs of development of new oximes is underlined.

  4. Computational characterization of how the VX nerve agent binds human serum paraoxonase 1.

    PubMed

    Fairchild, Steven Z; Peterson, Matthew W; Hamza, Adel; Zhan, Chang-Guo; Cerasoli, Douglas M; Chang, Wenling E

    2011-01-01

    Human serum paraoxonase 1 (HuPON1) is an enzyme that can hydrolyze various chemical warfare nerve agents including VX. A previous study has suggested that increasing HuPON1's VX hydrolysis activity one to two orders of magnitude would make the enzyme an effective countermeasure for in vivo use against VX. This study helps facilitate further engineering of HuPON1 for enhanced VX-hydrolase activity by computationally characterizing HuPON1's tertiary structure and how HuPON1 binds VX. HuPON1's structure is first predicted through two homology modeling procedures. Docking is then performed using four separate methods, and the stability of each bound conformation is analyzed through molecular dynamics and solvated interaction energy calculations. The results show that VX's lone oxygen atom has a strong preference for forming a direct electrostatic interaction with HuPON1's active site calcium ion. Various HuPON1 residues are also detected that are in close proximity to VX and are therefore potential targets for future mutagenesis studies. These include E53, H115, N168, F222, N224, L240, D269, I291, F292, and V346. Additionally, D183 was found to have a predicted pKa near physiological pH. Given D183's location in HuPON1's active site, this residue could potentially act as a proton donor or accepter during hydrolysis. The results from the binding simulations also indicate that steered molecular dynamics can potentially be used to obtain accurate binding predictions even when starting with a closed conformation of a protein's binding or active site.

  5. Evidence for nonacetylcholinesterase targets of organophosphorus nerve agent: supersensitivity of acetylcholinesterase knockout mouse to VX lethality.

    PubMed

    Duysen, E G; Li, B; Xie, W; Schopfer, L M; Anderson, R S; Broomfield, C A; Lockridge, O

    2001-11-01

    The possibility that organophosphate toxicity is due to inhibition of targets other than acetylcholinesterase (AChE, EC 3.1.1.7) was examined in AChE knockout mice. Mice (34-55 days old) were grouped for this study, after it was determined that AChE, butyrylcholinesterase (BChE), and carboxylesterase activities had reached stable values by this age. Mice with 0, 50, or 100% AChE activity were treated subcutaneously with the nerve agent VX. The LD50 for VX was 10 to 12 microg/kg in AChE-/-, 17 microg/kg in AChE+/-, and 24 microg/kg in AChE+/+ mice. The same cholinergic signs of toxicity were present in AChE-/- mice as in wild-type mice, even though AChE-/- mice have no AChE whose inhibition could lead to cholinergic signs. Wild-type mice, but not AChE-/- mice, were protected by pretreatment with atropine. Tissues were extracted from VX-treated and untreated animals and tested for AChE, BChE, and acylpeptide hydrolase activity. VX treatment inhibited 50% of the AChE activity in brain and muscle of AChE+/+ and +/- mice, 50% of the BChE activity in all three AChE genotypes, but did not significantly inhibit acylpeptide hydrolase activity. It was concluded that the toxicity of VX must be attributed to inhibition of nonacetylcholinesterase targets in the AChE-/- mouse. Organophosphorus ester toxicity in wild-type mice is probably due to inhibition or binding to several proteins, only one of which is AChE.

  6. Neuroprotective effects of imidazenil against chemical warfare nerve agent soman toxicity in guinea pigs.

    PubMed

    Wang, Ying; Oguntayo, Samuel; Wei, Yanling; Wood, Elisa; Brown, Ammon; Jensen, Neil; Auta, James; Guiodotti, Alessandro; Doctor, Bhupendra P; Nambiar, Madhusoodana P

    2012-03-01

    The chemical warfare nerve agent, soman irreversibly inhibits acetylcholinesterase (AChE) leading to hypercholinergy and seizures which trigger glutamate toxicity and status epilepticus ultimately resulting in neuropathology and neurobehavioral deficits. The standard emergency treatment comprising of anticholinergic, AChE reactivator and anticonvulsant does not completely protect against soman toxicity. We have evaluated imidazenil, a new anticonvulsant imidazo benzodiazepine with high affinity and intrinsic efficacy at α5-, α2-, and α3- but low intrinsic efficacy at α1-containing GABA(A) receptors and is devoid of cardiorespiratory depression, sedative/hypnoitc and amnestic actions and does not elicit tolerance and dependence liabilities unlike diazepam, for protection against soman toxicity. Guinea pigs implanted with bipotential radiotelemetry probes for recording EEG and ECG were administered with 26 μg/kg pyridostigmine bromide 30 min prior to 2× LD(50) soman exposure and 1 min later treated with a combination of 2mg/kg atropine sulfate and 25mg/kg 2-pralidoxime and various doses of imidazenil. Intramuscular administration of imidazenil, dose-dependently protected against 2× LD(50) of soman toxicity up to 1mg/kg. Further increase in the dose of imidazenil to 2.5mg/kg was less effective than 1mg/kg probably due to non-specific actions at sites other than GABA(A) receptors. Compared to vehicle group, 1mg/kg imidazenil treatment showed optimal increase in survival rate, reduction in behavioral manifestations and high power of EEG spectrum as well as neuronal necrosis. These data suggest that imidazenil is an effective anticonvulsant for medical countermeasure against soman-induced toxicity.

  7. Selective extraction of organophosphorus nerve agent degradation products by molecularly imprinted solid-phase extraction.

    PubMed

    Le Moullec, Sophie; Bégos, Arlette; Pichon, Valérie; Bellier, Bruno

    2006-03-03

    The analysis of alkyl alkylphosphonic acids, the degradation products of V and G nerve agents as VX, Sarin or Soman, is an important task for the verification of compliance to the Chemical Weapons Convention. The detection of these contaminants at low concentration levels is often difficult in complex matrices due to the amount of interfering substances. Molecularly imprinted solid-phase extraction technique should allow a selective extraction of these compounds from complex samples, and thus make their detection easier. Two molecularly imprinted polymers (MIPs) prepared with methacrylic acid (MAA) as monomer and pinacolyl methylphosphonic acid (PMPA) as template molecule were synthesised and tested. The first polymer, MIP A, was prepared with ethylene glycol dimethacrylate (EGDMA) in dichloromethane. The second polymer, MIP B, was synthesised using trimethylolpropane trimethacrylate (TRIM) in acetonitrile. To evaluate the selectivity provided by these MIPs, the retention of the ethyl methylphosphonic acid (EMPA) target molecule was studied in parallel on a non-imprinted polymer (NIP). While MIP A does not show any difference compared to NIP A, a good selectivity was obtained for MIP B. After the optimisation of the extraction process, 60% of EMPA can be removed from the NIP B without affecting the retention on the MIP B. A recovery of extraction of 93% was then obtained on the MIP B. Its capacity was then measured and corresponds to 97 microg of EMPA per gram of MIP. Finally, the selectivity of MIP B was clearly demonstrated by applying it to the clean-up of a soil extract spiked with EMPA.

  8. Pseudocatalytic scavenging of the nerve agent VX with human blood components and the oximes obidoxime and HI-6.

    PubMed

    Wille, Timo; von der Wellen, Jens; Thiermann, Horst; Worek, Franz

    2017-03-01

    Despite six decades of extensive research in medical countermeasures against nerve agent poisoning, a broad spectrum acetylcholinesterase (AChE) reactivator is not yet available. One current approach is directed toward synthesizing oximes with high affinity and reactivatability toward butyrylcholinesterase (BChE) in plasma to generate an effective pseudocatalytic scavenger. An interim solution could be the administration of external AChE or BChE from blood products to augment pseudocatalytic scavenging with slower but clinically approved oximes to decrease nerve agent concentrations in the body. We here semiquantitatively investigate the ability of obidoxime and HI-6 to decrease the inhibitory activity of VX with human AChE and BChE from whole blood, erythrocyte membranes, erythrocytes, plasma, clinically available fresh frozen plasma and packed red blood cells. The main findings are that whole blood showed a VX concentration-dependent decrease in inhibitory activity with HI-6 being more potent than obidoxime. Using erythrocytes and erythrocyte membranes again, HI-6 was more potent compared to obidoxime. With freshly prepared plasma, obidoxime and HI-6 showed comparable results for the decrease in VX. The use of the clinically available blood products revealed that packed red blood cells showed similar kinetics as fresh erythrocytes. Fresh frozen plasma resulted in a slower and incomplete decrease in inhibitory plasma compared to freshly prepared plasma. In conclusion, the administration of blood products in combination with available oximes augments pseudocatalytic scavenging and might be useful to decrease the body load of persistent, highly toxic nerve agents.

  9. Characterization of a phosphodiesterase capable of hydrolyzing EA 2192, the most toxic degradation product of the nerve agent VX.

    PubMed

    Ghanem, Eman; Li, Yingchun; Xu, Chengfu; Raushel, Frank M

    2007-08-07

    Glycerophosphodiesterase (GpdQ) from Enterobacter aerogenes is a nonspecific diesterase that enables Escherichia coli to utilize alkyl phosphodiesters, such as diethyl phosphate, as the sole phosphorus source. The catalytic properties of GpdQ were determined, and the best substrate found was bis(p-nitrophenyl) phosphate with a kcat/Km value of 6.7 x 10(3) M-1 s-1. In addition, the E. aerogenes diesterase was tested as a catalyst for the hydrolysis of a series of phosphonate monoesters which are the hydrolysis products of the highly toxic organophosphonate nerve agents sarin, soman, GF, VX, and rVX. Among the phosphonate monoesters tested, the hydrolysis product of rVX, isobutyl methyl phosphonate, was the best substrate with a kcat/Km value of 33 M-1 s-1. The ability of GpdQ to hydrolyze the phosphonate monoesters provides an alternative selection strategy in the search of enhanced variants of the bacterial phosphotriesterase (PTE) for the hydrolysis of organophosphonate nerve agents. This investigation demonstrated that the previously reported activity of GpdQ toward the hydrolysis of methyl demeton-S is due to the presence of a diester contaminant in the commercial material. Furthermore, it was shown that GpdQ is capable of hydrolyzing a close analogue of EA 2192, the most toxic and persistent degradation product of the nerve agent VX.

  10. Structure of a prereaction complex between the nerve agent sarin, its biological target acetylcholinesterase, and the antidote HI-6

    PubMed Central

    Allgardsson, Anders; Berg, Lotta; Akfur, Christine; Hörnberg, Andreas; Linusson, Anna; Ekström, Fredrik J.

    2016-01-01

    Organophosphorus nerve agents interfere with cholinergic signaling by covalently binding to the active site of the enzyme acetylcholinesterase (AChE). This inhibition causes an accumulation of the neurotransmitter acetylcholine, potentially leading to overstimulation of the nervous system and death. Current treatments include the use of antidotes that promote the release of functional AChE by an unknown reactivation mechanism. We have used diffusion trap cryocrystallography and density functional theory (DFT) calculations to determine and analyze prereaction conformers of the nerve agent antidote HI-6 in complex with Mus musculus AChE covalently inhibited by the nerve agent sarin. These analyses reveal previously unknown conformations of the system and suggest that the cleavage of the covalent enzyme–sarin bond is preceded by a conformational change in the sarin adduct itself. Together with data from the reactivation kinetics, this alternate conformation suggests a key interaction between Glu202 and the O-isopropyl moiety of sarin. Moreover, solvent kinetic isotope effect experiments using deuterium oxide reveal that the reactivation mechanism features an isotope-sensitive step. These findings provide insights into the reactivation mechanism and provide a starting point for the development of improved antidotes. The work also illustrates how DFT calculations can guide the interpretation, analysis, and validation of crystallographic data for challenging reactive systems with complex conformational dynamics. PMID:27140636

  11. Efficient hydrolysis of the chemical warfare nerve agent tabun by recombinant and purified human and rabbit serum paraoxonase 1.

    PubMed

    Valiyaveettil, Manojkumar; Alamneh, Yonas; Biggemann, Lionel; Soojhawon, Iswarduth; Doctor, Bhupendra P; Nambiar, Madhusoodana P

    2010-12-03

    Paraoxonase 1 (PON1) has been described as an efficient catalytic bioscavenger due to its ability to hydrolyze organophosphates (OPs) and chemical warfare nerve agents (CWNAs). It is the future most promising candidate as prophylactic medical countermeasure against highly toxic OPs and CWNAs. Most of the studies conducted so far have been focused on the hydrolyzing potential of PON1 against nerve agents, sarin, soman, and VX. Here, we investigated the hydrolysis of tabun by PON1 with the objective of comparing the hydrolysis potential of human and rabbit serum purified and recombinant human PON1. The hydrolysis potential of PON1 against tabun, sarin, and soman was evaluated by using an acetylcholinesterase (AChE) back-titration Ellman method. Efficient hydrolysis of tabun (100 nM) was observed with ∼25-40 mU of PON1, while higher concentration (80-250 mU) of the enzyme was required for the complete hydrolysis of sarin (11 nM) and soman (3 nM). Our data indicate that tabun hydrolysis with PON1 was ∼30-60 times and ∼200-260 times more efficient than that with sarin and soman, respectively. Moreover, the catalytic activity of PON1 varies from source to source, which also reflects their efficiency of hydrolyzing different types of nerve agents. Thus, efficient hydrolysis of tabun by PON1 suggests its promising potential as a prophylactic treatment against tabun exposure.

  12. Single-Channel Microchip for Fast Screening and Detailed Identification of Nitroaromatic Explosives and Organophosphate Nerve Agents

    SciTech Connect

    Wang, Joseph; Pumera, Martin; Chatrathi, Madhu P.; Escarpa, Alberto; Musameh, Mustafa; Collins, George E.; Mulchandani, Ashok; Lin, Yuehe )

    2002-02-25

    A single-channel chip-based analytical microsystem which allows rapid flow-injection measurements of the total content of organic-explosive or nerve-agent compounds, as well as detailed micellar chromatographic identification of the individual ones is described. The protocol involves repetitive rapid flow-injection (screening) assays - for providing a timely warning and alarm - and switching to the separation (fingerprint identification) mode only when harmful compounds are detected. While micellar electrokinetic chromatography (MEKC), in the presence of sodium dodecyl sulfate (SDS), is used for separating the neutral nitroaromatic-explosive and nerve-agent compounds, an operation without SDS leads to high-speed measurements of the 'total' explosives or nerve-agent content. Switching between the 'flow-injection' and 'separation' modes is accomplished by rapidly exchanging the SDS-free and SDS-containing buffers in the separation channel. Amperometric detection was used for monitoring the separation. Key factors influencing the sample throughput, resolution, and sensitivity have been assessed and optimized. Assays rates of ca. 360 and 30 per hour can thus be realized for the 'total' screening and 'individual' measurements, respectively. Ultimately, such development will lead to the creation of a field-deployable microanalyzer, and will enable transporting the forensic laboratory to the sample source.

  13. Structure of a prereaction complex between the nerve agent sarin, its biological target acetylcholinesterase, and the antidote HI-6.

    PubMed

    Allgardsson, Anders; Berg, Lotta; Akfur, Christine; Hörnberg, Andreas; Worek, Franz; Linusson, Anna; Ekström, Fredrik J

    2016-05-17

    Organophosphorus nerve agents interfere with cholinergic signaling by covalently binding to the active site of the enzyme acetylcholinesterase (AChE). This inhibition causes an accumulation of the neurotransmitter acetylcholine, potentially leading to overstimulation of the nervous system and death. Current treatments include the use of antidotes that promote the release of functional AChE by an unknown reactivation mechanism. We have used diffusion trap cryocrystallography and density functional theory (DFT) calculations to determine and analyze prereaction conformers of the nerve agent antidote HI-6 in complex with Mus musculus AChE covalently inhibited by the nerve agent sarin. These analyses reveal previously unknown conformations of the system and suggest that the cleavage of the covalent enzyme-sarin bond is preceded by a conformational change in the sarin adduct itself. Together with data from the reactivation kinetics, this alternate conformation suggests a key interaction between Glu202 and the O-isopropyl moiety of sarin. Moreover, solvent kinetic isotope effect experiments using deuterium oxide reveal that the reactivation mechanism features an isotope-sensitive step. These findings provide insights into the reactivation mechanism and provide a starting point for the development of improved antidotes. The work also illustrates how DFT calculations can guide the interpretation, analysis, and validation of crystallographic data for challenging reactive systems with complex conformational dynamics.

  14. Antidiabetic Agents.

    ERIC Educational Resources Information Center

    Plummer, Nancy; Michael, Nancy, Ed.

    This module on antidiabetic agents is intended for use in inservice or continuing education programs for persons who administer medications in long-term care facilities. Instructor information, including teaching suggestions, and a listing of recommended audiovisual materials and their sources appear first. The module goal and objectives are then…

  15. A cyclization-induced emission enhancement (CIEE)-based ratiometric fluorogenic and chromogenic probe for the facile detection of a nerve agent simulant DCP.

    PubMed

    Mahapatra, Ajit Kumar; Maiti, Kalipada; Manna, Saikat Kumar; Maji, Rajkishor; Mondal, Sanchita; Das Mukhopadhyay, Chitrangada; Sahoo, Prithidipa; Mandal, Debasish

    2015-06-14

    The first ratiometric fluorescent probe for the detection of a nerve agent simulant was developed based on tandem phosphorylation and intramolecular cyclization, by which high sensitivity as well as large emission shift could be achieved.

  16. Development of reactive topical skin protectants against sulfur mustard and nerve agents.

    PubMed

    Koper, O; Lucas, E; Klabunde, K J

    1999-12-01

    The potential for highly reactive nanoparticles (RNP) to absorb destructively, i.e. to neutralize highly toxic substances such as the warfare agents GA, GB, HD and VX, has been demonstrated in the laboratory. Reactive nanoparticles represent a new class of nanoscale particles of metals and metal oxides that differ from other nanoparticles in reactivity and crystalline morphology. The potential for incorporating RNP into a protective barrier skin cream also has been demonstrated. Preliminary studies indicate that RNP are physically and chemically compatible with a base cream provided by the Army Medical Research Office and, importantly, remain reactive with chemical agents while promising to be compatible with skin contact.

  17. Novel bifunctional hybrid small molecule scavengers for mitigating nerve agents toxicity.

    PubMed

    Amitai, Gabriel; Gez, Rellie; Raveh, Lily; Bar-Ner, Nira; Grauer, Ettie; Chapman, Shira

    2016-11-25

    The antidotal treatment of organophosphates (OP) nerve agents (NA) poisoning is based on anticholinergics (e.g. atropine) combined with oxime reactivators (e.g. 2PAM) of acetylcholinesterase (AChE). This treatment is symptomatic and does not degrade the OP. New small-molecule OP scavengers were developed as bifunctional hybrids. Their molecular design was based on combining a nucleophile that directly degrades OP with a moiety that reactivates OP-inhibited AChE. The OP degrading moiety is either benzhydroxamic acid (BHA) or 4-pyridinehydroxamic acid (4PHA) coupled via (CH2)n, (n = 1 or 3) to 2PAM. Three newly synthesized oxime-hydroxamate hybrids: 2PAMPr4PHA, 2PAMMeBHA and 2,4-DiPAMMeBHA were found to detoxify sarin, cyclosarin and soman in solution at 3-10-fold faster rate than 2PAM and to reactivate OP-AChE in vitro. 2PAMPr4PHA displayed 18-fold faster reactivation than 2-PAM of cyclosarin-inhibited HuAChE (kr = 3.6 × 10(2) vs. 0.2 × 10(2) M(-1)min(-1), respectively, 37 °C). These hybrids inhibited AChE reversibly, IC50 = 16-48 μM, thereby decreasing the inhibition rates by OPs. The LD50 (im) of 2PAMPr4PHA, 2PAMMeBHA and 2,4DiPAMMeBHA are >568, 508 and >506 μmol/kg in rats and 144, 203 and >506 μmol/kg in guinea pigs. The rate of blood ChE recovery by the hybrids administered either pre- or post-exposure to 0.8xLD50 sarin was comparable or faster than 2PAM. Antidotal efficacy of 2PAMPr4PHA, 2PAMMeBHA and 2,4DiPAMMeBHA administered with atropine, as pre-treatment to sarin in rats (im), yielded protection ratios (PR) 11.6, 11.5 and 4.7, respectively, vs. 5.5 with 2PAM. Post-treatment against various OPs in rats and guinea-pigs yielded PRs higher or similar to that of 2 PAM. Our in vivo data indicates that some hybrids may serve as efficient small molecule scavengers for mitigating the toxicity of OP NAs.

  18. Anticonvulsant efficacy of antihistamine cyproheptadine in rats exposed to the chemical warfare nerve agent soman.

    PubMed

    Winkler, Jennifer L; Skovira, Jacob W; Kan, Robert K

    2017-01-01

    Organophosphate compounds, such as soman and sarin, are highly toxic chemical warfare nerve agents that cause a build-up of acetylcholine in synapses and neuromuscular junctions. Current therapies aim to prevent seizures and protect against brain injury following exposure. The present study was designed to evaluate the effectiveness of the antihistamine cyproheptadine in improving survival and controlling seizures in rats exposed to soman. Rats were pretreated with the oxime reactivator HI-6 (125mg/kg, ip) 30min prior to soman exposure (225μg/kg, sc) and then treated with atropine methylnitrate (AMN, 2.0mg/kg, im) 1min after soman. Cyproheptadine (10, 13, 16 or 20mg/kg, ip) was given at one of three time points: 1min after soman intoxication, at the onset of soman-induced seizures or 5min after seizure onset. Control animals were exposed to soman and given an equivalent volume of sterile water instead of cyproheptadine. The incidence of seizures, mortality, neuron counts, neuropathology and apoptosis in specific regions of the brain were evaluated. In animals given HI-6 and AMN the incidence of soman-induced seizure and mortality rate within the first 24h were 100%. When cyproheptadine was given at a dose of 13 or 20mg/kg 1min after soman exposure, the incidence of seizures was reduced from 100% to 13% and 30%, respectively. In addition, cyproheptadine given at 1min after soman exposure increased the survival rate to 100% regardless of dose. When cyproheptadine was administered at seizure onset, seizures were terminated in 100% of the animals at doses above 10mg/kg. The survival rate with cyproheptadine treatment at the onset of seizure was ≥83%. Seizures terminated in ≥75% of the animals that received cyproheptadine 5min after soman-induced seizure onset. When given at 5min after seizure onset the survival rate was 100% at all tested doses of cyproheptadine. The neuropathology scores and the number of TUNEL positive cells in the brain regions examined

  19. Assessing Protection Against OP Pesticides and Nerve Agents Provided by Wild-Type HuPON1 Purified from Trichoplusia ni Larvae or Induced via Adenoviral Infection

    DTIC Science & Technology

    2013-01-01

    organophosphorus (OP) pesticides and nerve agents. We assessed the potential of this enzyme to protect against OP poison - ing using two different paradigms...6,10–13]. PON1 is believed to play an important role in determining the resistance or susceptibility to OP pesticide poisoning , in that PON1 knockout...type nerve agent are inadequate to protect against poisoning by these compounds [17,18]. In contrast, injection of exogenous wild-type HuPON1 has

  20. In vivo microdialysis and electroencephalographic activity in freely moving guinea pigs exposed to organophosphorus nerve agents sarin and VX: analysis of acetylcholine and glutamate.

    PubMed

    O'Donnell, John C; McDonough, John H; Shih, Tsung-Ming

    2011-12-01

    Organophosphorus nerve agents such as sarin (GB) and VX irreversibly inhibit acetylcholinesterase, causing a buildup of acetylcholine (ACh) in synapses and neuromuscular junctions, which leads to excess bronchial secretions, convulsions, seizures, coma, and death. Understanding the unique toxic characteristics of different nerve agents is vital in the effort to develop broad spectrum medical countermeasures. To this end, we employed a repeated measure multivariate design with striatal microdialysis collection and high-performance liquid chromatography analysis to measure changes in concentrations of several neurotransmitters (ACh, glutamate, aspartate, GABA) in the same samples during acute exposure to GB or VX in freely moving guinea pigs. Concurrent with microdialysis collection, we used cortical electrodes to monitor brain seizure activity. This robust double multivariate design provides greater fidelity when comparing data while also reducing the required number of subjects. No correlation between nerve agents' propensity for causing seizure and seizure-related lethality was observed. The GB seizure group experienced more rapid and severe cholinergic toxicity and lethality than that of the VX seizure group. Seizures generated from GB and VX exposure resulted in further elevation of ACh level and then a gradual return to baseline. Glutamate levels increased in the GB, but not in the VX, seizure group. There were no consistent changes in either aspartate or GABA as a result of either nerve agent. These observations reinforce findings with other nerve agents that seizure activity per se contributes to the elevated levels of brain ACh observed after nerve agent exposure.

  1. Feature generation and statistical analysis of physiological responses to nerve-agent exposure. Final report, January 1984-January 1985

    SciTech Connect

    Fu; Swain, P.H.; Anuta, P.E.

    1986-04-01

    This report describes research carried out on the problem of automated information extraction from multichannel physiological signals. Analog tapes were obtained of data recorded during an animal study of the ventilatory requirements after nerve-agent exposure. The main objective of the research was to determine if the physiological signals contained information relevant to the state of the subject. It was also of great interest to determine if the feature condition of the subject could be predicted from the data obtained at a point shortly after initial contact with the agent. This study also included development of techniques for compression and processing of large volumes of data. This report covers data digitalization, feature generation, and data analysis. Because of the limited numbers of tapes available with adequate quality signals, only three experiments were analyzed in depth. Feature generation and analysis algorithms were developed and used on data from these experiments. Statistical and physiological feature evaluations of the data revealed that information from several signals, when displayed as biplots, permitted differentiation among the carrying states of the animals. Results of this contract indicate that these techniques may be useful in developing algorithms which predict the consequences for casualties based on data obtained shortly after nerve agent exposure.

  2. Derivatization of organophosphorus nerve agent degradation products for gas chromatography with ICPMS and TOF-MS detection.

    PubMed

    Richardson, Douglas D; Caruso, Joseph A

    2007-06-01

    Separation and detection of seven V-type (venomous) and G-type (German) organophosphorus nerve agent degradation products by gas chromatography with inductively coupled plasma mass spectrometry (GC-ICPMS) is described. The nonvolatile alkyl phosphonic acid degradation products of interest included ethyl methylphosphonic acid (EMPA, VX acid), isopropyl methylphosphonic acid (IMPA, GB acid), ethyl hydrogen dimethylamidophosphate sodium salt (EDPA, GA acid), isobutyl hydrogen methylphosphonate (IBMPA, RVX acid), as well as pinacolyl methylphosphonic acid (PMPA), methylphosphonic acid (MPA), and cyclohexyl methylphosphonic acid (CMPA, GF acid). N-(tert-Butyldimethylsilyl)-N-methyltrifluroacetamide with 1% TBDMSCl was utilized to form the volatile TBDMS derivatives of the nerve agent degradation products for separation by GC. Exact mass confirmation of the formation of six of the TBDMS derivatives was obtained by GC-time of flight mass spectrometry (TOF-MS). The method developed here allowed for the separation and detection of all seven TBDMS derivatives as well as phosphate in less than ten minutes. Detection limits for the developed method were less than 5 pg with retention times and peak area precisions of less than 0.01 and 6%, respectively. This method was successfully applied to river water and soil matrices. To date this is the first work describing the analysis of chemical warfare agent (CWA) degradation products by GC-ICPMS.

  3. In situ determination of nerve agents in various matrices by portable capillary electropherograph with contactless conductivity detection.

    PubMed

    Kubáň, Petr; Seiman, Andrus; Makarõtševa, Natalja; Vaher, Merike; Kaljurand, Mihkel

    2011-05-06

    Rapid, efficient and robust methods for sampling and extracting genuine nerve agents sarin, soman and VX were developed for analyzing these compounds on various solid matrices, such as concrete, tile, soil and vegetation. A portable capillary electrophoretic (CE) system with contactless conductometric detection was used for the in situ analysis of the extracted samples. A 7.5 mM MES/HIS-based separation electrolyte accomplished the analysis of target analytes in less than 5 min. The overall duration of the process including instrument start-up, sample extraction and analysis was less than 10 min, which is the fastest screening of nerve agents achieved with liquid phase separation methods to date. The procedure can easily be performed by a person in a protective suit and is therefore suitable for real-life applications. The CE results were validated by an independent GC-MS method and a satisfactory correlation was obtained. The use of a proper sampling strategy with two internal standards and "smart" data-processing software can overcome the low reproducibility of CE. This has a significant impact on the potential acceptance of portable CE instrumentation for the detection and analysis of genuine chemical warfare agents (CWA).

  4. Promethazine as a Novel Prophylaxis and Treatment for Nerve Agent Poisoning

    DTIC Science & Technology

    2008-12-01

    between bregma -2.30 mm and -3.80 mm, as described by Paxinos and Watson ( Paxinos and Watson, 1998), were stained with hematoxylin and eosin (H&E...related brain damage induced by cholinergic agents, Journal?, 301(5900), 520- 522. Paxinos , G., and Watson, C., 1998: The rat brain in stereotaxic

  5. Human plasma-derived BuChE as a stoichiometric bioscavenger for treatment of nerve agent poisoning.

    PubMed

    Mumford, Helen; Docx, Cerys J; Price, Matthew E; Green, A Christopher; Tattersall, John E H; Armstrong, Stuart J

    2013-03-25

    Potent organophosphorous (OP) agents, such as VX, are hazardous by absorption through the skin and are resistant to conventional pharmacological antidotal treatments. The residence time of a stoichiometric bioscavenger, human butyrylcholinesterase (huBuChE), in the plasma more closely matches that of VX than do the residence times of conventional therapy drugs (oxime, anti-muscarinic, anticonvulsant). Intramuscular (i.m.) huBuChE afforded almost complete protection when administered prior to the onset of observable cholinergic signs of VX poisoning, but once signs of poisoning became evident the efficacy of i.m. huBuChE decreased. A combination of nerve agent therapy drugs (oxime, anti-muscarinic, anticonvulsant) with huBuChE (i.m.) protected 100% (8/8) of guinea-pigs from a lethal dose of VX (0.74 mg/kg) to 48 h, even when administered on signs of poisoning. Survival was presumed to be due to immediate alleviation of the cholinergic crisis by the conventional pharmacological treatment drugs, in conjunction with bioscavenger that prevented further absorbed agent reaching the AChE targets. Evidence to support this proposed mechanism of action was obtained from PKPD experiments in which multiple blood samples and microdialysate samples were collected from individual conscious ambulatory animals. Plasma concentrations of intramuscularly-administered atropine, diazepam and HI-6 reached a peak within 15 min and were eliminated rapidly within 4h. Plasma concentrations of huBuChE administered by the i.m. route took approximately 24h to reach a peak, but were well-maintained over the subsequent 7days. Thus, the pharmacological therapy rapidly treated the initial signs of poisoning, whilst the bioscavenger provided prolonged protection by neutralising further nerve agent entering the bloodstream and preventing it from reaching the target organs.

  6. Efficacy evaluation of physostigmine and anticholinergic adjuncts as a pretreatment for nerve agent intoxication. (Reannouncement with new availability information)

    SciTech Connect

    von Bredow, J.; Corcoran, K.; Maitland, G.; Kaminskis, A.; Adams, N.

    1991-12-31

    Pretreatment of nonhuman primates with physostigmine (Phy) and scopolamine or physostigmine and trihexyphenidyl 25 min before exposure to 2 LD50 soman im resulted in complete survival without convulsions or loss of consciousness. When identically pretreated animals were challenged with 5 LD50s of soman followed by atropine and 2-PAM therapy 1 min later, all animals experienced a loss of consciousness for approximately 10 min followed by functional recovery within an additional 20 min. These findings indicated that a pretreatment regimen composed of Phy and cholinolytic is capable of protecting primates from an absolute lethal dose of soman with rapid recovery from incapacitation. Physostigmine, nerve agent pretreatment, cynomolgus monkeys soman (GD).

  7. New Autoinductive Cascade for the Optical Sensing of Fluoride: Application in the Detection of Phosphoryl Fluoride Nerve Agents.

    PubMed

    Sun, Xiaolong; Dahlhauser, Samuel D; Anslyn, Eric V

    2017-04-05

    A new autoinductive cascade employing benzoyl fluoride as a latent source of fluoride is reported for signal amplification and optical detection of fluoride. The autoinduction leads to a maximum 4-fold signal enhancement for each fluoride generated, as well as a self-propagating cycle that generates three fluorophores for each single fluoride released. A two-step integrated protocol creates a more rapid autoinductive cascade than previously reported, as well as a highly sensitive diagnostic assay for the ultratrace quantitation of a phosphoryl fluoride nerve agent surrogate.

  8. Quantitation of organophosphorus nerve agent metabolites in human urine using isotope dilution gas chromatography-tandem mass spectrometry.

    PubMed

    Driskell, W Jack; Shih, Ming; Needham, Larry L; Barr, Dana B

    2002-01-01

    An isotope dilution gas chromatography-tandem mass spectrometric (GC-MS-MS) method was developed for quantitating the urinary metabolites of the organophosphorus nerve agents sarin, soman, tabun (GA), VX, and GF. Urine samples were concentrated by codistillation with acetonitrile, derivatized by methylation with diazomethane, and analyzed by GC-MS-MS. The limits of detection were less than 4 microg/L for all the analytes except for the GA metabolite, which had a limit of detection of less than 20 microg/L.

  9. Toxicity and medical countermeasure studies on the organophosphorus nerve agents VM and VX.

    PubMed

    Rice, Helen; Dalton, Christopher H; Price, Matthew E; Graham, Stuart J; Green, A Christopher; Jenner, John; Groombridge, Helen J; Timperley, Christopher M

    2015-04-08

    To support the effort to eliminate the Syrian Arab Republic chemical weapons stockpile safely, there was a requirement to provide scientific advice based on experimentally derived information on both toxicity and medical countermeasures (MedCM) in the event of exposure to VM, VX or VM-VX mixtures. Complementary in vitro and in vivo studies were undertaken to inform that advice. The penetration rate of neat VM was not significantly different from that of neat VX, through either guinea pig or pig skin in vitro. The presence of VX did not affect the penetration rate of VM in mixtures of various proportions. A lethal dose of VM was approximately twice that of VX in guinea pigs poisoned via the percutaneous route. There was no interaction in mixed agent solutions which altered the in vivo toxicity of the agents. Percutaneous poisoning by VM responded to treatment with standard MedCM, although complete protection was not achieved.

  10. Mutagenesis of organophosphorus hydrolase to enhance hydrolysis of the nerve agent VX.

    PubMed

    Gopal, S; Rastogi, V; Ashman, W; Mulbry, W

    2000-12-20

    Organophosphorus hydrolase (OPH) is capable of hydrolyzing a wide variety of organophosphorus pesticides and chemical warfare agents. However, the hydrolytic activity of OPH against the warfare agent VX is less than 0.1% relative to its activity against parathion and paraoxon. Based on the crystal structure of OPH and the similarities it shares with acetylcholinesterase, eight OPH mutants were constructed with the goal of increasing OPH activity toward VX. The activities of crude extracts from these mutants were measured using VX, demeton-S methyl, diisopropylfluoro-phosphate, ethyl parathion, paraoxon, and EPN as substrates. One mutant (L136Y) displayed a 33% increase in the relative VX hydrolysis rate compared to wild type enzyme. The other seven mutations resulted in 55-76% decreases in the relative rates of VX hydrolysis. There was no apparent relationship between the hydrolysis rates of VX and the rates of the other organophosphorus compounds tested.

  11. Toxicity and medical countermeasure studies on the organophosphorus nerve agents VM and VX

    PubMed Central

    Rice, Helen; Dalton, Christopher H.; Price, Matthew E.; Graham, Stuart J.; Green, A. Christopher; Jenner, John; Groombridge, Helen J.; Timperley, Christopher M.

    2015-01-01

    To support the effort to eliminate the Syrian Arab Republic chemical weapons stockpile safely, there was a requirement to provide scientific advice based on experimentally derived information on both toxicity and medical countermeasures (MedCM) in the event of exposure to VM, VX or VM–VX mixtures. Complementary in vitro and in vivo studies were undertaken to inform that advice. The penetration rate of neat VM was not significantly different from that of neat VX, through either guinea pig or pig skin in vitro. The presence of VX did not affect the penetration rate of VM in mixtures of various proportions. A lethal dose of VM was approximately twice that of VX in guinea pigs poisoned via the percutaneous route. There was no interaction in mixed agent solutions which altered the in vivo toxicity of the agents. Percutaneous poisoning by VM responded to treatment with standard MedCM, although complete protection was not achieved. PMID:27547080

  12. KGB agents

    NASA Astrophysics Data System (ADS)

    Gaina, Alex

    A short story is reported in which the activity of Communist Party of the USSR and secret KGB agents, which were payed by the State, in view of controlling of the conscience of population. The story reffers to the Physics Department of the Moscow University, Planing Institute of the Gosplan of Moldavian S.S.R. and Chishinau Technical University (actually: Technical University of Moldova), where the author has worked during Soviet times. Almost every 6-th citizen in the USSR was engaged in this activity, while actually the former communists rule in the Republic of Moldova.

  13. Determination of LCt50s in Anesthetized Rats Exposed to Aerosolized Nerve Agents

    DTIC Science & Technology

    2013-01-01

    kg ketamine. Following anesthesia, rats were intubated with a glass endotracheal tube (ET) and placed in a glove box. The ET was connected to a...using an aerosolization technique, directly into the intubated airway of anes- thetized rats using a small animal ventilator (Harvard Model 683...and the endotracheal tube. Agent off-gassing from the lung into the expira- tion air outflow was trapped in 10% NaOH (or char- coal) prior to the

  14. Comprehensive gas chromatography with Time of Flight MS and large volume introduction for the detection of fluoride-induced regenerated nerve agent in biological samples.

    PubMed

    van der Meer, J A; Trap, H C; Noort, D; van der Schans, M J

    2010-05-15

    Recently, several methods have been developed to verify exposure to nerve agents. Most of these methods, such as the fluoride reactivation technique and the analysis of inhibited phosphonylated butyrylcholinesterase (BuChE), are based on mass spectrometry. The high specificity of the mass spectrometer might also imply a disadvantage, because the acquisition mass, i.e. the identity of the analyte must be known beforehand in order to direct the MS analysis in the most sensitive mode. In real cases, the identity of the nerve agent is not always known beforehand and the mass spectrometer should be operated in a scanning mode, with the consequence that sensitivity of the method will be lower. Comprehensive GC, or GC x GC, is a technique which offers enhanced separation. The implied larger selectivity of the GC separation allows mass spectrometry to be conducted in a less specific, scanning, mode. By the use of this configuration, the identity of the nerve agent does not have to be known beforehand but can be traced. In order to be able to detect lower concentrations and assess lower exposure levels, a large volume injection technique was developed allowing sample sizes up to 100 microL. The technique was tested with plasma samples that had been inhibited with various nerve agents. Subsequently, the cholinesterase-bound nerve agent was regenerated by the fluoride reactivation technique. Using the newly developed comprehensive GC-MS method it was possible to detect nerve agent at an exposure level of 1% BuChE inhibition, which is approximately 70 pg nerve agent/mL. These low exposure levels cannot be verified with a cholinesterase (ChE) activity assay. Moreover, the identity of the regenerated nerve agent was verified by the mass spectrum that was generated by the TOF mass spectrometer. This paper presents a technique able to deliver full-scan data on the analysis of nerve agents in biomedical samples at relevant exposure levels (1% BuChE inhibition). This full-scan data

  15. Toxicokinetics of the nerve agent (+/-)-VX in anesthetized and atropinized hairless guinea pigs and marmosets after intravenous and percutaneous administration.

    PubMed

    van der Schans, Marcel J; Lander, Brenda J; van der Wiel, Herma; Langenberg, Jan P; Benschop, Hendrik P

    2003-08-15

    In continuation of our investigations on the toxicokinetics of the volatile nerve agents C(+/-)P(+/-)-soman and (+/-)-sarin, we now report on the toxicokinetics of the rather nonvolatile agent (+/-)-VX. A validated method was developed to determine blood levels of (+/-)-VX by means of achiral gas chromatography at blood levels > or =10 pg/ml. The ratio of the two enantiomers of VX in blood could be measured at levels > or =1 ng/ml by using chiral HPLC in combination with off-line gas chromatographic analysis. In order to obtain basic information on the toxicokinetics of (+/-)-VX, i.e., under conditions of 100% bioavailability, the blood levels of this agent were measured in hairless guinea pigs at iv doses corresponding with 1 and 2 LD50. The derived AUCs indicate a reasonable linearity of the toxicokinetics with dose. Also, the toxicokinetics in marmoset primates was studied at an absolute iv dose corresponding with 1 LD50 in the hairless guinea pig which led to approximately the same levels of (+/-)-VX in blood as observed at 2 LD50 in the hairless guinea pig. Finally, the toxicokinetics of (+/-)-VX were measured in hairless guinea pigs via the most relevant porte d' entrée for this agent, which is the percutaneous route at a dose corresponding with 1 LD50 (pc). Large variations were observed between individual animals in the rate of penetration of (+/-)-VX and in concomitant progression of AChE inhibition in blood of these animals. Blood levels of (+/-)-VX increased gradually over a 6-h period of time. After a 7-h penetration period, the total AUC corresponded with 2.5% bioavailability relative to iv administration. In contrast with the G-agents C(+/-)P(+/-)-soman and (+/-)-sarin, stereospecificity in the sequestration of the two enantiomers of (+/-)-VX is not a prominent phenomenon. It appears that (+/-)-VX is substantially more persistent in vivo than the two G-agents. This persistence may undermine the efficacy of pretreatment with carbamates of percutaneous

  16. Ionization mechanism of the ambient pressure pyroelectric ion source (APPIS) and its applications to chemical nerve agent detection.

    PubMed

    Neidholdt, Evan L; Beauchamp, J L

    2009-11-01

    We present studies of the ionization mechanism operative in the ambient pressure pyroelectric ionization source (APPIS), along with applications that include detection of simulants for chemical nerve agents. It is found that ionization by APPIS occurs in the gas-phase. As the crystal is thermally cycled over a narrow temperature range, electrical discharges near the surface of the crystal produce energetic species which, through reactions with atmospheric molecules, result in reactant ions such as protonated water clusters or clusters of hydroxide and water. Reactant ions can be observed directly in the mass spectrometer. These go on to react with trace neutrals via proton transfer reactions to produce the ions observed in mass spectra, which are usually singly protonated or deprotonated species. Further implicating gas-phase ionization, observed product distributions are highly dependent on the composition of ambient gases, especially the concentration of water vapor and oxygen surrounding the source. For example, basic species such as triethylamine are observed as singly protonated cations at a water partial pressure of 10 torr. At a water pressure of 4 torr, reactive oxygen species are formed and lead to observation of protonated amine oxides. The ability of the APPIS source to detect basic molecules with high proton affinities makes it highly suited for the detection of chemical nerve agents. We demonstrate this application using simulants corresponding to VX and GA (Tabun). With the present source configuration pyridine is detected readily at a concentration of 4 ppm, indicating ultimate sensitivity in the high ppb range.

  17. Quantification of nerve agent adducts with albumin in rat plasma using liquid chromatography-isotope dilution tandem mass spectrometry.

    PubMed

    Bao, Yi; Liu, Qin; Chen, Jia; Lin, Ying; Wu, Bidong; Xie, Jianwei

    2012-03-16

    A sensitive method for the determination of the organophosphorus nerve agents sarin, soman and VX adducts with tyrosine residue of albumin in rat plasma has been developed and validated using liquid chromatography-isotope dilution tandem mass spectrometry (LC-IDMS/MS). O-(O-Alkyl methylphosphonyl) tyrosine adducts and their deuterated products that were used as the internal standards were synthesised to establish the quantitative isotope-dilution method. Protein purification and solid-phase extraction (SPE) were applied to improve the recovery efficiency, reduce interference and achieve high sensitivity. The method provided a detection limit of 0.01 ng/mL for sarin and soman adducts and 0.05 ng/mL for the VX adduct. The value of the intra-day relative standard deviation over the calibration range was less than 6.16% (n=6), and that of the inter-day was less than 12.7% (n=6). The recovery varied from 86% to 111%. This sensitive method was successfully applied to the analysis of adducts in rat plasma after nerve agent exposure, and the results demonstrated the dose-effect relationships.

  18. A highly stable minimally processed plant-derived recombinant acetylcholinesterase for nerve agent detection in adverse conditions.

    PubMed

    Rosenberg, Yvonne J; Walker, Jeremy; Jiang, Xiaoming; Donahue, Scott; Robosky, Jason; Sack, Markus; Lees, Jonathan; Urban, Lori

    2015-08-13

    Although recent innovations in transient plant systems have enabled gram quantities of proteins in 1-2 weeks, very few have been translated into applications due to technical challenges and high downstream processing costs. Here we report high-level production, using a Nicotiana benthamiana/p19 system, of an engineered recombinant human acetylcholinesterase (rAChE) that is highly stable in a minimally processed leaf extract. Lyophylized clarified extracts withstand prolonged storage at 70 °C and, upon reconstitution, can be used in several devices to detect organophosphate (OP) nerve agents and pesticides on surfaces ranging from 0 °C to 50 °C. The recent use of sarin in Syria highlights the urgent need for nerve agent detection and countermeasures necessary for preparedness and emergency responses. Bypassing cumbersome and expensive downstream processes has enabled us to fully exploit the speed, low cost and scalability of transient production systems resulting in the first successful implementation of plant-produced rAChE into a commercial biotechnology product.

  19. Verification of exposure to cholinesterase inhibitors: generic detection of OPCW Schedule 1 nerve agent adducts to human butyrylcholinesterase.

    PubMed

    van der Schans, M J; Fidder, A; van Oeveren, D; Hulst, A G; Noort, D

    2008-01-01

    Phosphylated butyrylcholinesterase is one of the most important biomarkers to verify an exposure to nerve agents, and it can be analyzed with liquid chromatography-tandem mass spectrometry (LC-MS-MS) by detection of a phosphylated nonapeptide that results after digestion of butyrylcholinesterase (BuChE) with pepsin. For a sensitive analysis (low degree of BuChE inhibition), the identity of the cholinesterase inhibitor has to be known in order to use the LC-MS-MS instrument in the most sensitive selected reaction monitoring mode. In practice, the identity of the cholinesterase inhibitor will not be known beforehand, and the number of possible organophosphates is greater than 1000. However, the number of possible molecular masses of organophosphates is approximately 170. A method for which only 34 transitions in the multiple reaction monitoring mode have to be acquired in order to screen for an exposure to all Organization for the Prohibition of Chemical Weapons Schedule 1 nerve agents was developed.

  20. A highly stable minimally processed plant-derived recombinant acetylcholinesterase for nerve agent detection in adverse conditions

    PubMed Central

    Rosenberg, Yvonne J.; Walker, Jeremy; Jiang, Xiaoming; Donahue, Scott; Robosky, Jason; Sack, Markus; Lees, Jonathan; Urban, Lori

    2015-01-01

    Although recent innovations in transient plant systems have enabled gram quantities of proteins in 1–2 weeks, very few have been translated into applications due to technical challenges and high downstream processing costs. Here we report high-level production, using a Nicotiana benthamiana/p19 system, of an engineered recombinant human acetylcholinesterase (rAChE) that is highly stable in a minimally processed leaf extract. Lyophylized clarified extracts withstand prolonged storage at 70 °C and, upon reconstitution, can be used in several devices to detect organophosphate (OP) nerve agents and pesticides on surfaces ranging from 0 °C to 50 °C. The recent use of sarin in Syria highlights the urgent need for nerve agent detection and countermeasures necessary for preparedness and emergency responses. Bypassing cumbersome and expensive downstream processes has enabled us to fully exploit the speed, low cost and scalability of transient production systems resulting in the first successful implementation of plant-produced rAChE into a commercial biotechnology product. PMID:26268538

  1. Immobilization of organophosphate hydrolase on biocompatible gelatin pads and its use in removal of organophosphate compounds and nerve agents.

    PubMed

    Kanugula, Anantha KoteswaraRao; Repalle, Elisha Raju; Pandey, Jay Prakash; Sripad, Gunwar; Mitra, Chanchal Kumar; Dubey, Devender Kumar; Siddavattam, Dayananda

    2011-02-01

    Bacterial organophosphate hydrolases (OPH) have been shown to hydrolyze structurally diverse group of organophosphate (OP) compounds and nerve agents. Due to broad substrate range and unusual catalytic properties, the OPH has successfully been used to develop eco-friendly strategies for detection and decontamination of OP compounds. However, their usage has failed to gain necessary acceptance, due to short half-life of the enzyme and loss of activity during process development. In the present study, we report a simple procedure for immobilization of OPH on biocompatible gelatin pads. The covalent coupling of OPH using glutaraldehyde spacer has been found to dramatically improve the enzyme stability. There is no apparent loss of OPH activity in OPH-gelatin pads stored at room temperature for more than six months. As revealed by a number of kinetic parameters, the catalytic properties of immobilized enzyme are found to be comparable to the free enzyme. Further, the OPH-gelatin pads effectively eliminate OP insecticide methyl parathion and nerve agent sarin.

  2. Effects of the diacylglycerol complexing agent, cremophor, on nerve-conduction velocity and perfusion in diabetic rats.

    PubMed

    Jack, A M; Cameron, N E; Cotter, M A

    1999-01-01

    The contribution of diacylglycerol (DAG) and protein kinase C (PKC) to diabetic complications has been the subject of debate. In vascular tissues, diabetes increases DAG content, which activates PKC and causes abnormal tissue perfusion. Reduced nerve blood flow has been implicated in the development of neuropathy. However, nerve DAG/PKC activity is not increased and may even be reduced by diabetes, which has also been implicated in neuropathy. The aim was to test whether 2 weeks of treatment with cremophor, an agent that complexes DAG and prevents PKC activation, could correct nerve-conduction velocity (NCV) deficits in rats with 6 weeks of untreated diabetes, as predicted on a vascular hypothesis, or whether this worsened the deficits, as predicted for a direct effect on nerve fibers. Diabetes caused 17.9 +/- 0.9% (+/- SEM) and 15.5 +/- 1.6% reductions in sciatic motor and saphenous sensory NCV, respectively, that were largely (79.6 +/- 6.3% and 57.8 +/- 11.5%) corrected by 100 mg x kg(-1) x day(-1) cremophor treatment. The effects of cremophor on motor and sensory NCV were completely attenuated by co-treatment with the nitric oxide synthase inhibitor, N(G)-nitro-l-arginine. In contrast, co-treatment with the cyclooxygenase inhibitor, flurbiprofen, had no effect on NCV. Sciatic nutritive and total endoneurial perfusion were 49.7 +/- 3.4% and 51.8 +/- 4.2% reduced by diabetes, respectively, and these deficits were 69.5 +/- 7.4% and 79.0 +/- 11.6% corrected by cremophor treatment. Thus the data suggest that an increased DAG/PKC vascular mechanism, perhaps linked to the nitric oxide system, contributes to the etiology of diabetic nerve dysfunction.

  3. Comparison of status epilepticus models induced by pilocarpine and nerve agents - a systematic review of the underlying aetiology and adopted therapeutic approaches.

    PubMed

    Tang, F R; Loke, W K; Ling, E A

    2011-01-01

    Among potential radiological, nuclear, biological and chemical weapons, cholinergic nerve agents from chemical weapons remain a realistic terrorist threat due to its combination of high lethality, demonstrated use and relative abundance of un-destroyed stockpiles in various militaries around the world. While current fielded antidotes are able to mitigate acute poisoning, effective neuroprotection in the field remains a challenge amongst subjects with established status epilepticus following nerve agent intoxication. Due to ethical, safety and surety issues, extensive preclinical and clinical research on cholinergic nerve agents is not possible. This may have been a contributory factor for the slow progress in uncovering new neuroprotectants for nerve agent casualties with established status epilepticus. To overcome this challenge, comparative research with surrogate chemicals that produce similar hypercholinergic toxicity but with less security concerns would be a useful approach forward. In this paper, we will systemically compare the mechanism of seizure generation, propagation and the subsequent clinical, hematologic, and metabolic, biochemical, neuroinflammatory changes and current therapeutic approaches reported in pilocarpine, soman, and sarin models of seizures. This review will be an important first step in closing this knowledge gap among different closely related models of seizures and neurotoxicity. Hopefully, it will spur further efforts in using surrogate cholinergic models by the wider scientific community to expedite the development of a new generation of antidotes that are better able to protect against delayed neurological effects inflicted by nerve agents.

  4. A 10-minute point-of-care assay for detection of blood protein adducts resulting from low level exposure to organophosphate nerve agents.

    PubMed

    VanDine, Robert; Babu, Uma Mahesh; Condon, Peter; Mendez, Arlene; Sambursky, Robert

    2013-03-25

    The OrganoTox test is a rapid, point-of-care assay capable of detecting clinically relevant organophosphate (OP) poisoning after low-level exposure to sarin, soman, tabun, or VX chemical nerve agents. The test utilizes either a finger stick peripheral blood sample or plasma specimen. While high-level nerve agent exposure can quickly lead to death, low-level exposure produces vague, nondescript signs and symptoms that are not easily clinically differentiated from other conditions. In initial testing, the OrganoTox test was used to detect the presence of blood protein-nerve agent adducts in exposed blood samples. In order to mimic the in vivo exposure as closely as possible, nerve agents stored in organic solvents were spiked in minute quantities into whole blood samples. For performance testing, 40 plasma samples were spiked with sarin, soman, tabun, or VX and 10 normal plasma samples were used as the negative control. The 40 nerve agent-spiked plasma samples included 10 replicates of each agent. At the clinically relevant low-level exposure of 10 ng/ml, the OrganoTox test demonstrated 100% sensitivity for soman, tabun, and VX and 80% sensitivity for sarin. The OrganoTox test demonstrated greater than 97% specificity with 150 blood samples obtained from healthy adults. No cross-reactivity or interference from pesticide precursor compounds was found. A rapid test for nerve agent exposure will help identify affected patients earlier in the clinical course and trigger more appropriate medical management in a more timely manner.

  5. A microneedle biosensor for minimally-invasive transdermal detection of nerve agents.

    PubMed

    Mishra, Rupesh K; Vinu Mohan, A M; Soto, Fernando; Chrostowski, Robert; Wang, Joseph

    2017-03-13

    A microneedle electrochemical biosensor for the minimally invasive detection of organophosphate (OP) chemical agents is described. The new sensor relies on the coupling of the effective biocatalytic action of organophosphorus hydrolase (OPH) with a hollow-microneedle modified carbon-paste array electrode transducer, and involves rapid square-wave voltammetric (SWV) measurements of the p-nitrophenol product of the OPH enzymatic reaction in the presence of the OP substrate. The scanning-potential SWV transduction mode offers an additional dimension of selectivity compared to common fixed-potential OPH-amperometric biosensors. The microneedle device offers a highly linear response for methyl paraoxon (MPOx) over the range of 20-180 μM, high selectivity in the presence of excess co-existing ascorbic acid and uric acid and a high stability sensor upon exposure to the interstitial fluid (ISF). The OPH microneedle sensor was successfully tested ex vivo using mice skin samples exposed to MPOx, demonstrating its promise for minimally-invasive monitoring of OP agents and pesticides and as a wearable sensor for detecting toxic compounds, in general.

  6. Health care agents

    MedlinePlus

    Durable power of attorney for health care; Health care proxy; End-of-life - health care agent; Life support treatment - ... Respirator - health care agent; Ventilator - health care agent; Power of attorney - health care agent; POA - health care ...

  7. Detecting agents.

    PubMed Central

    Johnson, Susan C

    2003-01-01

    This paper reviews a recent set of behavioural studies that examine the scope and nature of the representational system underlying theory-of-mind development. Studies with typically developing infants, adults and children with autism all converge on the claim that there is a specialized input system that uses not only morphological cues, but also behavioural cues to categorize novel objects as agents. Evidence is reviewed in which 12- to 15-month-old infants treat certain non-human objects as if they have perceptual/attentional abilities, communicative abilities and goal-directed behaviour. They will follow the attentional orientation of an amorphously shaped novel object if it interacts contingently with them or with another person. They also seem to use a novel object's environmentally directed behaviour to determine its perceptual/attentional orientation and object-oriented goals. Results from adults and children with autism are strikingly similar, despite adults' contradictory beliefs about the objects in question and the failure of children with autism to ultimately develop more advanced theory-of-mind reasoning. The implications for a general theory-of-mind development are discussed. PMID:12689380

  8. Efficient heterogeneous and environmentally friendly degradation of nerve agents on a tungsten-based POM.

    PubMed

    Mizrahi, Dana M; Saphier, Sigal; Columbus, Ishay

    2010-07-15

    Common (chemical warfare agent) CWA decontaminants exhibit harsh and corrosive characteristics, and are harmful to the environment. In the course of our quest for active sorbents as efficient decontaminants, Keggin-type polyoxometalate (POM) (NH(4))(3)PW(12)O(40) was tested for oxidative degradation of CWAs. Although oxidation did not take place, sarin (GB) and VX were smoothly decontaminated to non-toxic products within 1 and 10 days, respectively. Degradation was carried out directly on the powder, eliminating the need for solvents. Mustard gas (HD), whose degradation is highly dependent on oxidation, was not decontaminated by this POM. Solid state MAS NMR ((31)P and (13)C) was utilized both for POM characterization and for decontamination studies monitoring.

  9. Butyrylcholinesterase in guinea pig lung lavage: a novel biomarker to assess lung injury following inhalation exposure to nerve agent VX.

    PubMed

    Graham, Jacob R; Wright, Benjamin S; Rezk, Peter E; Gordon, Richard K; Sciuto, Alfred M; Nambiar, Madhusoodana P

    2006-06-01

    Respiratory disturbances play a central role in chemical warfare nerve agent (CWNA) induced toxicity; they are the starting point of mass casualty and the major cause of death. We developed a microinstillation technique of inhalation exposure to nerve agent VX and assessed lung injury by biochemical analysis of the bronchoalveolar lavage fluid (BALF). Here we demonstrate that normal guinea pig BALF has a significant amount of cholinesterase activity. Treatment with Huperzine A, a specific inhibitor of acetylcholinesterase (AChE), showed that a minor fraction of BALF cholinesterase is AChE. Furthermore, treatment with tetraisopropyl pyrophosphoramide (iso-OMPA), a specific inhibitor of butyrylcholinesterase (BChE), inhibited more than 90% of BChE activity, indicating the predominance of BChE in BALF. A predominance of BChE expression in the lung lavage was seen in both genders. Substrate specific inhibition indicated that nearly 30% of the cholinesterase in lung tissue homogenate is AChE. BALF and lung tissue AChE and BChE activities were strongly inhibited in guinea pigs exposed for 5 min to 70.4 and 90.4 microg/m3 VX and allowed to recover for 15 min. In contrast, BALF AChE activity was increased 63% and 128% and BChE activity was increased 77% and 88% after 24 h of recovery following 5 min inhalation exposure to 70.4 microg/m3 and 90.4 mg/m3 VX, respectively. The increase in BALF AChE and BChE activity was dose dependent. Since BChE is synthesized in the liver and present in the plasma, an increase in BALF indicates endothelial barrier injury and leakage of plasma into lung interstitium. Therefore, a measure of increased levels of AChE and BChE in the lung lavage can be used to determine the chronology of barrier damage as well as the extent of lung injury following exposure to chemical warfare nerve agents.

  10. Integration of multi-array sensors and support vector machines for the detection and classification of organophosphate nerve agents

    NASA Astrophysics Data System (ADS)

    Land, Walker H., Jr.; Sadik, Omowunmi A.; Embrechts, Mark J.; Leibensperger, Dale; Wong, Lut; Wanekaya, Adam; Uematsu, Michiko

    2003-08-01

    Due to the increased threats of chemical and biological weapons of mass destruction (WMD) by international terrorist organizations, a significant effort is underway to develop tools that can be used to detect and effectively combat biochemical warfare. Furthermore, recent events have highlighted awareness that chemical and biological agents (CBAs) may become the preferred, cheap alternative WMD, because these agents can effectively attack large populations while leaving infrastructures intact. Despite the availability of numerous sensing devices, intelligent hybrid sensors that can detect and degrade CBAs are virtually nonexistent. This paper reports the integration of multi-array sensors with Support Vector Machines (SVMs) for the detection of organophosphates nerve agents using parathion and dichlorvos as model stimulants compounds. SVMs were used for the design and evaluation of new and more accurate data extraction, preprocessing and classification. Experimental results for the paradigms developed using Structural Risk Minimization, show a significant increase in classification accuracy when compared to the existing AromaScan baseline system. Specifically, the results of this research has demonstrated that, for the Parathion versus Dichlorvos pair, when compared to the AromaScan baseline system: (1) a 23% improvement in the overall ROC Az index using the S2000 kernel, with similar improvements with the Gaussian and polynomial (of degree 2) kernels, (2) a significant 173% improvement in specificity with the S2000 kernel. This means that the number of false negative errors were reduced by 173%, while making no false positive errors, when compared to the AromaScan base line performance. (3) The Gaussian and polynomial kernels demonstrated similar specificity at 100% sensitivity. All SVM classifiers provided essentially perfect classification performance for the Dichlorvos versus Trichlorfon pair. For the most difficult classification task, the Parathion versus

  11. α-Linolenic Acid, A Nutraceutical with Pleiotropic Properties That Targets Endogenous Neuroprotective Pathways to Protect against Organophosphate Nerve Agent-Induced Neuropathology.

    PubMed

    Piermartiri, Tetsade; Pan, Hongna; Figueiredo, Taiza H; Marini, Ann M

    2015-11-12

    α-Linolenic acid (ALA) is a nutraceutical found in vegetable products such as flax and walnuts. The pleiotropic properties of ALA target endogenous neuroprotective and neurorestorative pathways in brain and involve the transcription factor nuclear factor kappa B (NF-κB), brain-derived neurotrophic factor (BDNF), a major neuroprotective protein in brain, and downstream signaling pathways likely mediated via activation of TrkB, the cognate receptor of BDNF. In this review, we discuss possible mechanisms of ALA efficacy against the highly toxic OP nerve agent soman. Organophosphate (OP) nerve agents are highly toxic chemical warfare agents and a threat to military and civilian populations. Once considered only for battlefield use, these agents are now used by terrorists to inflict mass casualties. OP nerve agents inhibit the critical enzyme acetylcholinesterase (AChE) that rapidly leads to a cholinergic crisis involving multiple organs. Status epilepticus results from the excessive accumulation of synaptic acetylcholine which in turn leads to the overactivation of muscarinic receptors; prolonged seizures cause the neuropathology and long-term consequences in survivors. Current countermeasures mitigate symptoms and signs as well as reduce brain damage, but must be given within minutes after exposure to OP nerve agents supporting interest in newer and more effective therapies. The pleiotropic properties of ALA result in a coordinated molecular and cellular program to restore neuronal networks and improve cognitive function in soman-exposed animals. Collectively, ALA should be brought to the clinic to treat the long-term consequences of nerve agents in survivors. ALA may be an effective therapy for other acute and chronic neurodegenerative disorders.

  12. Quantitation of metabolites of the nerve agents sarin, soman, cyclohexylsarin, VX, and Russian VX in human urine using isotope-dilution gas chromatography-tandem mass spectrometry.

    PubMed

    Barr, John R; Driskell, W J; Aston, Linda S; Martinez, Rodolfo A

    2004-01-01

    Organophosphorus nerve agents are among the most toxic organic compounds known and continue to be a threat for both military and terrorist use. We have developed an isotope-dilution gas chromatography-tandem mass spectrometric (GC-MS-MS) method for quantitating the urinary metabolites of the organophosphorus nerve agents sarin (GB), soman (GD), VX, Russian VX (RVX), and cyclohexylsarin (GF). Urine samples were acidified, extracted into ether-acetonitrile, derivatized by methylation with diazomethane, and analyzed by GC-MS-MS. The limits of detection were less than 1 micro g/L for all analytes.

  13. Liquid chromatography tandem mass spectrometry applied to quantitation of the organophosphorus nerve agent VX in microdialysates from blood probes.

    PubMed

    Stubbs, S J; Read, R W

    2010-05-15

    VX (O-ethyl-S-[2(di-isopropylamino)ethyl] methylphosphonothiolate) is a low volatility organophosphorus (OP) nerve agent and therefore the most likely route of exposure is via percutaneous absorption. Microdialysis has been used as a tool to study percutaneous poisoning by VX in the anesthetised guinea pig. A liquid chromatography tandem mass spectrometry (LC-MS-MS) method using positive electrospray ionisation (ESI) was used to quantitate VX in microdialysate samples collected from microdialysis probes, implanted into a blood vessel of anesthetised guinea pigs. The method resulted from modification of a LC-MS-MS method previously developed for the analysis of dermal microdialysates. Modification increased the sensitivity of the method, allowing quantitation of the trace levels of VX in blood microdialysates, over the range 0.002-1 ng/ml, with linear calibration. Quantitative results have been used to determine the time course of VX concentrations in the blood of guinea pigs following percutaneous poisoning.

  14. Detection of DNT, TNT, HF, and nerve agents using photoluminescence and interferometry from a porous silicon chip

    NASA Astrophysics Data System (ADS)

    Sailor, Michael J.; Trogler, William C.; Content, Stephane; Letant, Sonia; Sohn, Honglae; Fainman, Yeshaiahu; Shames, Paul E.

    2000-07-01

    Porous silicon chips have been used to detect vapors of explosives and a simulant for the nerve agents Sarin, Soman, and GF using two different transduction modes: reflectivity and photoluminescence. Detection of nitroaromatic compounds is achieved by monitoring the photoluminescence of a nanocrystalline porous Si film on exposure to the analyte of interest in a flowing air stream. Photoluminescence is quenched on exposure to the nitroaromatic. Detection limits of 2 ppb and 1 ppb were observed for 2,4-dinitrotoluene, and 2,4,6-trinitrotoluene, respectively (exposure times of 5 min for each, in air). Specificity for detection is achieved in a two-channel system using catalytic oxidation of the nitroaromatic.

  15. Acute toxic effects of nerve agent VX on respiratory dynamics and functions following microinsillation inhalation exposure in guinea pigs.

    PubMed

    Rezk, Peter E; Graham, Jacob R; Moran, Theodore S; Gordon, Richard K; Sciuto, Alfred M; Doctor, Bhupendra P; Nambiar, Madhusoodana P

    2007-03-01

    Exposure to a chemical warfare nerve agent (CWNA) leads to severe respiratory distress, respiratory failure, or death if not treated. We investigated the toxic effects of nerve agent VX on the respiratory dynamics of guinea pigs following exposure to 90.4 mug/m3 of VX or saline by microinstillation inhalation technology for 10 min. Respiratory parameters were monitored by whole-body barometric plethysmography at 4, 24, and 48 h, 7 d, 18 d, and 4 wk after VX exposure. VX-exposed animals showed a significant decrease in the respiratory frequency (RF) at 24 and 48 h of recovery (p value .0329 and .0142, respectively) compared to the saline control. The tidal volume (TV) slightly increased in VX exposed animals at 24 and significantly at 48 h (p = .02) postexposure. Minute ventilation (MV) increased slightly at 4 h but was reduced at 24 h and remained unchanged at 48 h. Animals exposed to VX also showed an increase in expiratory (Te) and relaxation time (RT) at 24 and 48 h and a small reduction in inspiratory time (Ti) at 24 h. A significant increase in end expiratory pause (EEP) was observed at 48 h after VX exposure (p = .049). The pseudo lung resistance (Penh) was significantly increased at 4 h after VX exposure and remained slightly high even at 48 h. Time-course studies reveal that most of the altered respiratory dynamics returned to normal at 7 d after VX exposure except for EEP, which was high at 7 d and returned to normal at 18 d postexposure. After 1 mo, all the monitored respiratory parameters were within normal ranges. Bronchoalveolar lavage (BAL) 1 mo after exposure showed virtually no difference in protein levels, cholinesterase levels, cell number, and cell death in the exposed and control animals. These results indicate that sublethal concentrations of VX induce changes in respiratory dynamics and functions that over time return to normal levels.

  16. Medical countermeasure against respiratory toxicity and acute lung injury following inhalation exposure to chemical warfare nerve agent VX.

    PubMed

    Nambiar, Madhusoodana P; Gordon, Richard K; Rezk, Peter E; Katos, Alexander M; Wajda, Nikolai A; Moran, Theodore S; Steele, Keith E; Doctor, Bhupendra P; Sciuto, Alfred M

    2007-03-01

    To develop therapeutics against lung injury and respiratory toxicity following nerve agent VX exposure, we evaluated the protective efficacy of a number of potential pulmonary therapeutics. Guinea pigs were exposed to 27.03 mg/m(3) of VX or saline using a microinstillation inhalation exposure technique for 4 min and then the toxicity was assessed. Exposure to this dose of VX resulted in a 24-h survival rate of 52%. There was a significant increase in bronchoalveolar lavage (BAL) protein, total cell number, and cell death. Surprisingly, direct pulmonary treatment with surfactant, liquivent, N-acetylcysteine, dexamethasone, or anti-sense syk oligonucleotides 2 min post-exposure did not significantly increase the survival rate of VX-exposed guinea pigs. Further blocking the nostrils, airway, and bronchioles, VX-induced viscous mucous secretions were exacerbated by these aerosolized treatments. To overcome these events, we developed a strategy to protect the animals by treatment with atropine. Atropine inhibits muscarinic stimulation and markedly reduces the copious airway secretion following nerve agent exposure. Indeed, post-exposure treatment with atropine methyl bromide, which does not cross the blood-brain barrier, resulted in 100% survival of VX-exposed animals. Bronchoalveolar lavage from VX-exposed and atropine-treated animals exhibited lower protein levels, cell number, and cell death compared to VX-exposed controls, indicating less lung injury. When pulmonary therapeutics were combined with atropine, significant protection to VX-exposure was observed. These results indicate that combinations of pulmonary therapeutics with atropine or drugs that inhibit mucous secretion are important for the treatment of respiratory toxicity and lung injury following VX exposure.

  17. Enhanced Stability of Blood Matrices Using a Dried Sample Spot Assay to Measure Human Butyrylcholinesterase Activity and Nerve Agent Adducts

    PubMed Central

    Perez, Jonas W.; Pantazides, Brooke G.; Watson, Caroline M.; Thomas, Jerry D.; Blake, Thomas A.; Johnson, Rudolph C.

    2015-01-01

    Dried matrix spots are safer to handle and easier to store than wet blood products, but factors such as intra-spot variability and unknown sample volumes have limited their appeal as a sampling format for quantitative analyses. In this work, we introduce a dried spot activity assay for quantifying butyrylcholinesterase (BChE) specific activity which is BChE activity normalized to the total protein content in a sample spot. The method was demonstrated with blood, serum, and plasma spotted on specimen collection devices (cards) which were extracted to measure total protein and BChE activity using a modified Ellman assay. Activity recovered from dried spots was ∼80% of the initial spotted activity for blood and >90% for plasma and serum. Measuring total protein in the sample and calculating specific activity substantially improved quantification and reduced intra-spot variability. Analyte stability of nerve agent adducts was also evaluated, and the results obtained via BChE-specific activity measurements were confirmed by quantification of BChE adducts using a previously established LC-MS/MS method. The spotted samples were up to 10-times more resistant to degradation compared to unspotted control samples when measuring BChE inhibition by the nerve agents sarin and VX. Using this method, both BChE activity and adducts can be accurately measured from a dried sample spot. This use of a dried sample spot with normalization to total protein is robust, demonstrates decreased intra-spot variability without the need to control for initial sample volume, and enhances analyte stability. PMID:25955132

  18. Resveratrol induces catalytic bioscavenger paraoxonase 1 expression and protects against chemical warfare nerve agent toxicity in human cell lines.

    PubMed

    Curtin, Bryan F; Seetharam, Karthik I; Dhoieam, Pilin; Gordon, Richard K; Doctor, Bhupendra P; Nambiar, Madhusoodana P

    2008-04-01

    Current advances in enzyme bioscavenger prophylactic therapy against chemical warfare nerve agent (CWNA) exposure are moving towards the identification of catalytic bioscavengers that can degrade large doses of organophosphate (OP) nerve agents without self destruction. This is a preferred method compared to therapy with the purified stoichiometric bioscavenger, butyrylcholinesterase, which binds OPs 1:1 and would thus require larger doses for treatment. Paraoxonase-1 (PON-1) is one such catalytic bioscavenger that has been shown to hydrolyze OP insecticides and contribute to detoxification in animals and humans. Here we investigated the effects of a common red wine ingredient, Resveratrol (RSV), to induce the expression of PON-1 in the human hepatic cell line HC04 and evaluated the protection against CWNA simulants. Dose-response curves showed that a concentration of 20 microM RSV was optimal in inducing PON-1 expression in HC04 cells. RSV at 20 microM increased the extracellular PON-1 activity approximately 150% without significantly affecting the cells. Higher doses of RSV were cytotoxic to the cells. Resveratrol also induced PON-1 in the human lung cell line A549. RSV pre-treatment significantly (P = 0.05) protected the hepatic cells against exposure to 2x LD(50) of soman and sarin simulants. However, lung cells were protected against soman simulant exposure but not against sarin simulant exposure following RSV treatment. In conclusion, these studies indicate that dietary inducers, such as RSV, can up-regulate PON-1, a catalytic bioscavenger, which can then hydrolyze and protect against CWNA-induced toxicity, providing a prospective new method to protect against CWNA exposure.

  19. Tandem capillary column gas chromatography-mass spectrometric determination of the organophosphonate nerve agent surrogate dimethyl methylphosphonate in gaseous phase.

    PubMed

    McDaniel, Les N; Romero, Nicholas A; Boyd, Jonathan; Coimbatore, Gopal; Cobb, George P

    2010-06-15

    A procedure based on capillary column gas chromatographic-mass spectrometric (GC-MS) confirmation was developed for the verification of the ubiquitous and versatile chemical and nerve agent simulant, dimethyl methyl phosphonate (DMMP; CAS# 756-79-6), from gaseous samples. This method was developed to verify low nanogram DMMP concentrations during testing of a nerve agent detection system. Standard solutions of 1, 5, 10, 50, 100, 500, and 1000ng/ml DMMP in acetonitrile were employed. Through 15 calibration curves using the 5 lowest concentrations, coefficient of determination (r(2)) values showed a mean of 0.998 (0.992-1.000). An additional 15 calibration curves likewise containing 5 concentrations of DMMP spanning 3 orders of magnitude (1, 50, 100, 500, and 1000ng/ml) yielded a mean r(2) of 0.997 (0.991-1.000). Sixty-five nitrogen diluted gaseous samples varying from 1.0 to 10.0microl in volume were analyzed and concentrations of DMMP ranging from 1 to 1000ng/ml were confirmed. An additional 35 vapor samples in UHP N(2) ranging in DMMP concentration from 5.8microg/m(3) to 1.0mg/m(3) were analyzed by increasing sample volume range to between 10.0 and 100microl. For gaseous samples with volumes>1.0microl, the lowest concentration observed was 5.8microg/m(3). The method detection limit (Appendix B of Title 40 CFR, United States) for 1.0microl autoinjected standards in acetonitrile was determined to be 0.331ng/ml. Method precision for 15 independently analyzed standards of 25ng/ml had a relative standard deviation of 1.168. This method demonstrated high linearity across a wide range of concentrations, as well as excellent sensitivity and repeatability, and proved applicable to other lower alkyl-phosphonates.

  20. Medical countermeasure against respiratory toxicity and acute lung injury following inhalation exposure to chemical warfare nerve agent VX

    SciTech Connect

    Nambiar, Madhusoodana P.; Doctor, Bhupendra P.

    2007-03-15

    To develop therapeutics against lung injury and respiratory toxicity following nerve agent VX exposure, we evaluated the protective efficacy of a number of potential pulmonary therapeutics. Guinea pigs were exposed to 27.03 mg/m{sup 3} of VX or saline using a microinstillation inhalation exposure technique for 4 min and then the toxicity was assessed. Exposure to this dose of VX resulted in a 24-h survival rate of 52%. There was a significant increase in bronchoalveolar lavage (BAL) protein, total cell number, and cell death. Surprisingly, direct pulmonary treatment with surfactant, liquivent, N-acetylcysteine, dexamethasone, or anti-sense syk oligonucleotides 2 min post-exposure did not significantly increase the survival rate of VX-exposed guinea pigs. Further blocking the nostrils, airway, and bronchioles, VX-induced viscous mucous secretions were exacerbated by these aerosolized treatments. To overcome these events, we developed a strategy to protect the animals by treatment with atropine. Atropine inhibits muscarinic stimulation and markedly reduces the copious airway secretion following nerve agent exposure. Indeed, post-exposure treatment with atropine methyl bromide, which does not cross the blood-brain barrier, resulted in 100% survival of VX-exposed animals. Bronchoalveolar lavage from VX-exposed and atropine-treated animals exhibited lower protein levels, cell number, and cell death compared to VX-exposed controls, indicating less lung injury. When pulmonary therapeutics were combined with atropine, significant protection to VX-exposure was observed. These results indicate that combinations of pulmonary therapeutics with atropine or drugs that inhibit mucous secretion are important for the treatment of respiratory toxicity and lung injury following VX exposure.

  1. Polymer-based lanthanide luminescent sensor for detection of the hydrolysis product of the nerve agent Soman in water.

    PubMed

    Jenkins, A L; Uy, O M; Murray, G M

    1999-01-15

    The techniques of molecular imprinting and sensitized lanthanide luminescence have been combined to create the basis for a sensor that can selectively measure the hydrolysis product of the nerve agent Soman in water. The sensor functions by selectively and reversibly binding the phosphonate hydrolysis product of this agent to a functionality-imprinted copolymer possessing a coordinatively bound luminescent lanthanide ion, Eu3+. Instrumental support for this device is designed to monitor the appearance of a narrow luminescence band in the 610-nm region of the Eu3+ spectrum that results when the analyte is coordinated to the copolymer. The ligand field shifted luminescence was excited using 1 mW of the 465.8-nm line of an argon ion laser and monitored via an optical fiber using a miniature spectrometer. For this configuration, the limit of detection for the hydrolysis product is 7 parts per trillion (ppt) in solution with a linear range from 10 ppt to 10 ppm. Chemical and spectroscopic selectivities have been combined to reduce the likelihood of false positive analyses. Chemically analogous organophosphorus pesticides tested against the sensor have been shown to not interfere with determination.

  2. Detection of munitions grade g-series nerve agents using Raman excitation at 1064 nm

    NASA Astrophysics Data System (ADS)

    Roy, Eric; Wilcox, Phillip G.; Hoffland, Soren; Pardoe, Ian

    2015-05-01

    Raman spectroscopy is a powerful tool for obtaining molecular structure information of a sample. While Raman spectroscopy is a common laboratory based analytical tool, miniaturization of opto-electronic components has allowed handheld Raman analyzers to become commercially available. These handheld systems are utilized by Military and First Responder operators tasked with rapidly identifying potentially hazardous chemicals in the field. However, one limitation of many handheld Raman detection systems is strong interference caused by fluorescence of the sample or underlying surface which obscures the characteristic Raman signature of the target analyte. Munitions grade chemical warfare agents (CWAs) are produced and stored in large batches and typically have more impurities from the storage container, degradation, or unreacted precursors. In this work, Raman spectra of munitions grade CWAs were collected using a handheld Raman spectrometer with a 1064 nm excitation laser. While Raman scattering generated by a 1064 nm laser is inherently less efficient than excitation at shorter wavelengths, high quality spectra were easily obtained due to significantly reduced fluorescence of the munitions grade CWAs. The spectra of these less pure, but more operationally relevant, munitions grade CWAs were then compared to spectra of CASARM grade CWAs, as well as Raman spectra collected using the more common 785 nm excitation laser.

  3. An animal model to study health effects during continuous low-dose exposure to the nerve agent VX.

    PubMed

    Rocksén, David; Elfsmark, Daniel; Heldestad, Victoria; Wallgren, Karin; Cassel, Gudrun; Göransson Nyberg, Ann

    2008-08-19

    In the present study, we have developed an animal model to study long-term health effects of continuous exposure of toxic chemical agents, in awake, freely moving rats. The aim was to evaluate the effect of low-dose exposure of the nerve agent VX, and to find specific biomarkers for intoxication. To exclude the influence of stress, we used an implanted radio-telemetric device for online registration of physiological parameters, and an osmotic pump, implanted subcutaneously, for continuous exposure of the toxic agent. Our results showed that the lowest observable effect dose of VX in Wistar rats was 5 microg/kg/24 h, after continuous exposure by the osmotic pump. Although we observed significant inhibition of acetylcholinesterase (AChE) in blood and a significant decrease in body weight gain at this dose, no change in blood pressure, heart rate or respiratory rate was registered. However, a significant decrease in the thyroid hormone, free T4, was measured in blood after 8 weeks, indicating that low doses of VX might affect the thyroid function. Rats given repeated daily injections were more sensitive to VX and needed only 1/10 of the concentration to reach a similar level of AChE inhibition, compared to animals exposed by the osmotic pump. Moreover, the results showed that exposure of VX in our experimental design, does not induce an increase in corticosterone blood levels. Thus, the model used in this investigation renders minimal stress and will not cause unnecessary pain to the animals, indicating that this model could be a useful tool to study long-term effects of various toxic substances in freely moving rats.

  4. Crystal structures of brain group-VIII phospholipase A2 in nonaged complexes with the organophosphorus nerve agents soman and sarin.

    PubMed

    Epstein, Todd M; Samanta, Uttamkumar; Kirby, Stephen D; Cerasoli, Douglas M; Bahnson, Brian J

    2009-04-21

    Insecticide and nerve agent organophosphorus (OP) compounds are potent inhibitors of the serine hydrolase superfamily of enzymes. Nerve agents, such as sarin, soman, tabun, and VX exert their toxicity by inhibiting human acetycholinesterase at nerve synapses. Following the initial phosphonylation of the active site serine, the enzyme may reactivate spontaneously or through reaction with an appropriate nucleophilic oxime. Alternatively, the enzyme-nerve agent complex can undergo a secondary process, called "aging", which dealkylates the nerve agent adduct and results in a product that is highly resistant to reactivation by any known means. Here we report the structures of paraoxon, soman, and sarin complexes of group-VIII phospholipase A2 from bovine brain. In each case, the crystal structures indicate a nonaged adduct; a stereoselective preference for binding of the P(S)C(S) isomer of soman and the P(S) isomer of sarin was also noted. The stability of the nonaged complexes was corroborated by trypsin digest and electrospray ionization mass spectrometry, which indicates nonaged complexes are formed with diisopropylfluorophosphate, soman, and sarin. The P(S) stereoselectivity for reaction with sarin was confirmed by reaction of racemic sarin, followed by gas chromatography/mass spectrometry using a chiral column to separate and quantitate each stereoisomer. The P(S) stereoisomers of soman and sarin are known to be the more toxic stereoisomers, as they react preferentially to inhibit human acetylcholinesterase. The results obtained for nonaged complexes of group-VIII phospholipase A2 are compared to those obtained for other serine hydrolases and discussed to partly explain determinants of OP aging. Furthermore, structural insights can now be exploited to engineer variant versions of this enzyme with enhanced nerve agent binding and hydrolysis functions.

  5. Preparing Change Agents for Change Agent Roles.

    ERIC Educational Resources Information Center

    Sedlacek, James R.

    Seventy-seven Spanish- and Portuguese-speaking agricultural change agents from developing Central and South American countries responded to a questionnaire which sought perceptions of the roles in which the change agents felt they were involved and the roles for which they felt they were being trained. The agents were participating in training…

  6. Comparison of extracellular striatal acetylcholine and brain seizure activity following acute exposure to the nerve agents cyclosarin and tabun in freely moving guinea pigs.

    PubMed

    O'Donnell, John C; Acon-Chen, Cindy; McDonough, John H; Shih, Tsung-Ming

    2010-11-01

    Organophosphorus nerve agents like cyclosarin and tabun are potent cholinesterase inhibitors. The inhibition of acetylcholinesterase, which is responsible for breaking down acetylcholine (ACh) at the synapse and neuromuscular junction, leads to a build-up of extracellular ACh and a series of toxic consequences including hypersecretion, tremor, convulsion/seizure, respiratory distress, coma, and death. This study employed simultaneous and continuous electroencephalographic recording and striatal microdialysis collection for quantification of ACh changes (via subsequent HPLC analysis) during acute exposure to a 1.0 × LD(50) subcutaneous dose of either cyclosarin or tabun to investigate differences in cholinergic and behavioral effects. Information about the unique mechanisms and consequences of different nerve agents is intended to aid in the development of broad-spectrum medical countermeasures for nerve agents. At the dose administered, non-seizure and sustained seizure responses were observed in both agent groups and in the tabun-exposed group some subjects experienced an unsustained seizure response. Significant extracellular ACh increases were only observed in seizure groups. Cyclosarin and tabun were found to exhibit some unique cholinergic and ictogenic characteristics. Lethality only occurred in subjects experiencing sustained seizure, and there was no difference in lethality between agent groups that progressed to sustained seizure.

  7. The Use of Adenosine Agonists to Treat Nerve Agent-Induced Seizure and Neuropathology

    DTIC Science & Technology

    2016-09-01

    toxic sequelae. Drugs that block ACh receptors (e.g., atropine and scopolamine), increase the effect of γ-amino-butyric acid (GABAA) receptors...cell death.31 ADO’s inhibitory effect on neuronal excitability has also been exploited for the treatment of drug -resistant epilepsy.33-36 The A1...the nerve agent’s distribution throughout the body .38 To further investigate the link between CPA’s cardiovascular side effects and its

  8. Evaluation of nine oximes on in vivo reactivation of blood, brain, and tissue cholinesterase activity inhibited by organophosphorus nerve agents at lethal dose.

    PubMed

    Shih, Tsung-Ming; Skovira, Jacob W; O'Donnell, John C; McDonough, John H

    2009-09-01

    The capability of several oximes (HI-6, HLö7, MMB-4, TMB-4, carboxime, ICD 585, ICD 692, ICD 3805, and 2-PAM) to reactivate in vivo AChE inhibited by the nerve agents sarin, cyclosarin, VX, or VR in blood, brain regions, and peripheral tissues in guinea pigs was examined and compared. Animals were injected subcutaneously with 1.0 LD(50) of sarin, cyclosarin, VR, or VX, and treated intramuscularly 5 min later with one of these compounds. Toxic signs and lethality were monitored, and tissue AChE activities were determined at 60 min after nerve agent. The animals exposed to sarin or cyclosarin, alone or with non-oxime treatment, some died within 60 min; however, when treated with an oxime, no animal died. For VR or VX, all animals survived for 60 min after exposure, with or without non-oxime or oxime therapy. These nerve agents caused differential degrees of inhibition: in whole blood sarin = cyclosarin > VR = VX; in brain regions sarin > cyclosarin > VX > VR; and in peripheral tissues sarin > VX > cyclosarin > VR. These oximes exhibited differential potency in reactivating nerve agent-inhibited AChE in various peripheral tissues, but not AChE activity in the brain regions. There was no difference in the AChE reactivating potency between the dichloride and dimethanesulfonate salts of HI-6. AChE inhibited by sarin was the most and cyclosarin the least susceptible to oxime reactivation. Overall, MMB-4 appeared to be, among all oximes tested, the most effective in vivo AChE reactivator against the broadest spectrum of nerve agents.

  9. RSD931, a novel anti-tussive agent acting on airway sensory nerves

    PubMed Central

    Adcock, J J; Douglas, G J; Garabette, M; Gascoigne, M; Beatch, G; Walker, M; Page, C P

    2003-01-01

    .05) inhibited spontaneous and capsaicin-induced discharges in both pulmonary and bronchial C-fibres respectively. Lidocaine also significantly (P<0.05) reduced capsaicin-evoked bronchoconstriction. These studies suggest that the anti-tussive actions of RSD931 are mediated via inhibition of discharges in Aδ-fibres originating from airway RARs. The mechanism of action of RSD931 is distinct from that of the local anaesthetic lidocaine and RSD931 may represent a novel class of anti-tussive agent. PMID:12569065

  10. An unexpected plasma cholinesterase activity rebound after challenge with a high dose of the nerve agent VX.

    PubMed

    Dorandeu, F; Foquin, A; Briot, R; Delacour, C; Denis, J; Alonso, A; Froment, M T; Renault, F; Lallement, G; Masson, P

    2008-06-27

    Organophosphorus chemical warfare agents (nerve agents) are to be feared in military operations as well as in terrorist attacks. Among them, VX (O-ethyl-S-[2-(diisopropylamino)ethyl] methylphosphonothioate) is a low volatility liquid that represents a percutaneous as well as an inhalation hazard if aerosolized. It is a potent irreversible cholinesterase (ChE) inhibitor that causes severe signs and symptoms, including respiratory dysfunction that stems from different mechanisms. VX-induced pulmonary oedema was previously reported in dogs but mechanisms involved are not well understood, and its clinical significance remains to be assessed. An experimental model was thus developed to study VX-induced cardiovascular changes and pulmonary oedema in isoflurane-anaesthetized swine. In the course of this study, we observed a fast and unexpected rebound of plasma ChE activity following inhibition provoked by the intravenous injection of 6 and 12 microg kg(-1) of VX. In whole blood ChE activity, the rebound could stay unnoticed. Further investigations showed that the rebound of plasma esterase activity was neither related to spontaneous reactivation of ChE nor to VX-induced increase in paraoxonase/carboxylesterase activities. A bias in Ellman assay, haemoconcentration or severe liver cytolysis were also ruled out. All in all, these results suggest that the rebound was likely due to the release of butyrylcholinesterase into the blood stream from ChE producing organs. Nature of the organ(s) and mechanisms involved in enzyme release will need further investigations as it may represent a mechanism of defence, i.e. VX scavenging, that could advantageously be exploited.

  11. Rapid-releasing of HI-6 via brain-targeted mesoporous silica nanoparticles for nerve agent detoxification

    NASA Astrophysics Data System (ADS)

    Yang, Jun; Fan, Lixue; Wang, Feijian; Luo, Yuan; Sui, Xin; Li, Wanhua; Zhang, Xiaohong; Wang, Yongan

    2016-05-01

    The toxic nerve agent (NA) soman is the most toxic artificially synthesized compound that can rapidly penetrate into the brain and irreversibly inhibit acetylcholinesterase (AChE) activity, leading to immediate death. However, there are currently few brain-targeted nanodrugs that can treat acute chemical brain poisoning owing to the limited drug-releasing speed. The present study investigated the effectiveness of a nanodrug against NA toxicity that has high blood-brain barrier penetration and is capable of rapid drug release. Transferrin-modified mesoporous silica nanoparticles (TF-MSNs) were conjugated with the known AChE reactivator HI-6. This nanodrug rapidly penetrated the blood-brain barrier in zebrafish and mice and restored cerebral AChE activity via the released HI-6, preventing the brain damage caused by soman poisoning and increasing the survival rate in mice. Furthermore, there was no toxicity associated with the MSNs in mice or rats. These results demonstrate that TF-MSNs loaded with HI-6 represent the most effective antidote against NA poisoning by soman reported to date, and suggest that MSNs are a safe alternative to conventional drugs and an optimal nanocarrier for treating brain poisoning, which requires acute pulse cerebral administration.The toxic nerve agent (NA) soman is the most toxic artificially synthesized compound that can rapidly penetrate into the brain and irreversibly inhibit acetylcholinesterase (AChE) activity, leading to immediate death. However, there are currently few brain-targeted nanodrugs that can treat acute chemical brain poisoning owing to the limited drug-releasing speed. The present study investigated the effectiveness of a nanodrug against NA toxicity that has high blood-brain barrier penetration and is capable of rapid drug release. Transferrin-modified mesoporous silica nanoparticles (TF-MSNs) were conjugated with the known AChE reactivator HI-6. This nanodrug rapidly penetrated the blood-brain barrier in zebrafish and

  12. Gulf War Veterans and Iraqi Nerve Agents at Khamisiyah: Postwar Hospitalization Data Revisited

    DTIC Science & Technology

    2002-03-16

    pay grade , salary, Am J Epidemiol 2003;158:457-467 460 Smith et al. TABLE 1. Characteristics* of US Gulf War veterans possibly exposed to nerve...76,497 76.8 256,885 80.7 Reserve 23,117 23.2 61,573 19.3 Prewar hospitalization No 93,419 93.8 297,815 93.5 Yes 6,195 6.2 20,643 6.5 Military pay grade ...391,234 93.6 17.9 Yes 26,838 6.4 29.9 1.70 1.66,1.74 1.64 1.60,1.68 Military pay grade Commissioned officer 43,253 10.4 17.0 Warrant officer 7,131 1.7

  13. Screening of nerve agent markers with hollow fiber-chemosorption of phosphonic acids.

    PubMed

    Holmgren, Karin Höjer; Gustafsson, Tomas; Östin, Anders

    2016-10-15

    This report describes a method developed for extracting nerve gas markers such as phosphonic acids from urine and other aqueous samples. It involves single-step microextraction with chemosorption to hollow fibers that have been pre-soaked in a solution containing a derivatization reagent (3,5 triflouro methyl benzene diazomethane). The derivatives it forms with phosphonic acids can be sensitively detected by mass spectrometric detectors operating in negative chemical ionization (NCI) mode. Limits of quantification obtained in analyses of water and urine extracts by GC/MS in negative chemical ionization and selected ion monitoring mode were 0.1-10 and 0.5-10ng/mL, respectively. Pentaflourophenyl diazomethane can also be used as a derivatization reagent, and the micro-extracts (which generate low background signals) can be sensitively analyzed by GC-MS/MS in NCI selected reaction monitoring (SRM) mode, using two specific transitions for both reagents. Thus, this sensitive approach can be flexibly modified to obtain confirmatory information, or address potential problems caused by interferences in some samples.

  14. Liquid-liquid-solid microextraction and detection of nerve agent simulants by on-membrane Fourier transform infrared spectroscopy.

    PubMed

    Garg, Prabhat; Purohit, Ajay; Tak, Vijay K; Kumar, Ajeet; Dubey, D K

    2012-11-02

    A coupling of novel liquid-liquid-solid microextraction (LLSME) technique based on porous hydrophobic membrane and Fourier-transform infrared spectroscopy has been presented for the detection, identification and quantification of markers and simulants of nerve agents. Two isomers O,O'-dihexyl methylphosphonate (DHMP) and O,O'-dipentyl isopropylphosphonate (DPIPP) were chosen as model analytes for the study. In the present technique, organic phase was immobilised within the pores of membrane after fixing it in an assembly, which was then immersed into aqueous sample of target analytes for extraction. The analytes were directly determined on the surface of membrane by FTIR spectroscopy without elution. On comparison with solid phase microextraction (SPME), LLSME was found to be much more efficient. The method was optimised and quantitative analyses were performed using calibration curves obtained via Beer's law and employing processing of spectra obtained, via a multivariate calibration technique partial least square (PLS). Relative standard deviations (RSDs) for intraday repeatability and interday reproducibility were found to be in the range of 0.20-0.50% and 0.20-0.60%, respectively. Limit of detection (LOD) was achieved up to 15 ng mL(-1). Applicability of the method was tested with an unknown real sample obtained in an international official proficiency test (OPT).

  15. In situ infrared aerosol spectroscopy for a variety of nerve agent simulants using flow-through photoacoustics

    NASA Astrophysics Data System (ADS)

    Gurton, Kristan P.; Felton, Melvin; Dahmani, Rachid; Ligon, David

    2007-09-01

    We present newly measured results of an ongoing experimental program established to measure optical cross sections in the mid- and long-wave infrared for a variety of chemically and biologically based aerosols. For this study we consider only chemically derived aerosols, and in particular, a group of chemical compounds often used as simulants for the detection of extremely toxic organophosphorus nerve agents. These materials include: diethyl methylphosphonate (DEMP), dimethyl methylphosphonate (DMMP), diisopropyl methylphosphonate (DIMP), and diethyl phthalate (DEP). As reported in a prior study [Appl. Opt. 44, 4001 (2005)], we combine two optical techniques well suited for aerosol spectroscopy [i.e., flow-through photoacoustics and Fourier transform infrared (FTIR) emission spectroscopy], to measure in situ the absolute extinction and absorption cross sections over a variety of wavelengths spanning the IR spectral region from 3 to 13 μm. Aerosol size distribution(s), particle number density, and dosimetric measurements are recorded simultaneously in order to present optical cross sections that are aerosol mass normalized, i.e., m2/gram. Photoacoustic results, conducted at a series of CO2 laser lines, compare well with measured broadband FTIR spectral extinction. Both FTIR and photoacoustic data also compare well with Mie theory calculations based on measured size distributions and previously published complex indices of refraction.

  16. High-throughput immunomagnetic scavenging technique for quantitative analysis of live VX nerve agent in water, hamburger, and soil matrixes.

    PubMed

    Knaack, Jennifer S; Zhou, Yingtao; Abney, Carter W; Prezioso, Samantha M; Magnuson, Matthew; Evans, Ronald; Jakubowski, Edward M; Hardy, Katelyn; Johnson, Rudolph C

    2012-11-20

    We have developed a novel immunomagnetic scavenging technique for extracting cholinesterase inhibitors from aqueous matrixes using biological targeting and antibody-based extraction. The technique was characterized using the organophosphorus nerve agent VX. The limit of detection for VX in high-performance liquid chromatography (HPLC)-grade water, defined as the lowest calibrator concentration, was 25 pg/mL in a small, 500 μL sample. The method was characterized over the course of 22 sample sets containing calibrators, blanks, and quality control samples. Method precision, expressed as the mean relative standard deviation, was less than 9.2% for all calibrators. Quality control sample accuracy was 102% and 100% of the mean for VX spiked into HPLC-grade water at concentrations of 2.0 and 0.25 ng/mL, respectively. This method successfully was applied to aqueous extracts from soil, hamburger, and finished tap water spiked with VX. Recovery was 65%, 81%, and 100% from these matrixes, respectively. Biologically based extractions of organophosphorus compounds represent a new technique for sample extraction that provides an increase in extraction specificity and sensitivity.

  17. The determination of organophosphonate nerve agent metabolites in human urine by hydrophilic interaction liquid chromatography tandem mass spectrometry.

    PubMed

    Mawhinney, Douglas B; Hamelin, Elizabeth I; Fraser, Rheaclare; Silva, Sathya S; Pavlopoulos, Antonis J; Kobelski, Robert J

    2007-06-01

    A sensitive, robust isotope dilution LC/MS/MS method is presented for the quantitative analysis of human urine for the alkyl methylphosphonic acid metabolites of five organophosphorus nerve agents (VX, rVX or VR, GB or Sarin, GD or Soman, and GF or Cyclosarin). The selective sample preparation method employs non-bonded silica solid-phase extraction and is partially automated. While working with a mobile phase composition that enhances the electrospray ionization process, the hydrophilic interaction chromatography method results in a 5-min injection-to-injection cycle time, excellent peak shapes and adequate retention (k'=3.1). These factors lead to limits of detection for these metabolites as low as 30 pg/mL in a 1-mL sample of human urine. The quality control data (15 and 75 ng/mL) demonstrate accurate (-0.5 to +3.4%) and precise (coefficients of variation of 2.1-3.6%) quantitative results over the clinically relevant urine concentration range of 1-200 ng/mL for a validation set of 20 standard and quality control sets prepared by five analysts over 54 days. The selectivity of the method is demonstrated for a 100-individual reference range study, as well as the analysis of relevant biological samples. The combined sample preparation and analysis portions of this method have a throughput of 288 samples per day.

  18. Crystal Structures of Human Group-VIIA Phospholipase A2 Inhibited by Organophosphorus Nerve Agents Exhibit Non-aged Complexes ☆,☆☆

    PubMed Central

    Samanta, Uttamkumar; Kirby, Stephen D.; Srinivasan, Prabhavathi; Cerasoli, Douglas M.; Bahnson, Brian J.

    2009-01-01

    The enzyme group-VIIA phospholipase A2 (gVIIA-PLA2) is bound to lipoproteins in human blood and hydrolyzes the ester bond at the sn-2 position of phospholipid substrates with a short sn-2 chain. The enzyme belongs to a serine hydrolase superfamily of enzymes, which react with organophosphorus (OP) nerve agents. OPs ultimately exert their toxicity by inhibiting human acetycholinesterase at nerve synapses, but may additionally have detrimental effects through inhibition of other serine hydrolases. We have solved the crystal structures of gVIIA-PLA2 following inhibition with the OPs diisopropylfluorophosphate, sarin, soman and tabun. The sarin and soman complexes displayed a racemic mix of PR and PS stereoisomers at the P-chiral center. The tabun complex displayed only the PR stereoisomer in the crystal. In all cases, the crystal structures contained intact OP adducts that had not aged. Aging refers to a secondary process OP complexes can go through, which dealkylates the nerve agent adduct and results in a form that is highly resistant to either spontaneous or oxime-mediated reactivation. Non-aged OP complexes of the enzyme were corroborated by trypsin digest and matrix assisted laser desorption ionization mass spectrometry of OP-enzyme complexes. The lack of stereoselectivity of sarin reaction was confirmed by gas chromatography/mass spectrometry using a chiral column to separate and quantitate the unbound stereoisomers of sarin following incubation with enzyme. The structural details and characterization of nascent reactivity of several toxic nerve agents is discussed with a long term goal of developing gVIIA-PLA2 as a catalytic bioscavenger of OP nerve agents. PMID:19394314

  19. Biological warfare agents.

    PubMed

    Pohanka, Miroslav; Kuca, Kamil

    2010-01-01

    Biological warfare agents are a group of pathogens and toxins of biological origin that can be potentially misused for military or criminal purposes. The present review attempts to summarize necessary knowledge about biological warfare agents. The historical aspects, examples of applications of these agents such as anthrax letters, biological weapons impact, a summary of biological warfare agents and epidemiology of infections are described. The last section tries to estimate future trends in research on biological warfare agents.

  20. Spacecraft sanitation agent development

    NASA Technical Reports Server (NTRS)

    1972-01-01

    The development of an effective sanitizing agent that is compatible with the spacecraft environment and the human occupant is discussed. Experimental results show that two sanitation agents must be used to satisfy mission requirements: one agent for personal hygiene and one for equipment maintenance. It was also recommended that a water rinse be used with the agents for best results, and that consideration be given to using the agents pressure packed or in aerosol formulations.

  1. Novel pyrenehexafluoroisopropanol derivative-decorated single-walled carbon nanotubes for detection of nerve agents by strong hydrogen-bonding interaction.

    PubMed

    Kong, Lingtao; Wang, Jin; Luo, Tao; Meng, Fanli; Chen, Xing; Li, Mingqiang; Liu, Jinhuai

    2010-02-01

    Fabrication of hybridized single-walled carbon nanotube (SWNT) device based on novel sensing material N-4-Hexafluoroisopropanolphenyl-1-pyrenebutyramide (HFIPP) via facile approach has been reported for the first time. Considered that strong hydrogen-bonding can be formed between HFIPP and dimethyl methylphosphonate (DMMP) (simulant of nerve agent sarin), the HFIPP-decorated SWNT device has been employed to detect DMMP. The detection limit achieved with our sensor is as low as 50 ppb; moreover, the response and reproducibility can be presented clearly even at very low concentration of DMMP. Excellent sensitivity and selectivity of the hybridized SWNT-HFIPP device suggest that it has great potential application for detecting explosives and nerve agents. In order to investigate sensing mechanism of SWNT-HFIPP for DMMP, control electrical and fluorescent experiments have been carried out and discussed in the present paper.

  2. An in vitro and in vivo evaluation of the efficacy of recombinant human liver prolidase as a catalytic bioscavenger of chemical warfare nerve agents.

    PubMed

    Rezk, Peter E; Zdenka, Pierre; Sabnekar, Praveena; Kajih, Takwen; Mata, David G; Wrobel, Chester; Cerasoli, Douglas M; Chilukuri, Nageswararao

    2015-01-01

    In this study, we determined the ability of recombinant human liver prolidase to hydrolyze nerve agents in vitro and its ability to afford protection in vivo in mice. Using adenovirus containing the human liver prolidase gene, the enzyme was over expressed by 200- to 300-fold in mouse liver and purified to homogeneity by affinity and gel filtration chromatography. The purified enzyme hydrolyzed sarin, cyclosarin and soman with varying rates of hydrolysis. The most efficient hydrolysis was with sarin, followed by soman and by cyclosarin {apparent kcat/Km [(1.9 ± 0.3), (1.7 ± 0.2), and (0.45 ± 0.04)] × 10(5 )M(-1 )min(-1), respectively}; VX and tabun were not hydrolyzed by the recombinant enzyme. The enzyme hydrolyzed P (+) isomers faster than the P (-) isomers. The ability of recombinant human liver prolidase to afford 24 hour survival against a cumulative dose of 2 × LD50 of each nerve agent was investigated in mice. Compared to mice injected with a control virus, mice injected with the prolidase expressing virus contained (29 ± 7)-fold higher levels of the enzyme in their blood on day 5. Challenging these mice with two consecutive 1 × LD50 doses of sarin, cyclosarin, and soman resulted in the death of all animals within 5 to 8 min from nerve agent toxicity. In contrast, mice injected with the adenovirus expressing mouse butyrylcholinesterase, an enzyme which is known to afford protection in vivo, survived multiple 1 × LD50 challenges of these nerve agents and displayed no signs of toxicity. These results suggest that, while prolidase can hydrolyze certain G-type nerve agents in vitro, the enzyme does not offer 24 hour protection against a cumulative dose of 2 × LD50 of G-agents in mice in vivo.

  3. Optimization of Quantitative Proteomics Using 2-Dimensional Difference Gel Electrophoresis to Characterize Molecular Mechanisms of Chemical Warfare Nerve Agent Exposure in the Rat Brain

    DTIC Science & Technology

    2010-11-01

    protocol was optimized for whole rat brain, and purity was assessed using various biochemical assays. For isolation of mitochondria from brain...dependent hepatotoxicity . Journal of Biological Chemistry, 2004. 279(21): p. 22092-22101. 19. Mintz, H.A., et al., Morphological and biochemical ...Difference Gel Electrophoresis to Characterize Molecular Mechanisms of Chemical Warfare Nerve Agent Exposure in the Rat Brain Heidi M. Hoard

  4. Investigation of the persistence of nerve agent degradation analytes on surfaces through wipe sampling and detection with ultrahigh performance liquid chromatography-tandem mass spectrometry.

    PubMed

    Willison, Stuart A

    2015-01-20

    The persistence of chemical warfare nerve agent degradation analytes on surfaces is important, from indicating the presence of nerve agent on a surface to guiding environmental restoration of a site after a release. Persistence was investigated for several chemical warfare nerve agent degradation analytes on indoor surfaces and presents an approach for wipe sampling of surfaces, followed by wipe extraction and liquid chromatography-tandem mass spectrometry detection. Commercially available wipe materials were investigated to determine optimal wipe recoveries. Tested surfaces included porous/permeable (vinyl tile, painted drywall, and wood) and largely nonporous/impermeable (laminate, galvanized steel, and glass) surfaces. Wipe extracts were analyzed by ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). UPLC provides a separation of targeted degradation analytes in addition to being nearly four times faster than high-performance liquid chromatography, allowing for greater throughput after a large-scale contamination incident and subsequent remediation events. Percent recoveries from nonporous/impermeable surfaces were 60-103% for isopropyl methylphosphonate (IMPA), GB degradate; 61-91% for ethyl methylphosphonate (EMPA), VX degradate; and 60-98% for pinacolyl methylphosphonate (PMPA), GD degradate. Recovery efficiencies for methyl phosphonate (MPA), nerve agent degradate, and ethylhydrogen dimethylphosphonate (EHDMAP), GA degradate, were lower, perhaps due to matrix effects. Diisopropyl methylphosphonate, GB impurity, was not recovered from surfaces. The resulting detection limits for wipe extracts were 0.065 ng/cm(2) for IMPA, 0.079 ng/cm(2) for MPA, 0.040 ng/cm(2) for EMPA, 0.078 ng/cm(2) for EHDMAP, and 0.013 ng/cm(2) for PMPA. The data indicate that laboratories may hold wipe samples for up to 30 days prior to analysis. Target analytes were observed to persist on surfaces for at least 6 weeks.

  5. An in vitro and in vivo Evaluation of the Efficacy of Recombinant Human Liver Prolidase as a Catalytic Bioscavenger of Chemical Warfare Nerve Agents

    DTIC Science & Technology

    2015-01-01

    3. DATES COVERED (From - To) 4. TITLE AND SUBTITLE An in vitro and in vivo evaluation of the efficacy of recombinant human liver prolidase 5a...butyrylcholinesterase, catalytic bioscavenger, chemical warfare nerve agents, human liver prolidase, in vivo delivery 16. SECURITY CLASSIFICATION OF: 17...Healthcare USA, Inc. DOI: 10.3109/01480545.2014.900071 RESEARCH ARTICLE An in vitro and in vivo evaluation of the efficacy of recombinant human liver

  6. Novel nerve-agent antidote design based on crystallographic and mass spectrometric analyses of tabun-conjugated acetylcholinesterase in complex with antidotes.

    PubMed

    Ekström, F J; Astot, C; Pang, Y-P

    2007-09-01

    Organophosphorus compound-based nerve agents inhibit the essential enzyme acetylcholinesterase (AChE) causing acute toxicity and death. Clinical treatment of nerve-agent poisoning is to use oxime-based antidotes to reactivate the inhibited AChE. However, the nerve agent tabun is resistant to oximes. To design improved oximes, crystal structures of a tabun-conjugated AChE in complex with different oximes are needed to guide the structural modifications of known antidotes. However, this type of structure is extremely challenging to obtain because both deamidation of the tabun conjugate and reactivation of AChE occur during crystallographic experiments. Here we report, for the first time, the crystal structures of Ortho-7 and HLö-7 in complex with AChE that is conjugated to an intact tabun. These structures were determined by our new strategy of combining crystallographic and mass spectrometric analyses of AChE crystals. The results explain the relative reactivation potencies of the two oximes and offer insights into improving known medical antidotes.

  7. Using an object-based grid system to evaluate a newly developed EP approach to formulate SVMs as applied to the classification of organophosphate nerve agents

    NASA Astrophysics Data System (ADS)

    Land, Walker H., Jr.; Lewis, Michael; Sadik, Omowunmi; Wong, Lut; Wanekaya, Adam; Gonzalez, Richard J.; Balan, Arun

    2004-04-01

    This paper extends the classification approaches described in reference [1] in the following way: (1.) developing and evaluating a new method for evolving organophosphate nerve agent Support Vector Machine (SVM) classifiers using Evolutionary Programming, (2.) conducting research experiments using a larger database of organophosphate nerve agents, and (3.) upgrading the architecture to an object-based grid system for evaluating the classification of EP derived SVMs. Due to the increased threats of chemical and biological weapons of mass destruction (WMD) by international terrorist organizations, a significant effort is underway to develop tools that can be used to detect and effectively combat biochemical warfare. This paper reports the integration of multi-array sensors with Support Vector Machines (SVMs) for the detection of organophosphates nerve agents using a grid computing system called Legion. Grid computing is the use of large collections of heterogeneous, distributed resources (including machines, databases, devices, and users) to support large-scale computations and wide-area data access. Finally, preliminary results using EP derived support vector machines designed to operate on distributed systems have provided accurate classification results. In addition, distributed training time architectures are 50 times faster when compared to standard iterative training time methods.

  8. Fe3O4 magnetic nanoparticle peroxidase mimetic-based colorimetric assay for the rapid detection of organophosphorus pesticide and nerve agent.

    PubMed

    Liang, Minmin; Fan, Kelong; Pan, Yong; Jiang, Hui; Wang, Fei; Yang, Dongling; Lu, Di; Feng, Jing; Zhao, Jianjun; Yang, Liu; Yan, Xiyun

    2013-01-02

    Rapid and sensitive detection methods are in urgent demand for the screening of extensively used organophosphorus pesticides and highly toxic nerve agents for their neurotoxicity. In this study, we developed a novel Fe(3)O(4) magnetic nanoparticle (MNP) peroxidase mimetic-based colorimetric method for the rapid detection of organophosphorus pesticides and nerve agents. The detection assay is composed of MNPs, acetylcholinesterase (AChE), and choline oxidase (CHO). The enzymes AChE and CHO catalyze the formation of H(2)O(2) in the presence of acetylcholine, which then activates MNPs to catalyze the oxidation of colorimetric substrates to produce a color reaction. After incubation with the organophosphorus neurotoxins, the enzymatic activity of AChE was inhibited and produced less H(2)O(2), resulting in a decreased catalytic oxidation of colorimetric substrates over MNP peroxidase mimetics, accompanied by a drop in color intensity. Three organophosphorus compounds were tested on the assay: acephate and methyl-paraoxon as representative organophosphorus pesticides and the nerve agent Sarin. The novel assay displayed substantial color change after incubation in organophosphorus neurotoxins in a concentration-dependent manner. As low as 1 nM Sarin, 10 nM methyl-paraoxon, and 5 μM acephate are easily detected by the novel assay. In conclusion, by employing the peroxidase-mimicking activity of MNPs, the developed colorimetric assay has the potential of becoming a screening tool for the rapid and sensitive assessment of the neurotoxicity of an overwhelming number of organophosphate compounds.

  9. Delta agent (Hepatitis D)

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/000216.htm Delta agent (Hepatitis D) To use the sharing features on this page, please enable JavaScript. Delta agent is a type of virus called hepatitis ...

  10. Animal Capture Agents

    DTIC Science & Technology

    1990-01-01

    agents and delivery systems reviewed . Questionnaires were sent to 137 Air Force bases to obtain information about the chemical agents and delivery systems...used by animal control personnel. A literature review included chemical agents, delivery methods, toxicity information and emergency procedures from...34-like agent. Users should familiarize themselves with catatonia in general and particularly that its successful use as an immobilizer doesn’t necessarily

  11. Hydroxypyridonate chelating agents

    DOEpatents

    Raymond, Kenneth N.; Scarrow, Robert C.; White, David L.

    1987-01-01

    Chelating agents having 1-hydroxy-2-pyridinone (HOPO) and related moieties incorporated within their structures, including polydentate HOPO-substituted polyamines such as spermidine and spermine, and HOPO-substituted desferrioxamine. The chelating agents are useful in selectively removing certain cations from solution, and are particularly useful as ferric ion and actinide chelators. Novel syntheses of the chelating agents are provided.

  12. Intelligent Agents: A Primer.

    ERIC Educational Resources Information Center

    Yu, Edmund; Feldman, Susan

    1999-01-01

    Provides an in-depth introduction to the various technologies that are bringing intelligent agents into the forefront of information technology, explaining how such agents work, the standards involved, and how agent-based applications can be developed. (Author/AEF)

  13. The oxime pro-2-PAM provides minimal protection against the CNS effects of the nerve agents sarin, cyclosarin, and VX in guinea pigs.

    PubMed

    Shih, Tsung-Ming; Guarisco, John A; Myers, Todd M; Kan, Robert K; McDonough, John H

    2011-01-01

    This study examined whether pro-2-PAM, a pro-drug dihydropyridine derivative of the oxime 2-pralidoxime (2-PAM) that can penetrate the brain, could prevent or reverse the central toxic effects of three nerve agents; sarin, cyclosarin, and VX. The first experiment tested whether pro-2-PAM could reactivate guinea pig cholinesterase (ChE) in vivo in central and peripheral tissues inhibited by these nerve agents. Pro-2-PAM produced a dose-dependent reactivation of sarin- or VX-inhibited ChE in both peripheral and brain tissues, but with substantially greater reactivation in peripheral tissues compared to brain. Pro-2-PAM produced 9-25% reactivation of cyclosarin-inhibited ChE in blood, heart, and spinal cord, but no reactivation in brain or muscle tissues. In a second experiment, the ability of pro-2-PAM to block or terminate nerve agent-induced electroencephalographic seizure activity was evaluated. Pro-2-PAM was able to block sarin- or VX-induced seizures (16-33%) over a dose range of 24-32 mg/kg, but was ineffective against cyclosarin-induced seizures. Animals that were protected from seizures showed significantly less weight loss and greater behavioral function 24 h after exposure than those animals that were not protected. Additionally, brains were free from neuropathology when pro-2-PAM prevented seizures. In summary, pro-2-PAM provided modest reactivation of sarin- and VX-inhibited ChE in the brain and periphery, which was reflected by a limited ability to block or terminate seizures elicited by these agents. Pro-2-PAM was able to reactivate blood, heart, and spinal cord ChE inhibited by cyclosarin, but was not effective against cyclosarin-induced seizures.

  14. A comparison of the ability of a new bispyridinium oxime--1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium)butane dibromide and currently used oximes to reactivate nerve agent-inhibited rat brain acetylcholinesterase by in vitro methods.

    PubMed

    Kuca, K; Kassa, J

    2003-12-01

    The efficacy of a new bispyridinium oxime 1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium)butane dibromide, called K048, and currently used oximes (pralidoxime, obidoxime, the oxime HI-6) to reactivate acetylcholinesterase inhibited by various nerve agents (sarin, tabun, cyclosarin, VX) was tested by in vitro methods. The new oxime K048 was found to be a more efficacious reactivator of nerve agent-inhibited acetylcholinesterase than pralidoxime (in the case of VX, tabun and cyclosarin), obidoxime (cyclosarin and tabun) and HI-6 (tabun) but it did not reach the efficacy of currently used oximes for the reactivation of acetylcholinesterase inhibited by sarin. Thus, the oxime K048 seems to be a relatively efficacious broad spectrum acetylcholinesterase reactivator and, therefore, it could be useful for the treatment of a nerve agent-exposed population if information about detection of the type of nerve agent is not available.

  15. Standard Agent Framework 1

    SciTech Connect

    Goldsmith, Steven Y.

    1999-04-06

    The Standard Agent framework provides an extensible object-oriented development environment suitable for use in both research and applications projects. The SAF provides a means for constructing and customizing multi-agent systems through specialization of standard base classes (architecture-driven framework) and by composition of component classes (data driven framework). The standard agent system is implemented as an extensible object-centerd framework. Four concrete base classes are developed: (1) Standard Agency; (2) Standard Agent; (3) Human Factor, and (4) Resources. The object-centered framework developed and utilized provides the best comprimise between generality and flexibility available in agent development systems today.

  16. Unique emission from norbornene derived terpyridine--a selective chemodosimeter for G-type nerve agent surrogates.

    PubMed

    Sarkar, Santu; Mondal, Arobendo; Tiwari, Ashwani Kumar; Shunmugam, Raja

    2012-05-04

    A new chemodosimeter for a G-type agent that exploits norbornene derived terpyridine (NDT)-lanthanide unique emission is reported. The unusual emission between terpyridine and norbornene motifs of NDT is attributed to the significant difference in the position of the HOMO and LUMO wave functions that prevents the non-radiative relaxation pathway. An interesting magenta emission from NDT along with Eu(III) is utilized as a new fluorometric chemodosimeter that selectively detects (by changing the observed magenta emission to blue) G-type agent surrogates. A detection limit of 40 ppb is obtained and the selectivity for reactive surrogates over a variety of other close chemical analogs is demonstrated.

  17. The Utility of Human Plasma-Derived Butyrylcholinesterase (huBuChE) as a Therapeutic Measure in the Absence of Pre-Treatment or Conventional Post-Poisoning Therapies Against Nerve Agent

    DTIC Science & Technology

    2011-10-01

    Human butyrylcholinesterase (huBuChE) has investigational new drug (IND) status in the U.S. as a pretreatment against organophosphate poisoning in humans...huBuChE) as a therapeutic measure in the absence of pre-treatment or conventional post- poisoning therapies against nerve agent. PRINCIPAL...absence of pre- treatment or conventional post- poisoning therapies against nerve agent. 5a. CONTRACT NUMBER W81WXH-10- -0044 5b. GRANT NUMBER 5c

  18. Retrospective detection of exposure to nerve agents: analysis of phosphofluoridates originating from fluoride-induced reactivation of phosphylated BuChE.

    PubMed

    van der Schans, Marcel J; Polhuijs, Martine; van Dijk, Corry; Degenhardt, Carla E A M; Pleijsier, Kees; Langenberg, Jan P; Benschop, Hendrik P

    2004-09-01

    The utility was explored of a new approach to detect retrospectively exposure to nerve agents by means of conversion of the inhibitor moiety bound to the active site of the enzyme BuChE in plasma with fluoride ions into a phosphofluoridate which is subsequently analyzed by means of gas chromatography (GC). This quantifies >or=0.01% inhibition of BuChE and identifies the structure of the inhibitor except for the original leaving group. A three-tiered approach was followed involving the five classical nerve agents GA, GB, GF, GD, and VX, as well as the active metabolite of parathion, i.e., paraoxon: in vivo experiments in rhesus monkeys after iv administration of a sign-free dose of agent and concomitant in vitro experiments in plasma of rhesus monkeys and humans should allow an assessment of in vivo retrospectivity in humans. A systematic investigation was performed in order to find a single set of reaction conditions which yields a maximum amount of phosphofluoridate for all nerve agents. Fluoride-induced reactivation at 25 degrees C at a final concentration of 250 mM KF during 15 min in a pH-range between 4 and 6 appears to be effective. The in vitro decrease with time in reactivatibility of inhibited BuChE in plasma from humans and rhesus monkeys was largely due to aging of the phosphyl moiety, except for VX where spontaneous reactivation was a major cause. The decrease followed first-order except for a biphasic course in the case of GF in human and rhesus monkey plasma as well as of GD in rhesus plasma. In vitro half-lifes in human plasma ranged between ca. 14 h for GB and ca. 63 h for GA. A comparison of the in vivo data from rhesus monkeys and the in vitro data is complicated by the observation that the in vivo decrease with time of fluoride-reactivated phosphofluoridate is biphasic for all nerve agents. The terminal in vivo phase pertains to a small fraction of the amount of initially regenerated phosphofluoridate but is responsible for a considerable degree

  19. Absorption of the nerve agent VX (O-ethyl-S-[2(di-isopropylamino)ethyl] methyl phosphonothioate) through pig, human and guinea pig skin in vitro.

    PubMed

    Dalton, Christopher H; Hattersley, Ian J; Rutter, Stephen J; Chilcott, Robert P

    2006-12-01

    The physico-chemical properties of VX make the skin the most likely route of absorption into the human body. The development of effective medical countermeasures against such percutaneous threat agents relies on the use of appropriate animal models, as the inherent toxicity of nerve agents precludes the use of human volunteers. Previous studies have characterised the mechanism of nerve agent toxicity in rodent models, however, it is generally accepted that one of the most appropriate animal models for human skin absorption is the domestic pig. The purpose of the present study was to measure and compare the skin absorption kinetics of VX in vitro using pig, human and guinea pig skin to highlight any potential species differences in skin permeability. When undiluted VX was applied directly to the skin, the permeability of guinea pig skin was approximately 7-fold greater than human skin. There was no significant difference in the permeability of pig and human skin. When VX diluted with isopropyl alcohol was applied to the skin, the permeability of guinea pig skin was approximately 4-fold greater than human skin. There was no significant difference in the permeability of pig and human skin. From this data it may be inferred that dermatomed, abdominal pig skin is an appropriate model for the human skin absorption of VX.

  20. Coupling Activity-Based Detection, Target Amplification, Colorimetric and Fluorometric Signal Amplification, for Quantitative Chemosensing of Fluoride Generated from Nerve Agents.

    PubMed

    Sun, Xiaolong; Reuther, James F; Phillips, Scott T; Anslyn, Eric V

    2017-03-17

    The G-class nerve agents, which include sarin, soman, and cyclosarin, react readily with nucleophilic reagents to produce fluoride. Thus, a chemosensing protocol has been designed for these agents that pairs the nucleophilic reactivity of oximates for generating fluoride with an autoinductive target amplification reaction to amplify the quantity of fluoride for facile colorimetric and fluorescent optical quantification. The chemosensing protocol was demonstrated by using the nerve agent surrogate diisopropyl fluorophosphate (DFP) and benzaldoxime as the nucleophile. Autoinductive fluoride amplification responds to fluoride released from DFP by amplifying the fluoride concentration and a yellow reporter molecule. The reporter is a conjugated oligomer with a nominal repeating unit that originates from 4-aminobenzaldehyde. Exposure of the amplified fluoride to a fluoride-specific ratiometric fluorescent reporter provides a fluorescent readout, in which three fluorophores are generated per fluoride. Both colorimetric and fluorescent readouts enable quantitative assays with low micromolar limits of detection for fluoride resulting from DFP. More importantly, this work demonstrates the successful merging of multiple complex reactions for achieving selective, sensitive, and quantitative chemosensing.

  1. Fast, sensitive and cost-effective detection of nerve agents in the gas phase using a portable instrument and an electrochemical biosensor.

    PubMed

    Arduini, Fabiana; Amine, Aziz; Moscone, Danila; Ricci, Francesco; Palleschi, Giuseppe

    2007-07-01

    The nerve agents are chemical warfare agents known to be used during terrorist attacks. An inexpensive and portable system to be used by first responders and military personnel is of interest owing to the continuing threat of possible terrorist attacks. Amperometric biosensors based on cholinesterase inhibition show such potentialities. In this work butyrylcholinesterase was immobilized onto screen-printed electrodes modified with Prussian blue and the nerve agent detection was performed by measuring the residual activity of enzyme. The optimized biosensor was tested with sarin and VX standard solutions, showing detection limits of 12 and 14 ppb (10% of inhibition), respectively. The enzymatic inhibition was also obtained by exposing the biosensors to sarin in gas phase. Two different concentrations of sarin gas (0.1 and 0.5 mg m(-3)) at different incubation times (from 30 s up to 10 min) were tested. It is possible to detect sarin at a concentration of 0.1 mg m(-3) with 30-s incubation time, with a degree of inhibition of 34%, which match the legal limits (immediate danger to life and health).

  2. Use of the accelerating rotarod for assessment of motor performance decrement induced by potential anticonvulsant compounds in nerve agent poisoning. (Reannouncement with new availability information)

    SciTech Connect

    Capacio, B.R.; Harris, L.W.; Anderson, D.R.; Lennox, W.J.; Gales, V.

    1992-12-31

    The accelerating rotarod was used to assess motor performance decrement in rats after administration of candidate anticonvulsant compounds (acetazolamide, amitriptyline, chlordiazepoxide, diazepan, diazepam-lysine, lorazepam, loprazolam, midazolam, phenobarbital and scopolamine) against nerve agent poisoning. AH compounds were tested as the commercially available injectable preparation except for diazepam-lysine and loprazolam, which are not FDA approved. A peak effect time, as well as a dose to decrease performance time by 50% from control (PDD50), was determined. The calculated PDD50 (micrometer ol/kg) values and peak effect tunes were midazolam, 1.16 at 15 min; loprazolam, 1.17 at 15 min; diazepam-lysine, 4.17 at 30 min; lorazepwn, 4.98 at 15 min; diazepam, 5.27 at 15 min; phenobarbital, 101.49 at 45 min; chlordiazepoxide, 159.21 at 30 min; scopolamine, amitriptyline and acetazolamide did not demonstrate a performance decrement at any of the doses tested. The PDD50 values were compared with doses which have been utilized against nerve agent-induced convulsions or published ED50 values from standard anticonvulsant screening tests (maximal electroshock MES and subcutaneous pentylenetetrazol (scMET)). I serve agents, anticonvulsants, diazepam, accelerating rotarod, motor performance.

  3. Moral actor, selfish agent.

    PubMed

    Frimer, Jeremy A; Schaefer, Nicola K; Oakes, Harrison

    2014-05-01

    People are motivated to behave selfishly while appearing moral. This tension gives rise to 2 divergently motivated selves. The actor-the watched self-tends to be moral; the agent-the self as executor-tends to be selfish. Three studies present direct evidence of the actor's and agent's distinct motives. To recruit the self-as-actor, we asked people to rate the importance of various goals. To recruit the self-as-agent, we asked people to describe their goals verbally. In Study 1, actors claimed their goals were equally about helping the self and others (viz., moral); agents claimed their goals were primarily about helping the self (viz., selfish). This disparity was evident in both individualist and collectivist cultures, attesting to the universality of the selfish agent. Study 2 compared actors' and agents' motives to those of people role-playing highly prosocial or selfish exemplars. In content (Study 2a) and in the impressions they made on an outside observer (Study 2b), actors' motives were similar to those of the prosocial role-players, whereas agents' motives were similar to those of the selfish role-players. Study 3 accounted for the difference between the actor and agent: Participants claimed that their agent's motives were the more realistic and that their actor's motives were the more idealistic. The selfish agent/moral actor duality may account for why implicit and explicit measures of the same construct diverge, and why feeling watched brings out the better angels of human nature.

  4. Agent Architectures for Compliance

    NASA Astrophysics Data System (ADS)

    Burgemeestre, Brigitte; Hulstijn, Joris; Tan, Yao-Hua

    A Normative Multi-Agent System consists of autonomous agents who must comply with social norms. Different kinds of norms make different assumptions about the cognitive architecture of the agents. For example, a principle-based norm assumes that agents can reflect upon the consequences of their actions; a rule-based formulation only assumes that agents can avoid violations. In this paper we present several cognitive agent architectures for self-monitoring and compliance. We show how different assumptions about the cognitive architecture lead to different information needs when assessing compliance. The approach is validated with a case study of horizontal monitoring, an approach to corporate tax auditing recently introduced by the Dutch Customs and Tax Authority.

  5. Biosensor Based on Self-Assembling Acetylcholinesterase on Carbon Nanotubes for Flow injection/Amperometric Detection of Organophosphate Pesticides and Nerve Agents

    SciTech Connect

    Liu, Guodong; Lin, Yuehe

    2006-02-01

    A highly sensitive flow-injection amperometric biosensor for organophosphate pesticides and nerve agents based on self-assembly of acetylcholinesterase (AChE) on carbon nanotube (CNT)-modified glassy carbon (GC) electrode is described. AChE is immobilized on the negatively-charged CNT surface by alternatively assembling a cationic polydiallyldimethylammonium chloride (PDDA) layer and an AChE layer. Transmission electron microscopy images confirm the formation of layer-by-layer nanostructures on carboxyl functionalized CNTs. The unique sandwich-like structure (PDDA/AChE/PDDA) on the CNT surface formed by self-assembly provides a favorable microenvironment to keep the bioactivity of AChE and to prevent enzyme molecule leakage. The electrocatalytic activity of CNT leads to a greatly improved electrochemical detection of the enzymatically generated thiocholine product, including a low oxidation overvoltage (+150 mV), higher sensitivity, and stability. The developed PDDA/AChE/PDDA/CNT/GC biosensor integrated into a flow injection system was used to monitor organophosphate pesticides and nerve agents, such as paraoxon. The sensor performance, including inhibition time and regeneration conditions, was optimized with respect to operating conditions. Under the optimal conditions, the biosensor was used to measure as low as 0.4 pM paraoxon with a 6-min inhibition time. The biosensor had excellent operational lifetime stability with no decrease in the activity of enzymes for more than 20 repeated measurements over a 1-week period. The developed biosensor system is an ideal tool for online monitoring of organophosphate pesticides and nerve agents.

  6. A high-throughput UHPLC-MS/MS method for the quantification of five aged butyrylcholinesterase biomarkers from human exposure to organophosphorus nerve agents.

    PubMed

    Graham, Leigh Ann; Johnson, Darryl; Carter, Melissa D; Stout, Emily G; Erol, Huseyin A; Isenberg, Samantha L; Mathews, Thomas P; Thomas, Jerry D; Johnson, Rudolph C

    2017-04-01

    Organophosphorus nerve agents (OPNAs) are toxic compounds that are classified as prohibited Schedule 1 chemical weapons. In the body, OPNAs bind to butyrylcholinesterase (BChE) to form nerve agent adducts (OPNA-BChE). OPNA-BChE adducts can provide a reliable, long-term protein biomarker for assessing human exposure. A major challenge facing OPNA-BChE detection is hydrolysis (aging), which can continue to occur after a clinical specimen has been collected. During aging, the o-alkyl phosphoester bond hydrolyzes, and the specific identity of the nerve agent is lost. To better identify OPNA exposure events, a high-throughput method for the detection of five aged OPNA-BChE adducts was developed. This is the first diagnostic panel to allow for the simultaneous quantification of any Chemical Weapons Convention Schedule 1 OPNA by measuring the aged adducts methyl phosphonate, ethyl phosphonate, propyl phosphonate, ethyl phosphoryl, phosphoryl and unadducted BChE. The calibration range for all analytes is 2.00-250. ng/mL, which is consistent with similar methodologies used to detect unaged OPNA-BChE adducts. Each analytical run is 3 min, making the time to first unknown results, including calibration curve and quality controls, less than 1 h. Analysis of commercially purchased individual serum samples demonstrated no potential interferences with detection of aged OPNA-BChE adducts, and quantitative measurements of endogenous levels of BChE were similar to those previously reported in other OPNA-BChE adduct assays.

  7. Solvent Effects on the Reactions of the Nerve Agent VX with KF/Al2O3: Heterogeneous or Homogeneous Decontamination?

    PubMed

    Fridkin, Gil; Yehezkel, Lea; Columbus, Ishay; Zafrani, Yossi

    2016-03-04

    Solvent effects on the reactions of the extremely toxic nerve agent VX with KF/Al2O3 powder were explored. Small quantities of water or methanol (5-10 wt %), which effectively mobilized all components while maintaining the heterogeneous nature of the reaction, promoted much faster rates than those obtained with larger quantities. Any amount of acetonitrile resulted in extremely slow transformations. Surprisingly, 5-50 wt % of heptane led to fast reactions due to the combination of its ability to mediate fast diffusion of VX and a MAS centrifugation effect.

  8. In Vivo Reactivation by Oximes of Inhibited Blood, Brain and Peripheral Tissue Cholinesterase Activity Following Exposure to Nerve Agents in Guinea Pigs

    DTIC Science & Technology

    2010-01-01

    nerve agent intoxication ( salivation , rhinorrhea, tremors,muscle asciculations, convulsions) at 60min following the 1.0× LD50 dose f GB, GF, VR or VX...reactivation of GF-, soman-, or VR-inhibited enzyme byHI-6 andHLö7. However, these in vitro experiments [24,25] were conducted with a pH of 8.0 at 25 ◦C...data. Even the study of Worek et al. [23] that was performed at a pH of 7.4 at 37 ◦C, whose in vitro kinetic data obtained from guinea pig RBC ghosts

  9. A Structural Biology and Protein Engineering Approach to the Development of Antidotes Against the Inhibition of Human Acetylcholinesterase by OP-based Nerve Agents

    DTIC Science & Technology

    2015-05-01

    and will be reacted with coumarin. Synthesis of the pure chiral forms of the coumarin surrogate of VX, both the toxic Sp isomer, and the much less...of EMP-CHMC (the O-ethylmethylphosphonyl ester of cyanohydroxymethylcoumarin), to yield both racemic EMP-CHMC and the resolved chiral forms, [+]-EMP...oxime-induced reactivation, and in the velocity of the ‘aging’ reaction, for the hAChE conjugates of the SP and RP chiral forms of OP nerve agents

  10. Kromoscopy for detection of chemical warfare agents

    NASA Astrophysics Data System (ADS)

    Ewing, Kenneth J.; Sanghera, Jas; Aggarwal, Ishwar D.; Block, Myron J.

    2004-12-01

    The ability of a Kromoscope to discriminate between chemical warfare agent simulants and toxic industrial chemicals is evaluated. The Kromoscope response to the simulants DMMP and DIMP is compared to a pesticide (diazanon) and cyclopentanol. The response of a mid-infrared Kromoscope to the nerve agents VX and GB and the stimulant DF are calculated.

  11. Change Agent Survival Guide

    ERIC Educational Resources Information Center

    Dunbar, Folwell L.

    2011-01-01

    Consulting is a rough racket. Only a tarantula hair above IRS agents, meter maids and used car sales people, the profession is a prickly burr for slings and arrows. Throw in education, focus on dysfunctional schools and call oneself a "change agent," and this bad rap all but disappears. Unfortunately, though, consulting/coaching/mentoring in…

  12. Detecting biological warfare agents.

    PubMed

    Song, Linan; Ahn, Soohyoun; Walt, David R

    2005-10-01

    We developed a fiber-optic, microsphere-based, high-density array composed of 18 species-specific probe microsensors to identify biological warfare agents. We simultaneously identified multiple biological warfare agents in environmental samples by looking at specific probe responses after hybridization and response patterns of the multiplexed array.

  13. Travel Agent Course Outline.

    ERIC Educational Resources Information Center

    British Columbia Dept. of Education, Victoria.

    Written for college entry-level travel agent training courses, this course outline can also be used for inservice training programs offered by travel agencies. The outline provides information on the work of a travel agent and gives clear statements on what learners must be able to do by the end of their training. Material is divided into eight…

  14. Detecting Biological Warfare Agents

    PubMed Central

    Song, Linan; Ahn, Soohyoun

    2005-01-01

    We developed a fiber-optic, microsphere-based, high-density array composed of 18 species-specific probe microsensors to identify biological warfare agents. We simultaneously identified multiple biological warfare agents in environmental samples by looking at specific probe responses after hybridization and response patterns of the multiplexed array. PMID:16318712

  15. How do agents represent?

    NASA Astrophysics Data System (ADS)

    Ryan, Alex

    Representation is inherent to the concept of an agent, but its importance in complex systems has not yet been widely recognised. In this paper I introduce Peirce's theory of signs, which facilitates a definition of representation in general. In summary, representation means that for some agent, a model is used to stand in for another entity in a way that shapes the behaviour of the agent with respect to that entity. Representation in general is then related to the theories of representation that have developed within different disciplines. I compare theories of representation from metaphysics, military theory and systems theory. Additional complications arise in explaining the special case of mental representations, which is the focus of cognitive science. I consider the dominant theory of cognition — that the brain is a representational device — as well as the sceptical anti-representational response. Finally, I argue that representation distinguishes agents from non-representational objects: agents are objects capable of representation.

  16. Detection of V-type nerve agent degradation products at electrodes modified by PPy/PQQ using CaCl2 as supporting electrolyte.

    PubMed

    Shulga, Olga V; Palmer, Christopher

    2006-07-01

    Electrochemical detection without derivatization was used to detect thiol-containing degradation products of V-type nerve agents. Electropolymerization of pyrrole was used for entrapment of the biocatalyst PQQ to produce a sensor. Various parameters which affect the detection processes such as the type of the supporting electrolyte used during electrodeposition and the thickness of the polypyrrole film were examined and optimized. Electocatalytic oxidation of thiols by the PPy/PQQ electrode was strongly affected by the presence of Ca2+ cations during electrodeposition of the PPy/PQQ. Cyclic voltammetry, linear sweep voltammetry and amperometry have been used for electrode characterization. Amperometric detection of the V-type nerve agent thiol degradation products 2-(dimethylamino)ethanethiol (DMAET) and 2-(diethylamino)ethanethiol (DEAET) was performed at 0.38 V. Linear calibration plots were observed for these compounds. The detection limits of 4.5 and 3 microM were obtained for DMAET and DEAET respectively, with sensitivities of 1.18 and 1.37 nA microM(-1) cm(-2).

  17. Determination of nerve agent metabolites in human urine by isotope-dilution gas chromatography-tandem mass spectrometry after solid phase supported derivatization.

    PubMed

    Lin, Ying; Chen, Jia; Yan, Long; Guo, Lei; Wu, Bidong; Li, Chunzheng; Feng, Jianlin; Liu, Qin; Xie, Jianwei

    2014-08-01

    A simple and sensitive method has been developed and validated for determining ethyl methylphosphonic acid (EMPA), isopropyl methylphosphonic acid (IMPA), isobutyl methylphosphonic acid (iBuMPA), and pinacolyl methylphosphonic acid (PMPA) in human urine using gas chromatography-tandem mass spectrometry (GC-MS/MS) coupled with solid phase derivatization (SPD). These four alkyl methylphosphonic acids (AMPAs) are specific hydrolysis products and biomarkers of exposure to classic organophosphorus (OP) nerve agents VX, sarin, RVX, and soman. The AMPAs in urine samples were directly derivatized with pentafluorobenzyl bromide on a solid support and then extracted by liquid-liquid extraction. The analytes were quantified with isotope-dilution by negative chemical ionization (NCI) GC-MS/MS in a selected reaction monitoring (SRM) mode. This method is highly sensitive, with the limits of detection of 0.02 ng/mL for each compound in a 0.2 mL sample of human urine, and an excellent linearity from 0.1 to 50 ng/mL. It is proven to be very suitable for the qualitative and quantitative analyses of degradation markers of OP nerve agents in biomedical samples.

  18. Detection and classification characteristics of arrays of carbon black/organic polymer composite chemiresistive vapor detectors for the nerve agent simulants Dimethylmethylphosphonate and Diisopropy

    NASA Astrophysics Data System (ADS)

    Hopkins, Alan R.; Lewis, Nathan S.

    2002-06-01

    Arrays of conducting polymer composite vapor detectors have been evaluated for performance in the presence of the nerve agent simulants dimethylmethylphosphonate (DMMP) and diisopropylmethylphosponate (DIMP). Limits of detection for DMMP on unoptimized carbon black-organic polymer composite vapor detectors in laboratory air were estimated to be 0.047-0.24 mg m-3. These values are lower than the EC50 value for the nerve agents sarin (methylphosphonofluoridic acid, (1-methylethyl) ester) and soman, which have been established as equals 0.8 mg m-3. Arrays of these vapor detectors were easily able to resolve signatures due to exposures to DMMP from those due to DIMP or due to a variety of other test analytes in a laboratory air background. In addition, DMMP at 27 mg m-3 could be detected and differentiated from the signatures of the other test analytes in the presence of backgrounds of potential interferents in the background ambient, including water, methanol, benzene, toluene, diesel fuel, lighter fluid, vinegar and tetrahydrofuran, even when these interferents were present in much higher concentrations than that of the DMMP or DIMP being detected.

  19. Hydrolysis of DFP and the nerve agent (S)-sarin by DFPase proceeds along two different reaction pathways: implications for engineering bioscavengers.

    PubMed

    Wymore, Troy; Field, Martin J; Langan, Paul; Smith, Jeremy C; Parks, Jerry M

    2014-05-01

    Organophosphorus (OP) nerve agents such as (S)-sarin are among the most highly toxic compounds that have been synthesized. Engineering enzymes that catalyze the hydrolysis of nerve agents ("bioscavengers") is an emerging prophylactic approach to diminish their toxic effects. Although its native function is not known, diisopropyl fluorophosphatase (DFPase) from Loligo vulgaris catalyzes the hydrolysis of OP compounds. Here, we investigate the mechanisms of diisopropylfluorophosphate (DFP) and (S)-sarin hydrolysis by DFPase with quantum mechanical/molecular mechanical umbrella sampling simulations. We find that the mechanism for hydrolysis of DFP involves nucleophilic attack by Asp229 on phosphorus to form a pentavalent intermediate. P-F bond dissociation then yields a phosphoacyl enzyme intermediate in the rate-limiting step. The simulations suggest that a water molecule, coordinated to the catalytic Ca(2+), donates a proton to Asp121 and then attacks the tetrahedral phosphoacyl intermediate to liberate the diisopropylphosphate product. In contrast, the calculated free energy barrier for hydrolysis of (S)-sarin by the same mechanism is highly unfavorable, primarily because of the instability of the pentavalent phosphoenzyme species. Instead, simulations suggest that hydrolysis of (S)-sarin proceeds by a mechanism in which Asp229 could activate an intervening water molecule for nucleophilic attack on the substrate. These findings may lead to improved strategies for engineering DFPase and related six-bladed β-propeller folds for more efficient degradation of OP compounds.

  20. Quantification of organophosphorus nerve agent metabolites using a reduced-volume, high-throughput sample processing format and liquid chromatography-tandem mass spectrometry.

    PubMed

    Swaim, Leigh L; Johnson, Rudolph C; Zhou, Yingtao; Sandlin, Chris; Barr, John R

    2008-01-01

    A reduced-volume, high-throughput analytical method has been developed for the quantification of organophosphorus (OP) nerve agent metabolites in human urine. Metabolites of soman, sarin, cyclohexyl-sarin, VX, and Russian-VX were quantified down to a lowest reportable limit of 1 ng/mL in human urine. One hundred microliter urine samples were preconcentrated using normal-phase 96-well solid-phase extraction silica sorbent beds. Dual-column hydrophilic interaction liquid chromatography was applied in a 2.5-min isocratic separation followed by negative electrospray isotope-dilution multiple-reaction-monitoring mass spectrometry. Method validation included the characterization of two synthetic urine pools, relative recovery experiments, and calculation of the method limit of detection. All liquid handling steps were processed in a high-density 96-well format, including sample aliquoting, extraction, dry-down, and reconstitution. This allows up to 3840 unknown samples, plus calibrators and quality control materials, to be prepared on a single liquid handler in a 24-h period. In a public health emergency involving OP-nerve agents, this method provides the sample preparation and analytical capacity to respond rapidly to a large number of patient samples.

  1. Detection and classification characteristics of arrays of carbon black/organic polymer composite chemiresistive vapor detectors for the nerve agent simulants dimethylmethylphosphonate and diisopropylmethylphosponate.

    PubMed

    Hopkins, A R; Lewis, N S

    2001-03-01

    Arrays of conducting polymer composite vapor detectors have been evaluated for performance in the presence of the nerve agent simulants dimethylmethylphosphonate (DMMP) and diisopropylmethylphosponate (DIMP). Limits of detection for DMMP on unoptimized carbon black/ organic polymer composite vapor detectors in laboratory air were estimated to be 0.047-0.24 mg m(-3). These values are lower than the EC50 value (where EC50 is the airborne concentration sufficient to induce severe effects in 50% of those exposed for 30 min) for the nerve agents sarin (methylphosphonofluoridic acid, 1-methylethyl ester) and soman (methylphosphonofluoridic acid, 1,2,2-trimethylpropyl ester), which has been established as approximately 0.8 mg m(-3). Arrays of these vapor detectors were easily able to resolve signatures due to exposures to DMMP from those due to DIMP or due to a variety of other test analytes (including water, methanol, benzene, toluene, diesel fuel, lighter fluid, vinegar, and tetrahydrofuran) in a laboratory air background. In addition, DMMP at 27 mg m(-3) could be detected and differentiated from the signatures of the other test analytes in the presence of backgrounds of potential interferences, including water, methanol, benzene, toluene, diesel fuel, lighter fluid, vinegar, and tetrahydrofuran, even when these interferents were present in much higher concentrations than that of the DMMP or DIMP being detected.

  2. Hydrolysis of DFP and the Nerve Agent (S)-Sarin by DFPase Proceeds Along Two Different Reaction Pathways: Implica-tions for Engineering Bioscavengers

    SciTech Connect

    Wymore, Troy W; Langan, Paul; Smith, Jeremy C; Field, Martin J.; Parks, Jerry M

    2014-01-01

    Organophosphorus (OP) nerve agents such as (S)-sarin are among the most highly toxic compounds that have been synthesized. Engineering enzymes that catalyze the hydrolysis of nerve agents ( bioscavengers ) is an emerging prophylactic approach to diminishing their toxic effects. Although its native function is not known, diisopropyl fluorophosphatase (DFPase) from Loligo vulgaris catalyzes the hydrolysis of OP compounds. Here, we investigate the mechanisms of diisopropylfluorophosphate (DFP) and (S)-sarin hydrolysis by DFPase with quantum mechanical/molecular mechanical (QM/MM) umbrella sampling simulations. We find that the mechanism for hydrolysis of DFP involves nucleophilic attack by Asp229 on phosphorus to form a pentavalent intermediate. P F bond dissociation then yields a phosphoacyl enzyme intermediate in the rate-limiting step. The simulations suggest that a water molecule, coordinated to the catalytic Ca2+, donates a proton to Asp121 and then attacks the tetrahedral phosphoacyl intermediate to liberate the diisopropylphosphate product. In contrast, the calculated free energy barrier for hydrolysis of (S)-sarin by the same mechanism is highly unfavorable, primarily due to the instability of the pentavalent phosphoenzyme species. Instead, simulations suggest that hydrolysis of (S)-sarin proceeds by a mechanism in which Asp229 could activate an intervening water molecule for nucleophilic attack on the substrate. These findings may lead to improved strategies for engineering DFPase and related six-bladed -propeller folds for more efficient degradation of OP compounds.

  3. Hydrolysis of DFP and the Nerve Agent (S)-Sarin by DFPase Proceeds along Two Different Reaction Pathways: Implications for Engineering Bioscavengers

    PubMed Central

    2015-01-01

    Organophosphorus (OP) nerve agents such as (S)-sarin are among the most highly toxic compounds that have been synthesized. Engineering enzymes that catalyze the hydrolysis of nerve agents (“bioscavengers”) is an emerging prophylactic approach to diminish their toxic effects. Although its native function is not known, diisopropyl fluorophosphatase (DFPase) from Loligo vulgaris catalyzes the hydrolysis of OP compounds. Here, we investigate the mechanisms of diisopropylfluorophosphate (DFP) and (S)-sarin hydrolysis by DFPase with quantum mechanical/molecular mechanical umbrella sampling simulations. We find that the mechanism for hydrolysis of DFP involves nucleophilic attack by Asp229 on phosphorus to form a pentavalent intermediate. P–F bond dissociation then yields a phosphoacyl enzyme intermediate in the rate-limiting step. The simulations suggest that a water molecule, coordinated to the catalytic Ca2+, donates a proton to Asp121 and then attacks the tetrahedral phosphoacyl intermediate to liberate the diisopropylphosphate product. In contrast, the calculated free energy barrier for hydrolysis of (S)-sarin by the same mechanism is highly unfavorable, primarily because of the instability of the pentavalent phosphoenzyme species. Instead, simulations suggest that hydrolysis of (S)-sarin proceeds by a mechanism in which Asp229 could activate an intervening water molecule for nucleophilic attack on the substrate. These findings may lead to improved strategies for engineering DFPase and related six-bladed β-propeller folds for more efficient degradation of OP compounds. PMID:24720808

  4. Polysaccharide-thickened aqueous fluoride solutions for rapid destruction of the nerve agent VX. Introducing the opportunity for extensive decontamination scenarios.

    PubMed

    Elias, Shlomi; Saphier, Sigal; Columbus, Ishay; Zafrani, Yossi

    2014-01-01

    Among the chemical warfare agents, the extremely toxic nerve agent VX (O-ethyl S-2-(diisopropylamino)ethyl methylphosphonothioate) is a target of high importance in the development of decontamination methods, due to its indefinite persistence on common environmental surfaces. Liquid decontaminants are mostly characterized by high corrosivity, usually offer poor coverage, and tend to flow and accumulate in low areas. Therefore, the development of a noncorrosive decontaminant, sufficiently viscous to resist dripping from the contaminated surface, is necessary. In the present paper we studied different polysaccharides-thickened fluoride aqueous solutions as noncorrosive decontaminants for rapid and efficient VX degradation to the nontoxic product EMPA (ethyl methylphosphonic acid). Polysaccharides are environmentally benign, natural, and inexpensive. Other known decontaminants cannot be thickened by polysaccharides, due to the sensitivity of the latter toward basic or oxidizing agents. We found that the efficiency of VX degradation in these viscous solutions in terms of kinetics and product identity is similar to that of KF aqueous solutions. Guar gum (1.5 wt %) with 4 wt % KF was chosen for further evaluation. The benign nature, rheological properties, adhering capabilities to different surfaces, and decontamination from a porous matrix were examined. This formulation showed promising properties for implementation as a spray decontaminant for common and sensitive environmental surfaces.

  5. Role of percutaneous posterior tibial nerve stimulation either alone or combined with an anticholinergic agent in treating patients with overactive bladder

    PubMed Central

    Kızılyel, Sadık; Karakeçi, Ahmet; Ozan, Tunç; Ünüş, İhsan; Barut, Osman; Onur, Rahmi

    2015-01-01

    Objective To evaluate the efficacy of percutaneous tibial nerve stimulation (PTNS), either alone or combined with an anticholinergic agent, in treating patients with an overactive bladder (OAB) in whom previous conservative treatment failed. Material and methods In this study, we included a total of 30 female patients with OAB in whom all conventional therapies failed between January 2010 and April 2011. Patients were randomly divided into three groups: Group 1, PTNS group; Group 2, patients receiving an anticholinergic agent; and Group 3, patients receiving both PTNS and anticholinergic agent. PTNS treatment continued for 12 weeks with each session lasting 30 min. Results All parameters of the bladder diary significantly improved in all groups (p<0.05). Similarly, all scores measured by questionnaires (UDI-6, IIQ-7, and OABSS) revealed significant improvements in all groups. When the improvements in symptoms were compared among the groups, there was a statistically significantly higher improvement in groups 1 and 3 than in Group 2. Conclusion PTNS is a safe, simple, and minimally invasive treatment modality in patients with OAB, and it may be suggested either alone or in combination with anticholinergics when conventional treatments fail. PMID:26623150

  6. Formation of pyrophosphate-like adducts from nerve agents sarin, soman and cyclosarin in phosphate buffer: implications for analytical and toxicological investigations.

    PubMed

    Gäb, Jürgen; John, Harald; Blum, Marc-Michael

    2011-01-15

    Phosphate buffer is frequently used in biological, biochemical and biomedical applications especially when pH is to be controlled around the physiological value of 7.4. One of the prerequisites of a buffer compound among good buffering capacity and pH stability over time is its non-reactivity with other constituents of the solution. This is especially important for quantitative analytical or toxicological assays. Previous work has identified a number of amino alcohol buffers like TRIS to react with G-type nerve agents sarin, soman and cyclosarin to form stable phosphonic diesters. In case of phosphate buffer we were able to confirm not only the rapid hydrolysis of these agents to the respective alkyl methylphosphonates but also the formation of substantial amounts of pyrophosphate-like adducts (phosphorylated methylphosphonates), which very slowly hydrolyzed following zero-order kinetics. This led to a complex mixture of phosphorus containing species with changing concentrations over time. We identified the molecular structure of these buffer adducts using 1D ¹H-³¹P HSQC NMR and LC-ESI-MS/MS techniques. Reaction rates of adduct formation are fast enough to compete with hydrolysis in aqueous solution and to yield substantial amounts of buffer adduct over the course of just a couple of minutes. Possible reaction mechanisms are discussed with respect to the formation and subsequent hydrolysis of the pyrophosphate-like compounds as well as the increased rate of hydrolysis of the nerve agent to the corresponding alkyl methylphosphonates. In summary, the use of phosphate buffer for the development of new assays with sarin, soman and cyclosarin is discouraged. Already existing protocols should be carefully reexamined on an individual basis.

  7. Development and Application of Acute Exposure Guideline Levels (AEGLs) for Chemical Warfare Nerve and Sulfur Mustard Agents.

    SciTech Connect

    Watson, Annetta Paule; Opresko, Dennis M; Young, Robert A; Hauschild, Veronique

    2006-01-01

    Acute exposure guideline levels (AEGLs) have been developed for the chemical warfare agents GB, GA, GD, GF, VX, and sulfur mustard. These AEGLs were approved by the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances after Federal Register publication and comment, and judged as scientifically valid by the National Research Council Committee on Toxicology Subcommittee on AEGLs. AEGLs represent general public exposure limits for durations ranging from 10 min to 8 h, and for three levels of severity (AEGL-1, AEGL-2, AEGL-3). Mild effects are possible at concentrations greater than AEGL-1, while life-threatening effects are expected at concentrations greater than AEGL-3. AEGLs can be applied to various civilian and national defense purposes, including evacuation and shelter-in-place protocols, reentry levels, protective clothing specifications, and analytical monitoring requirements. This report documents development and derivation of AEGL values for six key chemical warfare agents, and makes recommendations for their application to various potential exposure scenarios.

  8. Biological warfare agents.

    PubMed

    Thavaselvam, Duraipandian; Vijayaraghavan, Rajagopalan

    2010-07-01

    The recent bioterrorist attacks using anthrax spores have emphasized the need to detect and decontaminate critical facilities in the shortest possible time. There has been a remarkable progress in the detection, protection and decontamination of biological warfare agents as many instrumentation platforms and detection methodologies are developed and commissioned. Even then the threat of biological warfare agents and their use in bioterrorist attacks still remain a leading cause of global concern. Furthermore in the past decade there have been threats due to the emerging new diseases and also the re-emergence of old diseases and development of antimicrobial resistance and spread to new geographical regions. The preparedness against these agents need complete knowledge about the disease, better research and training facilities, diagnostic facilities and improved public health system. This review on the biological warfare agents will provide information on the biological warfare agents, their mode of transmission and spread and also the detection systems available to detect them. In addition the current information on the availability of commercially available and developing technologies against biological warfare agents has also been discussed. The risk that arise due to the use of these agents in warfare or bioterrorism related scenario can be mitigated with the availability of improved detection technologies.

  9. Topical hemostatic agents: a review.

    PubMed

    Palm, Melanie D; Altman, Jeffrey S

    2008-04-01

    Topical hemostatic agents play an important role in both common and specialized dermatologic procedures. These agents can be classified based on their mechanism of action and include physical or mechanical agents, caustic agents, biologic physical agents, and physiologic agents. Some agents induce protein coagulation and precipitation resulting in occlusion of small cutaneous vessels, while others take advantage of latter stages in the coagulation cascade, activating biologic responses to bleeding. Traditional and newer topical hemostatic agents are discussed in this review, and the benefits and costs of each agent will be provided.

  10. Agent oriented programming

    NASA Technical Reports Server (NTRS)

    Shoham, Yoav

    1994-01-01

    The goal of our research is a methodology for creating robust software in distributed and dynamic environments. The approach taken is to endow software objects with explicit information about one another, to have them interact through a commitment mechanism, and to equip them with a speech-acty communication language. System-level applications include software interoperation and compositionality. A government application of specific interest is an infrastructure for coordination among multiple planners. Daily activity applications include personal software assistants, such as programmable email, scheduling, and new group agents. Research topics include definition of mental state of agents, design of agent languages as well as interpreters for those languages, and mechanisms for coordination within agent societies such as artificial social laws and conventions.

  11. Agility: Agent - Ility Architecture

    DTIC Science & Technology

    2002-10-01

    Figure 2: Overview of eGents 9 Specific scientific and engineering subgoals were: • develop a lightweight agent system that uses email- based ...applets makes them hard to operate over corporate firewalls. eGents e - mail based ACL bus imposes fewer requirements on agents that use it, and firewalls...do not pose a problem for an e - mail based ACL bus. While applets limit 35 JATLites range of applications, they also make JATlite easy to deploy

  12. Stereo-specific Synthesis of Analogs of Nerve Agents And Their Utilization For Selection And Characterization of Paraoxonase (PON1) Catalytic Scavengers

    PubMed Central

    Ashani, Y.; Gupta, R.D.; Goldsmith, M.; Silman, I.; Sussman, J.L.; Tawfik, D. S.; Leader, H.

    2010-01-01

    Fluorogenic organophosphate inhibitors of acetylcholinesterase (AChE) homologous in structure to nerve agents provide useful probes for high throughput screening of mammalian paraoxonase (PON1) libraries generated by directed evolution of an engineered PON1 variant with wild-type like specificity (rePON1). Wt PON1 and rePON1 hydrolyze preferentially the less-toxic RP enantiomers of nerve agents and of their fluorogenic surrogates containing the fluorescent leaving group, 3-cyano-7-hydroxy-4-methylcoumarin (CHMC). To increase the sensitivity and reliability of the screening protocol so as to directly select rePON1 clones displaying stereo-preference towards the toxic SP enantiomer, and to determine accurately Km and kcat values for the individual isomers, two approaches were used to obtain the corresponding SP and RP isomers: (a) stereo-specific synthesis of the O-ethyl, O-n-propyl, and O-i-propyl analogs; (b) enzymic resolution of a racemic mixture of O-cyclohexyl methylphosphonylated CHMC. The configurational assignments of the SP and RP isomers, as well as their optical purity, were established by X-ray diffraction, reaction with sodium fluoride, hydrolysis by selected rePON1 variants, and inhibition of AChE. The SP configuration of the tested surrogates was established for the enantiomer with the more potent anti-AChE activity, with SP/RP inhibition ratios of 10–100, whereas the RP isomers of the O-ethyl and O-n-propyl were hydrolyzed by wt rePON1 about 600- and 70-fold faster, respectively, than the SP counterpart. Wt rePON1-induced RP/SP hydrolysis ratios for the O-cyclohexyl and O-i-propyl analogs are estimated to be ≫1000. The various SP enantiomers of O-alkyl-methylphosphonyl esters of CHMC provide suitable ligands for screening rePON1 libraries, and can expedite identification of variants with enhanced catalytic proficiency towards the toxic nerve agents. PMID:20303930

  13. Determination of nerve agent degradation products by capillary electrophoresis using field-amplified sample stacking injection with the electroosmotic flow pump and contactless conductivity detection.

    PubMed

    Xu, Li; Hauser, Peter C; Lee, Hian Kee

    2009-07-31

    In the present study, field-amplified sample stacking injection using the electroosmotic flow pump (FAEP) was developed for the capillary electrophoretic separation of the four nerve agent degradation products methylphosphonic acid (MPA), ethyl methylphosphonic acid (EMPA), isopropyl methylphosphonic acid (IMPA) and cyclohexyl methylphosphonic acid (CMPA). Coupled to contactless conductivity detection, direct quantification of these non-UV active compounds could be achieved. Sensitivity enhancement of up to 500 to 750-fold could be obtained. The newly established approach was applied to the determination of the analytes in river water and aqueous extracts of soil. Detection limits of 0.5, 0.7, 1.4 and 2.7 ng/mL were obtained for MPA, EMPA, IMPA and CMPA, respectively, in river water and 0.09, 0.14, 0.44 and 0.22 microg/g, respectively, in soil.

  14. In-line respeciation: an ion-exchange ion chromatographic method applied to the separation of degradation products of chemical warfare nerve agents in soil.

    PubMed

    Vermillion, W D; Crenshaw, M D

    1997-05-16

    The natural background of anions encountered when analyzing soil samples by ion chromatography (IC) present significant problems in the separation, detection and quantification of isopropyl methylphosphonic acid (IMPA) and methylphosphonic acid (MPA), the degradation products of sarin, a chemical warfare nerve agent. Using chemically-suppressed IC with conductivity detection, a commercially available ion-exchange column, and an isocratic binary eluent system, IMPA and MPA were determined in aqueous extracts of soil at sub-ppm (microgram/g) concentrations without the need for gradient elution or organic solvent eluent modifiers. Common soil anions such as chloride, nitrate, sulfate and phosphate do not interfere with the analysis method due to the composition of the binary eluent allowing for greater mobilization of multivalent anions (e.g., MPA, carbonate, and sulfate) while monovalent anions (e.g., IMPA and nitrate) are relatively unaffected. Carbonate is selectively removed by in-line respeciation to bicarbonate.

  15. Catalytic-site conformational equilibrium in nerve-agent adducts of acetylcholinesterase: possible implications for the HI-6 antidote substrate specificity.

    PubMed

    Artursson, Elisabet; Andersson, Per Ola; Akfur, Christine; Linusson, Anna; Börjegren, Susanne; Ekström, Fredrik

    2013-05-01

    Nerve agents such as tabun, cyclosarin and Russian VX inhibit the essential enzyme acetylcholinesterase (AChE) by organophosphorylating the catalytic serine residue. Nucleophiles, such as oximes, are used as antidotes as they can reactivate and restore the function of the inhibited enzyme. The oxime HI-6 shows a notably low activity on tabun adducts but can effectively reactivate adducts of cyclosarin and Russian VX. To examine the structural basis for the pronounced substrate specificity of HI-6, we determined the binary crystal structures of Mus musculus AChE (mAChE) conjugated by cyclosarin and Russian VX and found a conformational mobility of the side chains of Phe338 and His447. The interaction between HI-6 and tabun-adducts of AChE were subsequently investigated using a combination of time resolved fluorescence spectroscopy and X-ray crystallography. Our findings show that HI-6 binds to tabun inhibited Homo sapiens AChE (hAChE) with an IC50 value of 300μM and suggest that the reactive nucleophilic moiety of HI-6 is excluded from the phosphorus atom of tabun. We propose that a conformational mobility of the side-chains of Phe338 and His447 is a common feature in nerve-agent adducts of AChE. We also suggest that the conformational mobility allow HI-6 to reactivate conjugates of cyclosarin and Russian VX while a reduced mobility in tabun conjugated AChE results in steric hindrance that prevents efficient reactivation.

  16. Cloning and expression of a gene encoding a bacterial enzyme for decontamination of organophosphorus nerve agents and nucleotide sequence of the enzyme.

    PubMed Central

    Cheng, T C; Harvey, S P; Chen, G L

    1996-01-01

    Organophosphorus acid (OPA) anhydrolase enzymes have been found in a wide variety of prokaryotic and eukaryotic organisms. Interest in these enzymes has been prompted by their ability to catalyze the hydrolysis of toxic organophosphorus cholinesterase-inhibiting compounds, including pesticides and chemical nerve agents. The natural substrates for these enzymes are unknown. The gene (opaA) which encodes an OPA anhydrolase (OPAA-2) was isolated from an Alteromonas sp. strain JD6.5 EcoRI-lambda ZAPII chromosomal library expressed in Escherichia coli and identified by immunodetection with anti-OPAA-2 serum. OPA anhydrolase activity expressed by the immunopositive recombinant clones was demonstrated by using diisopropylfluorophosphate (DFP) as a substrate. A comparison of the recombinant enzyme with native, purified OPAA-2 showed they had the same apparent molecular mass (60 kDa), antigenic properties, and enzyme activity against DFP and the chemical nerve agents sarin, soman, and O-cyclohexyl methylphosphonofluoridate. The gene expressing this activity was found in a 1.74-kb PstI-HindIII fragment of the original 6.1-kb EcoRI DNA insert. The nucleotide sequence of this PstI-HindIII fragment revealed an open reading frame of 1,551 nucleotides, coding for a protein of 517 amino acid residues. Amino acid sequence comparison of OPAA-2 with the protein database showed that OPAA-2 is similar to a 647-amino-acid sequence produced by an open reading frame which appears to be the E. coli pepQ gene. Further comparison of OPAA-2, the E. coli PepQ protein sequence, E. coli aminopeptidase P, and human prolidase showed regions of different degrees of similarity or functionally conserved amino acid substitutions. These findings, along with preliminary data confirming the presence of prolidase activity expressed by OPAA-2, suggest that the OPAA-2 enzyme may, in nature, be used in peptide metabolism. PMID:8633861

  17. Sunscreening agents: a review.

    PubMed

    Latha, M S; Martis, Jacintha; Shobha, V; Sham Shinde, Rutuja; Bangera, Sudhakar; Krishnankutty, Binny; Bellary, Shantala; Varughese, Sunoj; Rao, Prabhakar; Naveen Kumar, B R

    2013-01-01

    The increasing incidence of skin cancers and photodamaging effects caused by ultraviolet radiation has increased the use of sunscreening agents, which have shown beneficial effects in reducing the symptoms and reoccurrence of these problems. Many sunscreen compounds are in use, but their safety and efficacy are still in question. Efficacy is measured through indices, such as sun protection factor, persistent pigment darkening protection factor, and COLIPA guidelines. The United States Food and Drug Administration and European Union have incorporated changes in their guidelines to help consumers select products based on their sun protection factor and protection against ultraviolet radiation, whereas the Indian regulatory agency has not yet issued any special guidance on sunscreening agents, as they are classified under cosmetics. In this article, the authors discuss the pharmacological actions of sunscreening agents as well as the available formulations, their benefits, possible health hazards, safety, challenges, and proper application technique. New technologies and scope for the development of sunscreening agents are also discussed as well as the role of the physician in patient education about the use of these agents.

  18. Agent independent task planning

    NASA Technical Reports Server (NTRS)

    Davis, William S.

    1990-01-01

    Agent-Independent Planning is a technique that allows the construction of activity plans without regard to the agent that will perform them. Once generated, a plan is then validated and translated into instructions for a particular agent, whether a robot, crewmember, or software-based control system. Because Space Station Freedom (SSF) is planned for orbital operations for approximately thirty years, it will almost certainly experience numerous enhancements and upgrades, including upgrades in robotic manipulators. Agent-Independent Planning provides the capability to construct plans for SSF operations, independent of specific robotic systems, by combining techniques of object oriented modeling, nonlinear planning and temporal logic. Since a plan is validated using the physical and functional models of a particular agent, new robotic systems can be developed and integrated with existing operations in a robust manner. This technique also provides the capability to generate plans for crewmembers with varying skill levels, and later apply these same plans to more sophisticated robotic manipulators made available by evolutions in technology.

  19. 'Dilute-and-shoot' RSLC-MS-MS method for fast detection of nerve and vesicant chemical warfare agent metabolites in urine.

    PubMed

    Rodin, Igor; Braun, Arcady; Stavrianidi, Andrey; Baygildiev, Timur; Shpigun, Oleg; Oreshkin, Dmitry; Rybalchenko, Igor

    2015-01-01

    A sensitive screening method based on fast liquid chromatography tandem mass-spectrometry (RSLC-MS-MS) has shown the feasibility of separation and detection of low concentration β-lyase metabolites of sulfur mustard and of nerve agent phosphonic acids in urine. The analysis of these compounds is of interest because they are specific metabolites of the chemical warfare agents (CWAs), sulfur mustard (HD), sarin (GB), soman (GD), VX and Russian VX (RVX). The 'dilute-and-shoot' RSLC-MS-MS method provides a sensitive and direct approach for determining CWA exposure in non-extracted non-derivatized samples from urine. Chromatographic separation of the metabolites was achieved using a reverse phase column with gradient mobile phases consisting of 0.5% formic acid in water and acetonitrile. Identification and quantification of species were achieved using electrospray ionization-tandem mass-spectrometry monitoring two precursor-to-product ion transitions for each compound. The method demonstrates linearity over at least two orders of magnitude and had detection limits of 0.5 ng/mL in urine.

  20. Subchronic exposure to low-doses of the nerve agent VX: physiological, behavioral, histopathological and neurochemical studies.

    PubMed

    Bloch-Shilderman, Eugenia; Rabinovitz, Ishai; Egoz, Inbal; Raveh, Lily; Allon, Nahum; Grauer, Ettie; Gilat, Eran; Weissman, Ben Avi

    2008-08-15

    The highly toxic organophosphorous compound VX [O-ethyl-S-(isoporopylaminoethyl) methyl phosphonothiolate] undergoes an incomplete decontamination by conventional chemicals and thus evaporates from urban surfaces, e.g., pavement, long after the initial insult. As a consequence to these characteristics of VX, even the expected low levels should be examined for their potential to induce functional impairments including those associated with neuronal changes. In the present study, we developed an animal model for subchronic, low-dose VX exposure and evaluated its effects in rats. Animals were exposed to VX (2.25 microg/kg/day, 0.05 LD(50)) for three months via implanted mini osmotic pumps. The rapidly attained continuous and marked whole-blood cholinesterase inhibition (approximately 60%), fully recovered 96 h post pump removal. Under these conditions, body weight, blood count and chemistry, water maze acquisition task, sensitivity to the muscarinic agonist oxotremorine, peripheral benzodiazepine receptors density and brain morphology as demonstrated by routine histopathology, remained unchanged. However, animals treated with VX showed abnormal initial response in an Open Field test and a reduction (approximately 30%) in the expression of the exocytotic synaptobrevin/vesicle associate membrane protein (VAMP) in hippocampal neurons. These changes could not be detected one month following termination of exposure. Our findings indicate that following a subchronic, low-level exposure to the chemical warfare agent VX some important processes might be considerably impaired. Further research should be addressed towards better understanding of its potential health ramifications and in search of optimal countermeasures.

  1. [Preparation of antineoplastic agents].

    PubMed

    Descoutures, J-M

    2006-01-01

    In the last fifteen years, the preparation of antineoplastic agents has tended to be centralized in the hospital pharmacy for two main reasons: to enable better protection for the staff, to enable better safety for the patient. The consequences of this organization have led to standardization of techniques, implementation of a quality system and also a better use of antineoplastic agents. After protocols have been standardized by the physician and validated by the pharmacist, four main steps are necessary: phamaceutical validation of the prescription, preparation of IV admixtures according to a production file, control of the final product, dispatching of the preparation to the patient. Computer-controlled processes guarantee the safety of these different steps. The centralized preparations are made either with a vertical laminar flow hood or with an isolator. With the implementation of the National Cancer Plan, antineoplastic agents for patients on home treatments will also be prepared in centralized hospital pharmacies.

  2. Polyphenols as antimicrobial agents.

    PubMed

    Daglia, Maria

    2012-04-01

    Polyphenols are secondary metabolites produced by higher plants, which play multiple essential roles in plant physiology and have potential healthy properties on human organism, mainly as antioxidants, anti-allergic, anti-inflammatory, anticancer, antihypertensive, and antimicrobial agents. In the present review the antibacterial, antiviral, and antifungal activities of the most active polyphenol classes are reported, highlighting, where investigated, the mechanisms of action and the structure-activity relationship. Moreover, considering that the microbial resistance has become an increasing global problem, and there is a compulsory need to find out new potent antimicrobial agents as accessories to antibiotic therapy, the synergistic effect of polyphenols in combination with conventional antimicrobial agents against clinical multidrug-resistant microorganisms is discussed.

  3. Subchronic exposure to low-doses of the nerve agent VX: Physiological, behavioral, histopathological and neurochemical studies

    SciTech Connect

    Bloch-Shilderman, Eugenia Rabinovitz, Ishai; Egoz, Inbal; Raveh, Lily; Allon, Nahum; Grauer, Ettie; Gilat, Eran; Weissman, Ben Avi

    2008-08-15

    The highly toxic organophosphorous compound VX [O-ethyl-S-(isoporopylaminoethyl) methyl phosphonothiolate] undergoes an incomplete decontamination by conventional chemicals and thus evaporates from urban surfaces, e.g., pavement, long after the initial insult. As a consequence to these characteristics of VX, even the expected low levels should be examined for their potential to induce functional impairments including those associated with neuronal changes. In the present study, we developed an animal model for subchronic, low-dose VX exposure and evaluated its effects in rats. Animals were exposed to VX (2.25 {mu}g/kg/day, 0.05 LD{sub 50}) for three months via implanted mini osmotic pumps. The rapidly attained continuous and marked whole-blood cholinesterase inhibition ({approx} 60%), fully recovered 96 h post pump removal. Under these conditions, body weight, blood count and chemistry, water maze acquisition task, sensitivity to the muscarinic agonist oxotremorine, peripheral benzodiazepine receptors density and brain morphology as demonstrated by routine histopathology, remained unchanged. However, animals treated with VX showed abnormal initial response in an Open Field test and a reduction ({approx} 30%) in the expression of the exocytotic synaptobrevin/vesicle associate membrane protein (VAMP) in hippocampal neurons. These changes could not be detected one month following termination of exposure. Our findings indicate that following a subchronic, low-level exposure to the chemical warfare agent VX some important processes might be considerably impaired. Further research should be addressed towards better understanding of its potential health ramifications and in search of optimal countermeasures.

  4. Agent Persuasion Mechanism of Acquaintance

    NASA Astrophysics Data System (ADS)

    Jinghua, Wu; Wenguang, Lu; Hailiang, Meng

    Agent persuasion can improve negotiation efficiency in dynamic environment based on its initiative and autonomy, and etc., which is being affected much more by acquaintance. Classification of acquaintance on agent persuasion is illustrated, and the agent persuasion model of acquaintance is also illustrated. Then the concept of agent persuasion degree of acquaintance is given. Finally, relative interactive mechanism is elaborated.

  5. Model Checking Normative Agent Organisations

    NASA Astrophysics Data System (ADS)

    Dennis, Louise; Tinnemeier, Nick; Meyer, John-Jules

    We present the integration of a normative programming language in the MCAPL framework for model checking multi-agent systems. The result is a framework facilitating the implementation and verification of multi-agent systems coordinated via a normative organisation. The organisation can be programmed in the normative language while the constituent agents may be implemented in a number of (BDI) agent programming languages.

  6. Remote Agent Experiment

    NASA Technical Reports Server (NTRS)

    Benard, Doug; Dorais, Gregory A.; Gamble, Ed; Kanefsky, Bob; Kurien, James; Millar, William; Muscettola, Nicola; Nayak, Pandu; Rouquette, Nicolas; Rajan, Kanna; Norvig, Peter (Technical Monitor)

    2000-01-01

    Remote Agent (RA) is a model-based, reusable artificial intelligence (At) software system that enables goal-based spacecraft commanding and robust fault recovery. RA was flight validated during an experiment on board of DS1 between May 17th and May 21th, 1999.

  7. Can Subscription Agents Survive?

    ERIC Educational Resources Information Center

    Tuttle, Marcia

    1985-01-01

    With the saturation of traditional markets for their services, subscription agents have evolved from orders and invoices to serving customers by communicating with librarians and publishers and making automated and paper products available. Magazine fulfillment centers, publisher discounts, and electronic publishing will influence the subscription…

  8. E-Learning Agents

    ERIC Educational Resources Information Center

    Gregg, Dawn G.

    2007-01-01

    Purpose: The purpose of this paper is to illustrate the advantages of using intelligent agents to facilitate the location and customization of appropriate e-learning resources and to foster collaboration in e-learning environments. Design/methodology/approach: This paper proposes an e-learning environment that can be used to provide customized…

  9. Developmental Toxic Effects of Exposure to Chemical Warfare Nerve Agents in Rats: Effects on Brain and Behavior

    DTIC Science & Technology

    2014-10-01

    paucity of research directed toward the infant /juvenile population has raised concern because of the unique vulnerabilities of children. In the...GB), infants , children and adolescents are likely to be exposed. It is critical to evaluate whether countermeasures that are effective against nerve...catheters were exposed to 1.0 LD50 GB. Blood was collected at various time points after exposure and analyzed for cardiac troponin (cTnI) levels. At 72

  10. A proposed biologic cure for recurrent genital herpes simplex through injection of neurolytic agents into cutaneous sensory nerves.

    PubMed

    Bierman, S M

    1983-01-01

    It may be possible to eliminate Herpes simplex virus (HSV) from the skin of patients with chronic recurrent genital infections through destruction of the cutaneous sensory nerves of the genitals by injecting absolute alcohol into the affected areas. In so doing the latency of the virus in the sensory ganglia may be influenced, the immediate source of reinfection suppressed, and reactivation of HSV inhibited in the skin.

  11. Characterization of chemical agent transport in paints.

    PubMed

    Willis, Matthew P; Gordon, Wesley; Lalain, Teri; Mantooth, Brent

    2013-09-15

    A combination of vacuum-based vapor emission measurements with a mass transport model was employed to determine the interaction of chemical warfare agents with various materials, including transport parameters of agents in paints. Accurate determination of mass transport parameters enables the simulation of the chemical agent distribution in a material for decontaminant performance modeling. The evaluation was performed with the chemical warfare agents bis(2-chloroethyl) sulfide (distilled mustard, known as the chemical warfare blister agent HD) and O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate (VX), an organophosphate nerve agent, deposited on to two different types of polyurethane paint coatings. The results demonstrated alignment between the experimentally measured vapor emission flux and the predicted vapor flux. Mass transport modeling demonstrated rapid transport of VX into the coatings; VX penetrated through the aliphatic polyurethane-based coating (100 μm) within approximately 107 min. By comparison, while HD was more soluble in the coatings, the penetration depth in the coatings was approximately 2× lower than VX. Applications of mass transport parameters include the ability to predict agent uptake, and subsequent long-term vapor emission or contact transfer where the agent could present exposure risks. Additionally, these parameters and model enable the ability to perform decontamination modeling to predict how decontaminants remove agent from these materials.

  12. Abdominal bloating and irritable bowel syndrome like symptoms following microinstillation inhalation exposure to chemical warfare nerve agent VX in guinea pigs.

    PubMed

    Katos, Alexandre M; Conti, Michele L; Moran, Theodore S; Gordon, Richard K; Doctor, Bhupendra P; Sciuto, Alfred M; Nambiar, Madhusoodana P

    2007-05-01

    While assessing the methylphosphonothioic acid S-(2-(bis(1-methylethyl)amino)ethyl)O-ethyl ester (VX) induced respiratory toxicity and evaluating therapeutics against lung injury, we observed that the animals were experiencing abnormal swelling in the abdominal area. Nerve agent has been known to increase salivary, nasal and gastrointestinal secretion and cause diarrhea. This study was initiated to investigate the effect of VX on the gastrointestinal tract (GI) since abdominal pathology may affect breathing and contribute to the on going respiratory toxicity. The mid-abdominal diameter and the size of the lower left abdomen was measured before and after 27.3 mg/m3 VX exposure by microinstillation and at 30 min intervals up to 2 h post-VX exposure. Both VX and saline exposed animals exhibited a decrease in circumference of the upper abdomen, although the decrease was slightly higher in VX-exposed animals up to 1 h. The waist diameter increased slightly in VX-exposed animals from 60 to 90 min post-VX exposure but was similar to saline controls. The lower left abdomen near to the cecum, 6 cm below and 2cm to the right of the end of the sternum, showed an increase in size at 30-60 min that was significantly increased at 90-120 min post-VX exposure. In addition, VX-exposed animals showed loose fecal matter compared to controls. Necropsy at 24h showed an increased small intestine twisting motility in VX-exposed animals. Body tissue AChE assay showed high inhibition in the esophagus and intestine in VX-exposed animals indicating that a significant amount of the agent is localized to the GI following microinstillation exposure. These results suggest that microinstillatipn inhalation VX exposure induces gastrointestinal disturbances similar to that of irritable bowel syndrome and bloating.

  13. Identification of novel disulfide adducts between the thiol containing leaving group of the nerve agent VX and cysteine containing tripeptides derived from human serum albumin.

    PubMed

    Kranawetvogl, Andreas; Küppers, Jim; Gütschow, Michael; Worek, Franz; Thiermann, Horst; Elsinghorst, Paul W; John, Harald

    2016-12-09

    Chemical warfare agents represent a continuous and considerable threat to military personnel and the civilian population. Such compounds are prohibited by the Chemical Weapons Convention, to which adherence by the member states is strictly controlled. Therefore, reliable analytical methods for verification of an alleged use of banned substances are required. Accordingly, current research focuses on long-term biomarkers derived from covalent adducts with biomolecules such as proteins. Recently, we have introduced a microbore liquid chromatography/electrospray ionization high-resolution tandem mass spectrometry method allowing for the investigation of two different classes of adducts of the nerve agent VX with human serum albumin (HSA). Phosphonylated tyrosine residues and novel disulfide adducts at cysteine residues of HSA were produced by enzymatic cleavage with pronase and detected simultaneously. Notably, the thiol containing leaving group of VX (2-(diisopropylamino)ethanethiol, DPAET) formed disulfide adducts that were released as cysteine and proline containing dipeptides originating from at least two different sites of HSA. Aim of this study was to identify assumed and novel adducts of DPAET with HSA using synthetic peptide reference compounds. Two novel tripeptides were identified representing disulfide adducts with DPAET (Met-Pro-Cys-DPAET, MPC-DPAET and Asp-Ile-Cys-DPAET, DIC-DPAET). MPC-DPAET was shown to undergo partial in-source decay during electrospray ionization for MS detection thereby losing the N-terminal Met residue. This results in the more stable Pro-Cys-DPAET (PC-DPAET) dipeptide detectable as protonated ion. The limit of detection for MPC-DPAET was evaluated, revealing toxicologically relevant VX plasma concentrations. The results provide novel insights into the reactivity of VX and its endogenous targets. Copyright © 2016 John Wiley & Sons, Ltd.

  14. Magnetic Electrochemical Sensing Platform for Biomonitoring of Exposure to Organophosphorus Pesticides and Nerve Agents Based on Simultaneous Measurement of Total Enzyme Amount and Enzyme Activity

    SciTech Connect

    Du, Dan; Wang, Jun; Wang, Limin; Lu, Donglai; Smith, Jordan N.; Timchalk, Charles; Lin, Yuehe

    2011-05-15

    We report a new approach for electrochemical quantification of enzymatic inhibition and phosphorylation for biomonitoring of exposure to organophosphorus (OP) pesticides and nerve agents based on a magnetic beads (MBs) immunosensing platform. The principle of this approach is based on the combination of MBs immuno-capture based enzyme activity assay and competitive immunoassay of total amount of enzyme for simultaneous detection of enzyme inhibition and phosphorylation in biological fluids. Butyrylcholinesterase (BChE) was chosen as a model enzyme. In competitive immunoassay, the target total BChE in a sample (mixture of OP-inhibited BChE and active BChE) competes with the BChE modified on the MBs to bind to the limited anti-BChE antibody labeled with quantum dots (QDs-anti-BChE), and followed by electrochemical stripping analysis of the bound QDs conjugate on the MBs. This assay shows a linear response over the total BChE concentration range of 0.1~20 nM. Simultaneously, real time BChE activity was measured on an electrochemical carbon nanotube-based sensor coupled with microflow injection system after immuno-capture by MBs-anti-BChE conjugate. Therefore, the formed phosphorylated adduct (OP-BChE) can be estimated by the difference values of the total amount BChE (including active and OP-inhibited) and active BChE from established calibration curves. This approach not only eliminates the difficulty in screening of low-dose OP exposure (less than 20% inhibition of BChE) because of individual variation of BChE values, but also avoids the drawback of the scarce availability of OP-BChE antibody. It is sensitive enough to detect 0.5 nM OP-BChE, which is less than 2% BChE inhibition. This method offers a new method for rapid, accurate, selective and inexpensive quantification of phosphorylated adducts and enzyme inhibition for biomonitoring of OP and nerve agent exposures.

  15. A rat model of nerve agent exposure applicable to the pediatric population: The anticonvulsant efficacies of atropine and GluK1 antagonists

    SciTech Connect

    Miller, Steven L.; Aroniadou-Anderjaska, Vassiliki; Figueiredo, Taiza H.; Prager, Eric M.; Almeida-Suhett, Camila P.; Apland, James P.; and others

    2015-04-15

    Inhibition of acetylcholinesterase (AChE) after nerve agent exposure induces status epilepticus (SE), which causes brain damage or death. The development of countermeasures appropriate for the pediatric population requires testing of anticonvulsant treatments in immature animals. In the present study, exposure of 21-day-old (P21) rats to different doses of soman, followed by probit analysis, produced an LD{sub 50} of 62 μg/kg. The onset of behaviorally-observed SE was accompanied by a dramatic decrease in brain AChE activity; rats who did not develop SE had significantly less reduction of AChE activity in the basolateral amygdala than rats who developed SE. Atropine sulfate (ATS) at 2 mg/kg, administered 20 min after soman exposure (1.2 × LD{sub 50}), terminated seizures. ATS at 0.5 mg/kg, given along with an oxime within 1 min after exposure, allowed testing of anticonvulsants at delayed time-points. The AMPA/GluK1 receptor antagonist LY293558, or the specific GluK1 antagonist UBP302, administered 1 h post-exposure, terminated SE. There were no degenerating neurons in soman-exposed P21 rats, but both the amygdala and the hippocampus were smaller than in control rats at 30 and 90 days post-exposure; this pathology was not present in rats treated with LY293558. Behavioral deficits present at 30 days post-exposure, were also prevented by LY293558 treatment. Thus, in immature animals, a single injection of atropine is sufficient to halt nerve agent-induced seizures, if administered timely. Testing anticonvulsants at delayed time-points requires early administration of ATS at a low dose, sufficient to counteract only peripheral toxicity. LY293558 administered 1 h post-exposure, prevents brain pathology and behavioral deficits. - Highlights: • The LD{sub 50} of soman was determined in postnatal-day-21 rats. • Rats with no seizures after 1.2XLD{sub 50} soman had less reduction of AChE in the amygdala. • Atropine sulfate (ATS) at 2 mg/kg, given at 20 min after

  16. Pharmacology of antiplatelet agents.

    PubMed

    Kalra, Kiran; Franzese, Christopher J; Gesheff, Martin G; Lev, Eli I; Pandya, Shachi; Bliden, Kevin P; Tantry, Udaya S; Gurbel, Paul A

    2013-12-01

    Pharmacotherapies with agents that inhibit platelet function have proven to be effective in the treatment of acute coronary syndromes, and in the prevention of complications during and after percutaneous coronary intervention. Because of multiple synergetic pathways of platelet activation and their close interplay with coagulation, current treatment strategies are based not only on platelet inhibition, but also on the attenuation of procoagulant activity, inhibition of thrombin generation, and enhancement of clot dissolution. Current strategies can be broadly categorized as anticoagulants, antiplatelet agents, and fibrinolytics. This review focuses on the pharmacology of current antiplatelet therapy primarily targeting the inhibition of the enzyme cyclooxygenase 1, the P2Y12 receptor, the glycoprotein IIb/IIIa receptor, and protease-activated receptor 1.

  17. [The antiretroviral agent Fullevir].

    PubMed

    Nosik, D N; Lialina, I K; Kalnina, L B; Lobach, O A; Chataeva, M S; Rasnetsov, L D

    2009-01-01

    The antiretroviral properties of Fullevir (sodium salt of fullerenepolyhydropolyaminocaproic acid) manufactured by IntelFarm Co.) were studied in the human cell culture infected with human immunodeficiency virus (HIV). The agent was ascertained to be able to protect the cell from the cytopathic action of HIV. The 90% effective concentration (EF90) was 5 microg/ml. The 50% average toxic concentration was 400 microg/ml. Testing of different (preventive and therapeutic) Fullevir dosage regimens has shown that the drug is effective when used both an hour before and an hour after infection and when administered simultaneously with cell infection. The longer contact time for the agent with the cells increased the degree of antiviral defense. Co-administration of Fullevir and the HIV reverse transcriptase inhibitor Retrovir (azidothymidine) showed a synergistic antiretroviral effect. Thus, Fullevir may be regarded as a new promising antiretroviral drug for the treatment of HIV infection.

  18. Potentiation of responses to sympathetic nerve stimulation and vasoconstrictor agents by SK&F 103829 in the feline mesenteric circulation.

    PubMed Central

    Taylor, E. M.; Kaumann, A. J.

    1994-01-01

    1. The amplification of vasoconstrictor effects of several agonists and sympathetic nerve stimulation, caused by 5-HT2 receptor activation, was studied in the autoperfused mesenteric circulation of anaesthetized cats. To produce long lasting and selective 5-HT2 receptor stimulation we used SK&F 103829 (2,3,4,5 tetrahydro-8[methyl-sulphonyl]-1H3-benzazepin-7-ol methensulphonate). We assessed that SK&F 103829 was a strong contractile partial agonist in isolated preparations of rat tail artery and calf pulmonary artery. 2. The intrinsic activity of SK&F 103829 with respect to 5-hydroxytryptamine (5-HT) was 0.8 in rat tail artery and 0.6 in calf pulmonary artery. SK&F 103829-induced contractile responses were surmountably antagonized by ketanserin with a potency expected from its affinity for 5-HT2 receptors. SK&F 103829 surmountably antagonized the effects of 5-HT in rat tail artery with a pKp of 5.8. 3. Concentrations of SK&F 103829 causing greater than threshold constrictions enhanced vasoconstrictor responses of sympathetic nerve stimulation, noradrenaline, angiotensin II, methoxamine and alpha, beta-methylene ATP in the mesenteric arterial bed. Increases in mesenteric arterial pressure by noradrenaline, observed in the presence of prazosin, were also potentiated by SK&F 103829. 4. Ketanserin prevented both the constrictor effect of SK&F 103829 and the SK&F 103829-evoked potentiation of the responses to noradrenaline and angiotensin II in the mesenteric arterial bed. Ketanserin, however, failed to abolish (once established) the SK&F 103829-evoked potentiation of the constrictor effects caused by both noradrenaline and angiotensin II.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8012704

  19. Intelligent Agent Integration Technology

    DTIC Science & Technology

    1998-04-01

    and Manipulation Language (KQML) specification under the DARPA-sponsored Knowledge Sharing Initiative and the developing of a scaleable and an... Shared Communication Ontology ’$" 10.3 IMPLEMENTATION 151 10.3.1 Intelligent Resource Agent Architecture ^ 10.3.2 Application to K-12 Education 153...DARPA-sponsored Knowledge Sharing Initiative, the developing a scaleable and an efficient implementation of information system components for

  20. Pathophysiology of Anticholinesterase Agents

    DTIC Science & Technology

    1988-07-07

    PATHOPHYSIOLOGY OF ANTICHOLINESTERASE AGENTS Annual and Final Report DTIC ! ELECTEI aohn E. Rash, Ph. D. ALCTRf Julie K. Elmund, Ph.D. July 7 , 1988...Ph.D. ..-,. July 7 , 1988 Dis t Supported by A __ U. S. ARMY MEDICAL RESEARCH AND DEVELOPMENT COMMAND Fort Detrick, Frederick, Maryland 21701-5012...samples for electron microscopic analysis from diaphragm, soleus and extensor digitorum longus (EDL) muscles at J hour and 1, 7 , 14, 21, and 56 days

  1. Rigid bifunctional chelating agents

    DOEpatents

    Sweet, M.P.; Mease, R.C.; Srivastava, S.C.

    1998-07-21

    Bicyclo[2.2.2] octane-2,3 diamine-N,N,N`,N`-tetraacetic acids (BODTA) and bicyclo[2.2.1] heptane-2,3 diamine-N,N,N`,N`-tetraacetic acid (BHDTA) are chelating agents useful in forming detectably labeled bioconjugate compounds for diagnostic and therapeutic purposes. New compounds and processes of forming BODTA and BHDTA are disclosed. Radioimmunoconjugates of the present invention show high and prolonged tumor uptake with low normal tissue uptakes.

  2. Rigid bifunctional chelating agents

    DOEpatents

    Sweet, Mark P.; Mease, Ronnie C.; Srivastava, Suresh C.

    1998-07-21

    Bicyclo›2.2.2! octane-2,3 diamine-N,N,N',N'-tetraacetic acids (BODTA) and bicyclo›2.2.1! heptane-2,3 diamine-N,N,N',N'-tetraacetic acid (BHDTA) are chelating agents useful in forming detectably labeled bioconjugate compounds for diagnostic and therapeutic purposes. New compounds and processes of forming BODTA and BHDTA are disclosed. Radioimmunoconjugates of the present invention show high and prolonged tumor uptake with low normal tissue uptakes.

  3. Rigid bifunctional chelating agents

    DOEpatents

    Sweet, Mark P.; Mease, Ronnie C.; Srivastava, Suresh C.

    2000-02-08

    Bicyclo[2.2.2]octane-2,3 diamine-N,N,N',N'-tetraacetic acids (BODTA) and bicyclo[2.2.1]heptane-2,3 diamine-N,N,N',N'-tetraacetic acid (BHDTA) are chelating agents useful in forming detectably labeled bioconjugate compounds for diagnostic and therapeutic purposes. New compounds and processes of forming BODTA and BHDTA are disclosed. Radioimmunoconjugates of the present invention show high and prolonged tumor uptake with low normal tissue uptakes.

  4. Vaporizing Fire Extinguishing Agents

    DTIC Science & Technology

    1950-08-18

    the pro- ject under contract included: Dr. Earl T. McBee, Head, Chemistry Department; Dr. Zara D. Welch, Researbh Supervisor; and Dr’s T. R. Santelli...Aeronautics Authority kxperimental Station, Indianapolis, Indiana, which has supplied test data for inclusion in this report. The Medical Division of the...Development of sources of supply for agent anAL con- tainers. f. Service testing. This report oovers technical phases a, b, and a to 1 April 1950, and

  5. Agent Based Computing Machine

    DTIC Science & Technology

    2005-12-09

    coordinates as in cellular automata systems. But using biology as a model suggests that the most general systems must provide for partial, but constrained...17. SECURITY CLASSIFICATION OF 118. SECURITY CLASSIFICATION OF 19. SECURITY CLASSIFICATION OF 20. LIMITATION OF ABSTRA REPORT THIS PAGE ABSTRACT...system called an "agent based computing" machine (ABC Machine). The ABC Machine is motivated by cellular biochemistry and it is based upon a concept

  6. Surface polymerization agents

    SciTech Connect

    Taylor, C.; Wilkerson, C.

    1996-12-01

    This is the final report of a 1-year, Laboratory-Directed R&D project at LANL. A joint technical demonstration was proposed between US Army Missile Command (Redstone Arsenal) and LANL. Objective was to demonstrate that an unmanned vehicle or missile could be used as a platform to deliver a surface polymerization agent in such a manner as to obstruct the filters of an air-breathing mechanism, resulting in operational failure.

  7. Agents Technology Research

    DTIC Science & Technology

    2010-02-01

    62702F 6. AUTHOR(S) Robert Wright, Jeffrey Hudack, Nathaniel Gemelli, Steven Loscalzo, and Tsu Kong Lue 5d. PROJECT NUMBER 558S 5e. TASK...NAME OF RESPONSIBLE PERSON Robert Wright a. REPORT U b. ABSTRACT U c. THIS PAGE U 19b. TELEPHONE NUMBER (Include area code) N/A...avoided by the other agents removing the incentive to lie or free-load. This phenomenon is termed as the shadow of the future and was shown in Robert

  8. Newer antifungal agents.

    PubMed

    Türel, Ozden

    2011-03-01

    The frequency and spectrum of fungal infections have been increasing steadily over the last several decades. The reason for this increase may be explained by the increase in the number of immunocompromised patients due to malignancies, AIDS, invasive surgical procedures and transplantation. In parallel with this increase, several therapeutic options have become available but problems such as intrinsic or acquired antifungal resistance have led researchers to develop new antifungal drugs with expanded effectiveness. Reduced toxicity, enhancement of bioavailability and counteraction of resistance are features desired by clinicians. The aim of this article is to summarize the studies involving isavuconazole, ravuconazole, albaconazole, aminocandin and some other investigational antifungal agents. Most data on the clinical use of ravuconazole, isavuconazole and albaconazole are mainly available as meeting abstracts or limited to animal studies or Phase I/II studies in humans. These new antifungal agents in development offer extended half-lives, possibly reduced drug interaction profiles and good tolerance. In addition to activity against Candida and Aspergillus spp., they have a broad spectrum of activity including activity against resistant and emerging pathogens. The real possibilities of these agents will only be fully understood after adequate randomized clinical trials.

  9. Advanced scale conditioning agents

    SciTech Connect

    Davis, Jeff; Battaglia, Philip J.

    2004-06-01

    A technical description of Advanced Scale Conditioning Agents (ASCA) technology was published in the May-June 2003 edition of the Nuclear Plant Journal. That article described the development of programs of advanced scale conditioning agents and specific types to maintain the secondary side of steam generators within a pressurized water reactor free of deposited corrosion products and corrosion-inducing contaminants to ensure their long-term operation. This article describes the first two plant applications of advanced scale conditioning agents implemented at Southern Nuclear Operating Company's Vogtle Units 1 and 2 during their 2002 scheduled outages to minimize tube degradation and maintain full power operation using the most effective techniques while minimizing outage costs. The goal was to remove three to four fuel cycles of deposits from each steam generator so that after future chemical cleaning activities, ASCAs could be used to maintain the cleanliness of the steam generators without the need for additional chemical cleaning efforts. The goal was achieved as well as several other benefits that resulted in cost savings to the plant.

  10. Electro membrane isolation of nerve agent degradation products across a supported liquid membrane followed by capillary electrophoresis with contactless conductivity detection.

    PubMed

    Xu, Li; Hauser, Peter C; Lee, Hian Kee

    2008-12-19

    In the present study, electro membrane isolation (EMI) of four nerve agent degradation products has been successfully explored. In the procedure, a polypropylene sheet membrane folded into an envelope with an open end with its wall pores impregnated with 1-octanol was employed as the artificial supported liquid membrane (SLM). The envelope containing the extractant or aqueous acceptor phase (at pH 6.8) was immersed in the sample or donor phase (also aqueous at a pH of 6.8) for extraction. This ensured that the target analytes were fully ionized. A voltage was then applied, with the negative electrode placed in the donor phase with agitation, and the positive electrode in the acceptor phase. The ionized analytes were thus driven to migrate from the donor phase across the SLM to the acceptor phase. The factors influential to extraction: type of organic solvent, voltage, agitation speed, extraction time, pH of the donor and acceptor phase and concentration of humic acids were investigated in detail. After extraction, the acceptor phase was collected and directly injected for capillary electrophoretic (CE) analysis. Combined with capacitively coupled contactless conductivity detection (C(4)D), the direct detection of these compounds could be achieved. Moreover, large-volume sample injection was employed to further enhance the sensitivity of this method. Limits of detection (LODs) as low as ng/mL were reached for the studied analytes, with overall LOD enhancements of four orders of magnitude.

  11. Signature-discovery approach for sample matching of a nerve-agent precursor using liquid chromatography-mass spectrometry, XCMS, and chemometrics.

    PubMed

    Fraga, Carlos G; Clowers, Brian H; Moore, Ronald J; Zink, Erika M

    2010-05-15

    This report demonstrates the use of bioinformatic and chemometric tools on liquid chromatography-mass spectrometry (LC-MS) data for the discovery of trace forensic signatures for sample matching of ten stocks of the nerve-agent precursor known as methylphosphonic dichloride (dichlor). XCMS, a software tool primarily used in bioinformatics, was used to comprehensively search and find candidate LC-MS peaks in a known set of dichlor samples. These candidate peaks were down selected to a group of 34 impurity peaks. Hierarchal cluster analysis and factor analysis demonstrated the potential of these 34 impurities peaks for matching samples based on their stock source. Only one pair of dichlor stocks was not differentiated from one another. An acceptable chemometric approach for sample matching was determined to be variance scaling and signal averaging of normalized duplicate impurity profiles prior to classification by K-nearest neighbors. Using this approach, a test set of seven dichlor samples were all correctly matched to their source stock. The sample preparation and LC-MS method permitted the detection of dichlor impurities quantitatively estimated to be in the parts-per-trillion (w/w). The detection of a common impurity in all dichlor stocks that were synthesized over a 14-year period and by different manufacturers was an unexpected discovery. Our described signature-discovery approach should be useful in the development of a forensic capability to assist investigations following chemical attacks.

  12. Dispersive solid-phase extraction for in-sorbent Fourier-transform infrared detection and identification of nerve agent simulants in analysis for verification of chemical weapon convention.

    PubMed

    Garg, Prabhat; Pardasani, Deepak; Mazumder, Avik; Purohit, Ajay; Dubey, D K

    2011-01-01

    The combination of dispersive solid-phase extraction (DSPE) and Fourier-transform infrared (FTIR) spectroscopy is presented for detection and quantification of markers and simulants of nerve agents. Hydrophilic-lipophilic balance (HLB) sorbent was used for extraction and enrichment of organophosphonates from water. When the extraction efficiency of DSPE was compared with that of conventional solid-phase extraction (SPE), DSPE was more efficient. Extraction conditions such as extraction time, and type and quantity of sorbent material were optimized. In DSPE, extracted analytes are detected and quantified on the sorbent using FTIR as analytical technique. Absorbance in FTIR due to P-O-C stretching was used for detection and quantification. Infrared absorbance of different analytes were compared by determining their molar absorptivities (ε (max)). Quantitative analyses were performed employing modified Beer's law, and relative standard deviations (RSDs) for intraday repeatability and interday reproducibility were found to be in the range 0.30-0.90% and 0.10-0.80% respectively. The limit of detection (LOD) was 5-10 μg mL(-1). The applicability of the method was tested with an unknown sample prepared by mimicking the sample obtained in an international official proficiency test.

  13. Ion-pair liquid-liquid-liquid microextraction of nerve agent degradation products followed by capillary electrophoresis with contactless conductivity detection.

    PubMed

    Xu, Li; Gong, Xiao Yang; Lee, Hian Kee; Hauser, Peter C

    2008-09-26

    The four nerve agent degradation products methylphosphonic acid (MPA), ethyl methylphosphonic acid (EMPA), isopropyl methylphosphonic acid (IMPA) and cyclohexyl methylphosphonic acid (CMPA) have been successfully extracted from aqueous sample solution by ion-pair liquid-liquid-liquid microextraction. In this procedure, the target analytes in the sample solution were converted into their ion-pair complexes with tri-n-butyl amine and then extracted by an organic solvent (1-octanol) layer on top of the sample solution. Simultaneously, the analytes were back-extracted into a drop of an aqueous acceptor solution which was suspended in the organic phase at a microsyringe needle tip. The factors influential to extraction: type of organic solvent, type of ion-pair reagent and its concentration, pH values of sample solution and acceptor aqueous phase, stirring rate and extraction time were investigated in detail. After extraction, the drop of the acceptor solution was withdrawn into the syringe and injected into a capillary electrophoresis system for analysis. Using contactless conductivity detection, direct quantification of these compounds is possible. Moreover, large-volume sample injection was employed for further preconcentration. Improvements in the limits of detection between 2.5 and 4 orders of magnitude could be achieved and concentrations at the ng/mL level can be determined. This newly established approach was successfully applied to a spiked river water sample.

  14. On-line solid phase extraction-liquid chromatography-mass spectrometry for trace determination of nerve agent degradation products in water samples.

    PubMed

    Røen, Bent T; Sellevåg, Stig R; Lundanes, Elsa

    2013-01-25

    Three primary nerve agent degradation products (ethyl-, isopropyl- and pinacolyl methylphosphonic acid) have been determined in water samples using on-line solid phase extraction-liquid chromatography and mass spectrometry (SPE-LC-MS) with electrospray ionisation. Porous graphitic carbon was employed for analyte enrichment followed by hydrophilic interaction chromatography. Diethylphosphate was applied as internal standard for quantitative determination of the alkyl methylphosphonic acids (AMPAs). By treating the samples with strong cation-exhange columns on Ba, Ag and H form, the major inorganic anions in water were removed by precipitation prior to the SPE-LC-MS determination. The AMPAs could be determined in tap water with limits of detection of 0.01-0.07 μg L(-1) with the [M-H](-) ions extracted at an accuracy of ±5 mDa. The within and between assay precisions at analyte concentrations of 5 μg L(-1) were 2-3%, and 5-9% relative standard deviation, respectively. The developed method was employed for determination of the AMPAs in three natural waters and a simulated waste water sample, spiked at 5 μg L(-1). Recoveries of ethyl-, isopropyl- and pinacolyl methylphosphonic acid were 80-91%, 92-103% and 99-106%, respectively, proving the applicability of the technique for natural waters of various origins.

  15. Signature-Discovery Approach for Sample Matching of a Nerve-Agent Precursor using Liquid Chromatography–Mass Spectrometry, XCMS, and Chemometrics

    SciTech Connect

    Fraga, Carlos G.; Clowers, Brian H.; Moore, Ronald J.; Zink, Erika M.

    2010-05-15

    This report demonstrates the use of bioinformatic and chemometric tools on liquid chromatography mass spectrometry (LC-MS) data for the discovery of ultra-trace forensic signatures for sample matching of various stocks of the nerve-agent precursor known as methylphosphonic dichloride (dichlor). The use of the bioinformatic tool known as XCMS was used to comprehensively search and find candidate LC-MS peaks in a known set of dichlor samples. These candidate peaks were down selected to a group of 34 impurity peaks. Hierarchal cluster analysis and factor analysis demonstrated the potential of these 34 impurities peaks for matching samples based on their stock source. Only one pair of dichlor stocks was not differentiated from one another. An acceptable chemometric approach for sample matching was determined to be variance scaling and signal averaging of normalized duplicate impurity profiles prior to classification by k-nearest neighbors. Using this approach, a test set of dichlor samples were all correctly matched to their source stock. The sample preparation and LC-MS method permitted the detection of dichlor impurities presumably in the parts-per-trillion (w/w). The detection of a common impurity in all dichlor stocks that were synthesized over a 14-year period and by different manufacturers was an unexpected discovery. Our described signature-discovery approach should be useful in the development of a forensic capability to help in criminal investigations following chemical attacks.

  16. Single vial sample preparation of markers of nerve agents by dispersive solid-phase extraction using magnetic strong anion exchange resins.

    PubMed

    Singh, Varoon; Chinthakindi, Sridhar; Purohit, Ajay Kumar; Pardasani, Deepak; Tak, Vijay; Dubey, Devendra Kumar

    2015-05-22

    A sample preparation method involving extraction, enrichment and derivatization of acidic degradation products of nerve agents was developed using magnetic strong anion exchange resins (MSAX). The method was performed in a single vial involving magnetic dispersive solid phase extraction (MDSPE). Analytes were derivatized with N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) in the presence of resins. MSAX were custom synthesized using Fe3O4 nanoparticles as core, 4-vinylpyridine-co-divinylbenzene as polymer shell and quaternary pyridinium function as anion-exchanger. Hydroxide ions were the counter-anions of MSAX to effectively capture the acidic alkyl alkylphosphonic acids (AAPAs) and alkylphosphonic acids (APAs). Quantitative measurements of analytes were performed in the selected ion monitoring mode of GC-MS. Full scan mode of analysis was followed for identifications. Under the optimized conditions analytes were recovered in the range of 39.7-98.8% (n=3, relative standard deviations (RSD) from 0.3 to 6.5%). Limits of detection (LODs) were in the range of 0.1-1.1ngmL(-1); and the linear dynamic range was 5-1000ngmL(-1) with r(2) of 0.9977-0.9769. Applicability of the method was tested with rain-, tap-, muddy-water and Organization for Prohibition of Chemical Weapons (OPCW) Proficiency Test samples.

  17. Direct determination of p-nitrophenyl substituent organophosphorus nerve agents using a recombinant Pseudomonas putida JS444-modified Clark oxygen electrode.

    PubMed

    Lei, Yu; Mulchandani, Priti; Chen, Wilfred; Mulchandani, Ashok

    2005-02-09

    A microbial biosensor for rapid, sensitive, selective, and cost-effective determination of the total content of organophosphorus nerve agents with p-nitrophenyl substituent is reported. The biosensor consisted of genetically engineered PNP-degrader Pseudomonas putida JS444 expressing organophosphorus hydrolase (OPH) on its cell surface immobilized on a dissolved oxygen electrode. Surface-expressed OPH catalyzed the hydrolysis of organophosphorus pesticides with p-nitrophenyl substituent such as paraoxon, methyl parathion, and parathion to release p-nitrophenol that was oxidized by the enzymatic machinery of Pseudomonas putida JS444 to carbon dioxide while consuming oxygen. The oxygen consumption was measured and correlated to the concentration of organophosphates. The sensor signal and response time were optimized with 0.086 mg dry weight of cell and operating in 50 mM pH 7.5 citrate-phosphate buffer with 50 microM CoCl(2) at room temperature. When operated at optimized conditions, the biosensor measured as low as 55 ppb of paraoxon, 53 ppb of methyl parathion, and 58 ppb of parathion without interference from most phenolic compounds and other commonly used pesticides, such as atrazine, coumaphos, sutan, sevin, and diazinon. The operational life of the microbial biosensor was approximately 5 days when stored in the operating buffer at 4 degrees C.

  18. On-line high-performance liquid chromatography-ultraviolet-nuclear magnetic resonance method of the markers of nerve agents for verification of the Chemical Weapons Convention.

    PubMed

    Mazumder, Avik; Gupta, Hemendra K; Garg, Prabhat; Jain, Rajeev; Dubey, Devendra K

    2009-07-03

    This paper details an on-flow liquid chromatography-ultraviolet-nuclear magnetic resonance (LC-UV-NMR) method for the retrospective detection and identification of alkyl alkylphosphonic acids (AAPAs) and alkylphosphonic acids (APAs), the markers of the toxic nerve agents for verification of the Chemical Weapons Convention (CWC). Initially, the LC-UV-NMR parameters were optimized for benzyl derivatives of the APAs and AAPAs. The optimized parameters include stationary phase C(18), mobile phase methanol:water 78:22 (v/v), UV detection at 268nm and (1)H NMR acquisition conditions. The protocol described herein allowed the detection of analytes through acquisition of high quality NMR spectra from the aqueous solution of the APAs and AAPAs with high concentrations of interfering background chemicals which have been removed by preceding sample preparation. The reported standard deviation for the quantification is related to the UV detector which showed relative standard deviations (RSDs) for quantification within +/-1.1%, while lower limit of detection upto 16mug (in mug absolute) for the NMR detector. Finally the developed LC-UV-NMR method was applied to identify the APAs and AAPAs in real water samples, consequent to solid phase extraction and derivatization. The method is fast (total experiment time approximately 2h), sensitive, rugged and efficient.

  19. Determination of alkylmethylphosphonic acids, the main metabolites of organophosphorus nerve agents, in biofluids by gas chromatography-mass spectrometry and liquid-liquid-solid-phase-transfer-catalyzed pentafluorobenzylation.

    PubMed

    Miki, A; Katagi, M; Tsuchihashi, H; Yamashita, M

    1999-01-01

    A simple gas chromatography-mass spectrometry (GC-MS) procedure has been developed for the main metabolites of organophosphorus nerve agents, alkylmethylphosphonic acids (AMPAs; alkyl = Et, i-Pr, and pinacolyl) in biofluids via extractive pentafluorobenzylation. The derivatization was carried out under liquid-liquid-solid-phase-transfer conditions using a polymer-bound tri-n-butylmethylphosphonium bromide as a catalyst. AMPAs in aqueous samples were semiquantitatively extracted into a small-volume organic layer as their pentafluorobenzyl derivatives at pH 4.5 (85 degrees C). Sample pretreatments for urine, serum, and saliva were each examined to minimize matrix interference. The detection limits of APMAs by electron-impact ionization GC-MS were around 50 ng/mL and 2.5-10 ng/mL in the full-scan and selected-ion monitoring modes, respectively. In order to detect trace-level AMPAs, negative-ion chemical ionization (NICI) was also employed to enhance sensitivity. The detection limits of AMPAs in biofluids were typically 60 pg/mL by GC-NICI-MS.

  20. Liposome encapsulation of chelating agents

    DOEpatents

    Rahman, Yueh Erh

    1976-01-13

    A method for transferring a chelating agent across a cellular membrane by encapsulating the charged chelating agent within liposomes and carrying the liposome-encapsulated chelating agent to the cellular membrane where the liposomes containing the chelating agent will be taken up by the cells, thereby transferring the chelating agent across the cellular membrane. A chelating agent can be introduced into the interior of a cell of a living organism wherein the liposomes will be decomposed, releasing the chelating agent to the interior of the cell. The released chelating agent will complex intracellularly deposited toxic heavy metals, permitting the more soluble metal complex to transfer across the cellular membrane from the cell and subsequently be removed from the living organism.

  1. Biomaterials for mediation of chemical and biological warfare agents.

    PubMed

    Russell, Alan J; Berberich, Jason A; Drevon, Geraldine F; Koepsel, Richard R

    2003-01-01

    Recent events have emphasized the threat from chemical and biological warfare agents. Within the efforts to counter this threat, the biocatalytic destruction and sensing of chemical and biological weapons has become an important area of focus. The specificity and high catalytic rates of biological catalysts make them appropriate for decommissioning nerve agent stockpiles, counteracting nerve agent attacks, and remediation of organophosphate spills. A number of materials have been prepared containing enzymes for the destruction of and protection against organophosphate nerve agents and biological warfare agents. This review discusses the major chemical and biological warfare agents, decontamination methods, and biomaterials that have potential for the preparation of decontamination wipes, gas filters, column packings, protective wear, and self-decontaminating paints and coatings.

  2. Collaborating with Autonomous Agents

    NASA Technical Reports Server (NTRS)

    Trujillo, Anna C.; Cross, Charles D.; Fan, Henry; Hempley, Lucas E.; Motter, Mark A.; Neilan, James H.; Qualls, Garry D.; Rothhaar, Paul M.; Tran, Loc D.; Allen, B. Danette

    2015-01-01

    With the anticipated increase of small unmanned aircraft systems (sUAS) entering into the National Airspace System, it is highly likely that vehicle operators will be teaming with fleets of small autonomous vehicles. The small vehicles may consist of sUAS, which are 55 pounds or less that typically will y at altitudes 400 feet and below, and small ground vehicles typically operating in buildings or defined small campuses. Typically, the vehicle operators are not concerned with manual control of the vehicle; instead they are concerned with the overall mission. In order for this vision of high-level mission operators working with fleets of vehicles to come to fruition, many human factors related challenges must be investigated and solved. First, the interface between the human operator and the autonomous agent must be at a level that the operator needs and the agents can understand. This paper details the natural language human factors e orts that NASA Langley's Autonomy Incubator is focusing on. In particular these e orts focus on allowing the operator to interact with the system using speech and gestures rather than a mouse and keyboard. With this ability of the system to understand both speech and gestures, operators not familiar with the vehicle dynamics will be able to easily plan, initiate, and change missions using a language familiar to them rather than having to learn and converse in the vehicle's language. This will foster better teaming between the operator and the autonomous agent which will help lower workload, increase situation awareness, and improve performance of the system as a whole.

  3. 13 CFR 107.1620 - Functions of agents, including Central Registration Agent, Selling Agent and Fiscal Agent.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... Assistance SMALL BUSINESS ADMINISTRATION SMALL BUSINESS INVESTMENT COMPANIES SBA Financial Assistance for... will appoint or cause to be appointed agent(s) to perform functions necessary to market and service... Fiscal Agent to: (i) Establish performance criteria for Poolers. (ii) Monitor and evaluate the...

  4. 13 CFR 108.1620 - Functions of agents, including Central Registration Agent, Selling Agent and Fiscal Agent.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... Assistance SMALL BUSINESS ADMINISTRATION NEW MARKETS VENTURE CAPITAL (âNMVCâ) PROGRAM SBA Financial... financial markets to determine those factors that will minimize or reduce the cost of funding Debentures...) Agents. SBA may appoint or cause to be appointed agent(s) to perform functions necessary to market...

  5. 13 CFR 108.1620 - Functions of agents, including Central Registration Agent, Selling Agent and Fiscal Agent.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... Assistance SMALL BUSINESS ADMINISTRATION NEW MARKETS VENTURE CAPITAL (âNMVCâ) PROGRAM SBA Financial... financial markets to determine those factors that will minimize or reduce the cost of funding Debentures...) Agents. SBA may appoint or cause to be appointed agent(s) to perform functions necessary to market...

  6. 13 CFR 107.1620 - Functions of agents, including Central Registration Agent, Selling Agent and Fiscal Agent.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... Assistance SMALL BUSINESS ADMINISTRATION SMALL BUSINESS INVESTMENT COMPANIES SBA Financial Assistance for... will appoint or cause to be appointed agent(s) to perform functions necessary to market and service... Fiscal Agent to: (i) Establish performance criteria for Poolers. (ii) Monitor and evaluate the...

  7. Hydroxypyridonate and hydroxypyrimidinone chelating agents

    DOEpatents

    Raymond, Kenneth N.; Doble, Daniel M.; Sunderland, Christopher J.; Thompson, Marlon

    2005-01-25

    The present invention provides hydroxypyridinone and hydroxypyrimidone chelating agents. Also provides are Gd(III) complexes of these agents, which are useful as contrast enhancing agents for magnetic resonance imaging. The invention also provides methods of preparing the compounds of the invention, as well as methods of using the compounds in magnetic resonance imaging applications.

  8. Chemical warfare agents

    PubMed Central

    Ganesan, K.; Raza, S. K.; Vijayaraghavan, R.

    2010-01-01

    Among the Weapons of Mass Destruction, chemical warfare (CW) is probably one of the most brutal created by mankind in comparison with biological and nuclear warfare. Chemical weapons are inexpensive and are relatively easy to produce, even by small terrorist groups, to create mass casualties with small quantities. The characteristics of various CW agents, general information relevant to current physical as well as medical protection methods, detection equipment available and decontamination techniques are discussed in this review article. A brief note on Chemical Weapons Convention is also provided. PMID:21829312

  9. Pharmacologic agents targeting autophagy

    PubMed Central

    Vakifahmetoglu-Norberg, Helin; Xia, Hong-guang; Yuan, Junying

    2015-01-01

    Autophagy is an important intracellular catabolic mechanism critically involved in regulating tissue homeostasis. The implication of autophagy in human diseases and the need to understand its regulatory mechanisms in mammalian cells have stimulated research efforts that led to the development of high-throughput screening protocols and small-molecule modulators that can activate or inhibit autophagy. Herein we review the current landscape in the development of screening technology as well as the molecules and pharmacologic agents targeting the regulatory mechanisms of autophagy. We also evaluate the potential therapeutic application of these compounds in different human pathologies. PMID:25654545

  10. Holograms as Teaching Agents

    NASA Astrophysics Data System (ADS)

    Walker, Robin A.

    2013-02-01

    Hungarian physicist Dennis Gabor won the Pulitzer Prize for his 1947 introduction of basic holographic principles, but it was not until the invention of the laser in 1960 that research scientists, physicians, technologists and the general public began to seriously consider the interdisciplinary potentiality of holography. Questions around whether and when Three-Dimensional (3-D) images and systems would impact American entertainment and the arts would be answered before educators, instructional designers and students would discover how much Three-Dimensional Hologram Technology (3DHT) would affect teaching practices and learning environments. In the following International Symposium on Display Holograms (ISDH) poster presentation, the author features a traditional board game as well as a reflection hologram to illustrate conventional and evolving Three-Dimensional representations and technology for education. Using elements from the American children's toy Operation® (Hasbro, 2005) as well as a reflection hologram of a human brain (Ko, 1998), this poster design highlights the pedagogical effects of 3-D images, games and systems on learning science. As teaching agents, holograms can be considered substitutes for real objects, (human beings, organs, and animated characters) as well as agents (pedagogical, avatars, reflective) in various learning environments using many systems (direct, emergent, augmented reality) and electronic tools (cellphones, computers, tablets, television). In order to understand the particular importance of utilizing holography in school, clinical and public settings, the author identifies advantages and benefits of using 3-D images and technology as instructional tools.

  11. [New agents for hypercholesterolemia].

    PubMed

    Pintó, Xavier; García Gómez, María Carmen

    2016-02-19

    An elevated proportion of high cardiovascular risk patients do not achieve the therapeutic c-LDL goals. This owes to physicians' inappropriate or insufficient use of cholesterol lowering medications or to patients' bad tolerance or therapeutic compliance. Another cause is an insufficient efficacy of current cholesterol lowering drugs including statins and ezetimibe. In addition, proprotein convertase subtilisin kexin type 9 inhibitors are a new cholesterol lowering medications showing safety and high efficacy to reduce c-LDL in numerous already performed or underway clinical trials, potentially allowing an optimal control of hypercholesterolemia in most patients. Agents inhibiting apolipoprotein B synthesis and microsomal transfer protein are also providing a new potential to decrease cholesterol in patients with severe hypercholesterolemia and in particular in homozygote familial hypercholesterolemia. Last, cholesteryl ester transfer protein inhibitors have shown powerful effects on c-HDL and c-LDL, although their efficacy in cardiovascular prevention and safety has not been demonstrated yet. We provide in this article an overview of the main characteristics of therapeutic agents for hypercholesterolemia, which have been recently approved or in an advanced research stage.

  12. Model Checking Agent Communication

    NASA Astrophysics Data System (ADS)

    Bentahar, J.; Meyer, J.-J. Ch.; Wan, W.

    Model checking is a formal and automatic technique used to verify computational systems (e.g. communication protocols) against given properties. The purpose of this chapter is to describe a model checking algorithm to verify communication protocols used by autonomous agents interacting using dialogue games, which are governed by a set of logical rules. We use a variant of Extended Computation Tree Logic CTL* for specifying these dialogue games and the properties to be checked. This logic, called ACTL*, extends CTL* by allowing formulae to constrain actions as well as states. The verification method uses an on-the-fly efficient algorithm. It is based on translating formulae into a variant of alternating tree automata called Alternating Büchi Tableau Automata (ABTA). We present a tableau-based version of this algorithm and provide the soundness, completeness, termination and complexity results. Two case studies are discussed along with their respective implementations to illustrate the proposed approach. The first one is about an agent-based negotiation protocol and the second one considers a modified version of the NetBill protocol.

  13. Cleaning agents and asthma.

    PubMed

    Quirce, S; Barranco, P

    2010-01-01

    Although cleaners represent a significant part of the working population worldwide, they remain a relatively understudied occupational group. Epidemiological studies have shown an association between cleaning work and asthma, but the risk factors are uncertain. Cleaning workers are exposed to a large variety of cleaning products containing both irritants and sensitizers, as well as to common indoor allergens and pollutants. Thus, the onset or aggravation of asthma in this group could be related to an irritant-induced mechanism or to specific sensitization. The main sensitizers contained in cleaning products are disinfectants, quaternary ammonium compounds (such as benzalkonium chloride), amine compounds, and fragrances.The strongest airway irritants in cleaning products are bleach (sodium hypochlorite), hydrochloric acid, and alkaline agents (ammonia and sodium hydroxide), which are commonly mixed together. Exposure to the ingredients of cleaning products may give rise to both new-onset asthma, with or without a latency period, and work-exacerbated asthma. High-level exposure to irritants may induce reactive airways dysfunction syndrome. Cleaning workers may also have a greater relative risk of developing asthma due to prolonged low-to-moderate exposure to respiratory irritants. In addition, asthma-like symptoms without confirmed asthma are also common after exposure to cleaning agents. In many cleaners, airway symptoms induced by chemicals and odors cannot be explained by allergic or asthmatic reactions. These patients may have increased sensitivity to inhaled capsaicin, which is known to reflect sensory reactivity, and this condition is termed airway sensory hyperreactivity.

  14. [Bacteriophages as antibacterial agents].

    PubMed

    Shasha, Shaul M; Sharon, Nehama; Inbar, Michael

    2004-02-01

    Bacteriophages are viruses that only infect bacteria. They have played an important role in the development of molecular biology and have been used as anti-bacterial agents. Since their independent discovery by Twort and d'Herelle, they have been extensively used to prevent and treat bacterial infections, mainly in Eastern Europe and the former Soviet Union. In western countries this method has been sporadically employed on humans and domesticated animals. However, the discovery and widespread use of antibiotics, coupled with doubts about the efficacy of phage therapy, led to an eclipse in the use of phage in medicine. The emergence of antibiotic resistant bacteria, especially strains that are multiply resistant, has resulted in a renewed interest in alternatives to conventional drugs. One of the possible replacements for antibiotics is the use of bacteriophages as antimicrobial agents. This brief review aims to describe the history of bacteriophage and early clinical studies on their use in bacterial disease prophylaxis and therapy, and discuss the advantages and disadvantages of bacteriophage in this regard.

  15. Agent-Based Automated Algorithm Generator

    DTIC Science & Technology

    2010-01-12

    Detection and Isolation Agent (FDIA), Prognostic Agent (PA), Fusion Agent (FA), and Maintenance Mining Agent (MMA). FDI agents perform diagnostics...manner and loosely coupled). The library of D/P algorithms will be hosted in server-side agents, consisting of four types of major agents: Fault

  16. Flexible, secure agent development framework

    DOEpatents

    Goldsmith; Steven Y.

    2009-04-07

    While an agent generator is generating an intelligent agent, it can also evaluate the data processing platform on which it is executing, in order to assess a risk factor associated with operation of the agent generator on the data processing platform. The agent generator can retrieve from a location external to the data processing platform an open site that is configurable by the user, and load the open site into an agent substrate, thereby creating a development agent with code development capabilities. While an intelligent agent is executing a functional program on a data processing platform, it can also evaluate the data processing platform to assess a risk factor associated with performing the data processing function on the data processing platform.

  17. Learning models of intelligent agents

    SciTech Connect

    Carmel, D.; Markovitch, S.

    1996-12-31

    Agents that operate in a multi-agent system need an efficient strategy to handle their encounters with other agents involved. Searching for an optimal interactive strategy is a hard problem because it depends mostly on the behavior of the others. In this work, interaction among agents is represented as a repeated two-player game, where the agents` objective is to look for a strategy that maximizes their expected sum of rewards in the game. We assume that agents` strategies can be modeled as finite automata. A model-based approach is presented as a possible method for learning an effective interactive strategy. First, we describe how an agent should find an optimal strategy against a given model. Second, we present an unsupervised algorithm that infers a model of the opponent`s automaton from its input/output behavior. A set of experiments that show the potential merit of the algorithm is reported as well.

  18. Fluoroquinolone antimicrobial agents.

    PubMed Central

    Wolfson, J S; Hooper, D C

    1989-01-01

    The fluoroquinolones, a new class of potent orally absorbed antimicrobial agents, are reviewed, considering structure, mechanisms of action and resistance, spectrum, variables affecting activity in vitro, pharmacokinetic properties, clinical efficacy, emergence of resistance, and tolerability. The primary bacterial target is the enzyme deoxyribonucleic acid gyrase. Bacterial resistance occurs by chromosomal mutations altering deoxyribonucleic acid gyrase and decreasing drug permeation. The drugs are bactericidal and potent in vitro against members of the family Enterobacteriaceae, Haemophilus spp., and Neisseria spp., have good activity against Pseudomonas aeruginosa and staphylococci, and (with several exceptions) are less potent against streptococci and have fair to poor activity against anaerobic species. Potency in vitro decreases in the presence of low pH, magnesium ions, or urine but is little affected by different media, increased inoculum, or serum. The effects of the drugs in combination with a beta-lactam or aminoglycoside are often additive, occasionally synergistic, and rarely antagonistic. The agents are orally absorbed, require at most twice-daily dosing, and achieve high concentrations in urine, feces, and kidney and good concentrations in lung, bone, prostate, and other tissues. The drugs are efficacious in treatment of a variety of bacterial infections, including uncomplicated and complicated urinary tract infections, bacterial gastroenteritis, and gonorrhea, and show promise for therapy of prostatitis, respiratory tract infections, osteomyelitis, and cutaneous infections, particularly when caused by aerobic gram-negative bacilli. Fluoroquinolones have also proved to be efficacious for prophylaxis against travelers' diarrhea and infection with gram-negative bacilli in neutropenic patients. The drugs are effective in eliminating carriage of Neisseria meningitidis. Patient tolerability appears acceptable, with gastrointestinal or central nervous

  19. The Utility of Human Plasma Derived Butyrylcholinesterase (huBuChE) A Therapeutic Measure in the Absence of Pre-treatment or Conventional Post-poisoning Therapies Against Nerve Agent

    DTIC Science & Technology

    2011-04-01

    International, St Paul , USA). Animals were allowed to recover for 14 days prior to nerve agent dosing. In order to administer therapy via the...Kolarich D, Weber A, Pabst M, Stadlmann J, Teschner W, Ehrlich H. Glycoproteornic characterization of butyrylcholinesterase from human plasma...guinea-pig. Journal of Applied Toxicology 2008;28:694-702. 13 Mumford H, Price ME, Cerasoli DM, Teschner W, Ehrlich H, Schwarz HP. Efficacy and

  20. Effectiveness and reaction networks of H2O2 vapor with NH3 gas for decontamination of the toxic warfare nerve agent, VX on a solid surface.

    PubMed

    Gon Ryu, Sam; Wan Lee, Hae

    2015-01-01

    The nerve agent, O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate (VX) must be promptly eliminated following its release into the environment because it is extremely toxic, can cause death within a few minutes after exposure, acts through direct skin contact as well as inhalation, and persists in the environment for several weeks after release. A mixture of hydrogen peroxide vapor and ammonia gas was examined as a decontaminant for the removal of VX on solid surfaces at ambient temperature, and the reaction products were analyzed by gas chromatography-mass spectrometry (GC-MS) and nuclear magnetic resonance spectrometry (NMR). All the VX on glass wool filter disks was found to be eliminated after 2 h of exposure to the decontaminant mixtures, and the primary decomposition product was determined to be non-toxic ethyl methylphosphonic acid (EMPA); no toxic S-[2-(diisopropylamino)ethyl] methylphosphonothioic acid (EA-2192), which is usually produced in traditional basic hydrolysis systems, was found to be formed. However, other by-products, such as toxic O-ethyl S-vinyl methylphosphonothioate and (2-diisopropylaminoethyl) vinyl disulfide, were detected up to 150 min of exposure to the decontaminant mixture; these by-products disappeared after 3 h. The two detected vinyl byproducts were identified first in this study with the decontamination system of liquid VX on solid surfaces using a mixture of hydrogen peroxide vapor and ammonia gas. The detailed decontamination reaction networks of VX on solid surfaces produced by the mixture of hydrogen peroxide vapor and ammonia gas were suggested based on the reaction products. These findings suggest that the mixture of hydrogen peroxide vapor and ammonia gas investigated in this study is an efficient decontaminant mixture for the removal of VX on solid surfaces at ambient temperature despite the formation of a toxic by-product in the reaction process.

  1. Rapid screening of chemical warfare nerve agent metabolites in urine by atmospheric solids analysis probe-mass spectroscopy (ASAP-MS).

    PubMed

    Zydel, Frank; Smith, J Richard; Pagnotti, Vincent S; Lawrence, Richard J; McEwen, Charles N; Capacio, Benedict R

    2012-01-01

    Exposures to organophosphorus nerve agents (OPNA) remain a threat to both civilian and military populations. Verification of exposures typically involves determinations of urinary metabolites or adducted proteins in blood. Urinary alkyl methylphosphonic acid metabolites resulting from hydrolysis of OPNAs provide a convenient marker for OPNA exposure. In a military setting, urine is a relatively easy sample to obtain, and a rapid turnaround for analyses for the identification of metabolites is critical for field commanders. Timely information on use and identity of OPNAs facilitates decisions regarding employment of personal protective equipment and additional strategies to mitigate additional exposure(s). Herein, we report the development of a rapid mass spectrometric (MS) method to identify OPNA metabolites directly from urine with no sample preparation. Synthetic urine spiked with multiple OPNA metabolites was analyzed using an atmospheric solids analysis probe (ASAP) attached to a high resolution mass spectrometer. The alkyl methylphosphonic acid metabolites resulting from hydrolysis of sarin, cyclosarin, soman, and Russian VX were clearly detectable down to a level of 1.0 ng/ml. The ability to rapidly detect OPNA metabolites in unprepared urine allows for the design of a field-deployable device that could afford field personnel the ability to rapidly screen individuals for specific OPNA exposure. In addition, this provides proof-of-concept evidence that a fieldable ASAP-MS device could afford personnel the ability to rapidly detect OPNAs on skin, equipment, and other porous surfaces. Published 2012. This article is a US Government work and is in the public domain in the USA.

  2. Comparison of 2-PAM and pro-2-PAM containing treatment regimens as antagonists of nerve agent-induced lethality and incapacitation. Final report, June 1981-December 1985

    SciTech Connect

    Talbot, B.G.; Harris, L.W.; Lennox, W.J.; Anderson, D.A.; Green, M.D.

    1986-09-01

    In vivo, (2-Puridine Aldoxine Methioidide) reactivates phosphonylated acetylcholinesterase AChE peripherally, but is effective in restoring AChE centrally because the quaternary nitrogen atom of 2-PAM prevents penetration of the brain. The problem was solved by the synthesis of the 1,6-dihyropyridine derivative of 2-PAM, pro-2-PAM (PP). Functional brain AChE is related to return to control performance on an accelerating rotarod (ARR) in animals intoxicated with soman. There should be a difference in the time to recovery of control ARR performance between PP- and 2-PAM-treated, sarin-intoxicated animals. In the present work, an ARR decrement free dosage (DFD) of each of these oximes (30 mg/kg, im) in combination with DFD of atropine (A) and mecamylamine (M) (0.79 mg/kg each, im) was used as pretreatment against sarin-induced deficit. The same antidotes were given pre-and post- intoxication (as pretreatment and therapy) to anatagonize sarin-induced lethality; the PP containing antidote provided significantly greater protection than that by the 2-PAM antidote which in turn provided significant protection over control. Neither antidote when given as pretreatment and therapy provided protection above control against soman-induced physical incapacitation, but they were equally effective in antagonizing VX-induced physical incapacitation. The reversal of sarin-induced physical debilitation reflects the central actions of PP and supports the notion that functional brain AChE activity is essential for rapid recovery from the debilitating effeclts on nerve agents.

  3. Evaluation of acetylcholine, seizure activity and neuropathology following high-dose nerve agent exposure and delayed neuroprotective treatment drugs in freely moving rats.

    PubMed

    Acon-Chen, Cindy; Koenig, Jeffrey A; Smith, Garrett R; Truitt, Amber R; Thomas, Thaddeus P; Shih, Tsung-Ming

    2016-06-01

    Organophosphorus nerve agents such as soman (GD) inhibit acetylcholinesterase, producing an excess of acetylcholine (ACh), which results in respiratory distress, convulsions and status epilepticus that leads to neuropathology. Several drugs (topiramate, clobazam, pregnanolone, allopregnanolone, UBP 302, cyclopentyladenosine [CPA], ketamine, midazolam and scopolamine) have been identified as potential neuroprotectants that may terminate seizures and reduce brain damage. To systematically evaluate their efficacy, this study employed in vivo striatal microdialysis and liquid chromatography to respectively collect and analyze extracellular ACh in freely moving rats treated with these drugs 20 min after seizure onset induced by a high dose of GD. Along with microdialysis, EEG activity was recorded and neuropathology assessed at 24 h. GD induced a marked increase of ACh, which peaked at 30 min post-exposure to 800% of control levels and then steadily decreased toward baseline levels. Approximately 40 min after treatment, only midazolam (10 mg/kg) and CPA (60 mg/kg) caused a significant reduction of ACh levels, with CPA reducing ACh levels more rapidly than midazolam. Both drugs facilitated a return to baseline levels at least 55 min after treatment. At 24 h, only animals treated with CPA (67%), midazolam (18%) and scopolamine (27%) exhibited seizure termination. While all treatments except for topiramate reduced neuropathology, CPA, midazolam and scopolamine showed the greatest reduction in pathology. Our results suggest that delayed treatment with CPA, midazolam, or scopolamine is effective at reducing GD-induced seizure activity and neuropathology, with CPA and midazolam capable of facilitating a reduction in GD-induced ACh elevation.

  4. Highly Sensitive and Selective Immuno-capture/Electrochemical Assay of Acetylcholinesterase Activity in Red Blood Cells: A Biomarker of Exposure to Organophosphorus Pesticides and Nerve Agents

    SciTech Connect

    Chen, Aiqiong; Du, Dan; Lin, Yuehe

    2012-02-09

    Acetylcholinesterase (AChE) enzyme activity in red blood cells (RBCs) is a useful biomarker for biomonitoring of exposures to organophosphorus (OP) pesticides and chemical nerve agents. In this paper, we reported a new method for AChE activity assay based on selective immuno-capture of AChE from biological samples followed by enzyme activity assay of captured AChE using a disposable electrochemical sensor. The electrochemical sensor is based on multiwalled carbon nanotubes-gold nanocomposites (MWCNTs-Au) modified screen printed carbon electrode (SPCE). Upon the completion of immunoreaction, the target AChE (including active and inhibited) is captured onto the electrode surface and followed by an electrochemical detection of enzymatic activity in the presence of acetylthiocholine. A linear response is obtained over standard AChE concentration range from 0.1 to 10 nM. To demonstrate the capability of this new biomonitoring method, AChE solutions dosed with different concentration of paraoxon were used to validate the new AChE assay method. AChE inhibition in OP dosed solutions was proportional to its concentration from 0.2 to 50 nM. The new AChE activity assay method for biomonitoring of OP exposure was further validated with in-vitro paraoxon-dosed RBC samples. The established electrochemical sensing platform for AChE activity assay not only avoids the problem of overlapping substrate specificity with esterases by using selective antibody, but also eliminates potential interference from other electroactive species in biological samples. It offers a new approach for sensitive, selective, and rapid AChE activity assay for biomonitoring of exposures to OPs.

  5. Peptide Antimicrobial Agents

    PubMed Central

    Jenssen, Håvard; Hamill, Pamela; Hancock, Robert E. W.

    2006-01-01

    Antimicrobial host defense peptides are produced by all complex organisms as well as some microbes and have diverse and complex antimicrobial activities. Collectively these peptides demonstrate a broad range of antiviral and antibacterial activities and modes of action, and it is important to distinguish between direct microbicidal and indirect activities against such pathogens. The structural requirements of peptides for antiviral and antibacterial activities are evaluated in light of the diverse set of primary and secondary structures described for host defense peptides. Peptides with antifungal and antiparasitic activities are discussed in less detail, although the broad-spectrum activities of such peptides indicate that they are important host defense molecules. Knowledge regarding the relationship between peptide structure and function as well as their mechanism of action is being applied in the design of antimicrobial peptide variants as potential novel therapeutic agents. PMID:16847082

  6. [Chemotherapeutic agents under study].

    PubMed

    Kawahara, S

    1998-12-01

    The development of new drugs with strong antituberculous activity and fewer side effects which are not cross-resistant to conventional antituberculosis drugs is urgently desired now. The chemotherapeutic agents under study which are considered a candidate for a new antituberculosis drug are listed below. 1) Rifamycin derivatives: rifabutin, rifapentin, KRM-1648, FCE-22250, 22807, CGP-7040, 27557, 29035, 29861, P-DEA, SPA-S-565, R-76-1. 2) New quinolones: ofloxacin, ciprofloxacin, levofloxacin, sparfloxacin, gatifloxacin, CS-940, Du-6859a. 3) Phenazines: clofazimine, B746, B4101, B4154, B4157. 4) Pyrazinamide derivatives: N-hydroxy pyrazinamide, N-hydroxy pyrazinamide-4-oxide. 5) Nitroimidazole derivatives: metronidazole et al.

  7. Ultrasound contrast agents

    PubMed Central

    Ignee, Andre; Atkinson, Nathan S. S.; Schuessler, Gudrun; Dietrich, Christoph F.

    2016-01-01

    Endoscopic ultrasound (EUS) plays an important role in imaging of the mediastinum and abdominal organs. Since the introduction of US contrast agents (UCA) for transabdominal US, attempts have been made to apply contrast-enhanced US techniques also to EUS. Since 2003, specific contrast-enhanced imaging was possible using EUS. Important studies have been published regarding contrast-enhanced EUS and the characterization of focal pancreatic lesions, lymph nodes, and subepithelial tumors. In this manuscript, we describe the relevant UCA, their application, and specific image acquisition as well as the principles of image tissue characterization using contrast-enhanced EUS. Safety issues, potential future developments, and EUS-specific issues are reviewed. PMID:27824024

  8. Nerve Agent Sensing Biopolymer Wipe

    DTIC Science & Technology

    2003-04-01

    minutes. Polymer synthesis is complete in less than 10 minutes. The CO2 evolved during the reaction of water and isocyanate lifts the foam to a...concrete, stone and asphalt . Excessive dirt or any material that significantly masks clear viewing of the sensor polymer may invalidate sensor

  9. Collaborating Fuzzy Reinforcement Learning Agents

    NASA Technical Reports Server (NTRS)

    Berenji, Hamid R.

    1997-01-01

    Earlier, we introduced GARIC-Q, a new method for doing incremental Dynamic Programming using a society of intelligent agents which are controlled at the top level by Fuzzy Relearning and at the local level, each agent learns and operates based on ANTARCTIC, a technique for fuzzy reinforcement learning. In this paper, we show that it is possible for these agents to compete in order to affect the selected control policy but at the same time, they can collaborate while investigating the state space. In this model, the evaluator or the critic learns by observing all the agents behaviors but the control policy changes only based on the behavior of the winning agent also known as the super agent.

  10. Agent-based enterprise integration

    SciTech Connect

    N. M. Berry; C. M. Pancerella

    1998-12-01

    The authors are developing and deploying software agents in an enterprise information architecture such that the agents manage enterprise resources and facilitate user interaction with these resources. The enterprise agents are built on top of a robust software architecture for data exchange and tool integration across heterogeneous hardware and software. The resulting distributed multi-agent system serves as a method of enhancing enterprises in the following ways: providing users with knowledge about enterprise resources and applications; accessing the dynamically changing enterprise; locating enterprise applications and services; and improving search capabilities for applications and data. Furthermore, agents can access non-agents (i.e., databases and tools) through the enterprise framework. The ultimate target of the effort is the user; they are attempting to increase user productivity in the enterprise. This paper describes their design and early implementation and discusses the planned future work.

  11. Agent-based enterprise integration

    SciTech Connect

    N. M. Berry; C. M. Pancerella

    1999-05-01

    The authors are developing and deploying software agents in an enterprise information architecture such that the agents manage enterprise resources and facilitate user interaction with these resources. Their enterprise agents are built on top of a robust software architecture for data exchange and tool integration across heterogeneous hardware and software. The resulting distributed multi-agent system serves as a method of enhancing enterprises in the following ways: providing users with knowledge about enterprise resources and applications; accessing the dynamically changing enterprise; intelligently locating enterprise applications and services; and improving search capabilities for applications and data. Furthermore, agents can access non-agents (i.e., databases and tools) through the enterprise framework. The ultimate target of their effort is the user; they are attempting to increase user productivity in the enterprise. This paper describes their design and early implementation and discusses their planned future work.

  12. Polymeric gastrointestinal MR contrast agents.

    PubMed

    Tilcock, C; Unger, E C; Ahkong, Q F; Fritz, T; Koenig, S H; Brown, R D

    1991-01-01

    Combining either paramagnetic (gadolinium chelates) or superparamagnetic (ferrite) contrast agents with polymers such as polyethylene glycol or cellulose, or with simple sugars such as dextrose, results in mixtures that exhibit improved T1 and/or T2 relaxivity compared with that of the contrast agent alone. It is suggested that the addition of such inexpensive and nontoxic polymers or saccharides may improve the effectiveness and decrease the cost of enteric contrast agents.

  13. Antithrombotic agents: implications in dentistry.

    PubMed

    Little, James W; Miller, Craig S; Henry, Robert G; McIntosh, Bruce A

    2002-05-01

    Thrombosis and the complicating emboli that can result are important causes of illness and death. Thrombosis is of greater overall clinical importance in terms of morbidity and mortality than all of the hemorrhagic disorders combined. Agents such as heparin, low-molecular weight heparin, warfarin, aspirin, ticlopidine, clopidogrel, and tirofiban are used to prevent venous or arterial thrombosis. Patients taking these antithrombotic agents may be at risk for excessive bleeding after invasive dental procedures. The current antithrombotic agents used in medicine are reviewed, and the dental management of patients taking these agents is discussed.

  14. Broad-spectrum antiviral agents

    PubMed Central

    Zhu, Jun-Da; Meng, Wen; Wang, Xiao-Jia; Wang, Hwa-Chain R.

    2015-01-01

    Development of highly effective, broad-spectrum antiviral agents is the major objective shared by the fields of virology and pharmaceutics. Antiviral drug development has focused on targeting viral entry and replication, as well as modulating cellular defense system. High throughput screening of molecules, genetic engineering of peptides, and functional screening of agents have identified promising candidates for development of optimal broad-spectrum antiviral agents to intervene in viral infection and control viral epidemics. This review discusses current knowledge, prospective applications, opportunities, and challenges in the development of broad-spectrum antiviral agents. PMID:26052325

  15. Fluorescent discrimination between traces of chemical warfare agents and their mimics.

    PubMed

    Díaz de Greñu, Borja; Moreno, Daniel; Torroba, Tomás; Berg, Alexander; Gunnars, Johan; Nilsson, Tobias; Nyman, Rasmus; Persson, Milton; Pettersson, Johannes; Eklind, Ida; Wästerby, Pär

    2014-03-19

    An array of fluorogenic probes is able to discriminate between nerve agents, sarin, soman, tabun, VX and their mimics, in water or organic solvent, by qualitative fluorescence patterns and quantitative multivariate analysis, thus making the system suitable for the in-the-field detection of traces of chemical warfare agents as well as to differentiate between the real nerve agents and other related compounds.

  16. The Agent of Change: The Agent of Conflict.

    ERIC Educational Resources Information Center

    Hatfield, C. R., Jr.

    This speech examines the role of change agents in third world societies and indicates that the change agent must, to some extent, manipulate the social situation, even if his view of society is a more optimistic one than he finds in reality. If he considers strains and stresses to be the lubricants of change, then his focus on conflict as a…

  17. Incorporating BDI Agents into Human-Agent Decision Making Research

    NASA Astrophysics Data System (ADS)

    Kamphorst, Bart; van Wissen, Arlette; Dignum, Virginia

    Artificial agents, people, institutes and societies all have the ability to make decisions. Decision making as a research area therefore involves a broad spectrum of sciences, ranging from Artificial Intelligence to economics to psychology. The Colored Trails (CT) framework is designed to aid researchers in all fields in examining decision making processes. It is developed both to study interaction between multiple actors (humans or software agents) in a dynamic environment, and to study and model the decision making of these actors. However, agents in the current implementation of CT lack the explanatory power to help understand the reasoning processes involved in decision making. The BDI paradigm that has been proposed in the agent research area to describe rational agents, enables the specification of agents that reason in abstract concepts such as beliefs, goals, plans and events. In this paper, we present CTAPL: an extension to CT that allows BDI software agents that are written in the practical agent programming language 2APL to reason about and interact with a CT environment.

  18. Contrast agents for MRI.

    PubMed

    Shokrollahi, H

    2013-12-01

    Contrast agents are divided into two categories. The first one is paramagnetic compounds, including lanthanides like gadolinium, which mainly reduce the longitudinal (T1) relaxation property and result in a brighter signal. The second class consists of super-paramagnetic magnetic nanoparticles (SPMNPs) such as iron oxides, which have a strong effect on the transversal (T2) relaxation properties. SPMNPs have the potential to be utilized as excellent probes for magnetic resonance imaging (MRI). For instance, clinically benign iron oxide and engineered ferrite nanoparticles provide a good MRI probing capability for clinical applications. Furthermore, the limited magnetic property and inability to escape from the reticuloendothelial system (RES) of the used nanoparticles impede their further advancement. Therefore, it is necessary to develop the engineered magnetic nanoparticle probes for the next-generation molecular MRI. Considering the importance of MRI in diagnosing diseases, this paper presents an overview of recent scientific achievements in the development of new synthetic SPMNP probes whereby the sensitive and target-specific observation of biological events at the molecular and cellular levels is feasible.

  19. Plasmids encoding therapeutic agents

    DOEpatents

    Keener, William K.

    2007-08-07

    Plasmids encoding anti-HIV and anti-anthrax therapeutic agents are disclosed. Plasmid pWKK-500 encodes a fusion protein containing DP178 as a targeting moiety, the ricin A chain, an HIV protease cleavable linker, and a truncated ricin B chain. N-terminal extensions of the fusion protein include the maltose binding protein and a Factor Xa protease site. C-terminal extensions include a hydrophobic linker, an L domain motif peptide, a KDEL ER retention signal, another Factor Xa protease site, an out-of-frame buforin II coding sequence, the lacZ.alpha. peptide, and a polyhistidine tag. More than twenty derivatives of plasmid pWKK-500 are described. Plasmids pWKK-700 and pWKK-800 are similar to pWKK-500 wherein the DP178-encoding sequence is substituted by RANTES- and SDF-1-encoding sequences, respectively. Plasmid pWKK-900 is similar to pWKK-500 wherein the HIV protease cleavable linker is substituted by a lethal factor (LF) peptide-cleavable linker.

  20. Phytonutrients as therapeutic agents.

    PubMed

    Gupta, Charu; Prakash, Dhan

    2014-09-01

    Nutrients present in various foods plays an important role in maintaining the normal functions of the human body. The major nutrients present in foods include carbohydrates, proteins, lipids, vitamins, and minerals. Besides these, there are some bioactive food components known as "phytonutrients" that play an important role in human health. They have tremendous impact on the health care system and may provide medical health benefits including the prevention and/or treatment of disease and various physiological disorders. Phytonutrients play a positive role by maintaining and modulating immune function to prevent specific diseases. Being natural products, they hold a great promise in clinical therapy as they possess no side effects that are usually associated with chemotherapy or radiotherapy. They are also comparatively cheap and thus significantly reduce health care cost. Phytonutrients are the plant nutrients with specific biological activities that support human health. Some of the important bioactive phytonutrients include polyphenols, terpenoids, resveratrol, flavonoids, isoflavonoids, carotenoids, limonoids, glucosinolates, phytoestrogens, phytosterols, anthocyanins, ω-3 fatty acids, and probiotics. They play specific pharmacological effects in human health such as anti-microbial, anti-oxidants, anti-inflammatory, antiallergic, anti-spasmodic, anti-cancer, anti-aging, hepatoprotective, hypolipidemic, neuroprotective, hypotensive, diabetes, osteoporosis, CNS stimulant, analgesic, protection from UVB-induced carcinogenesis, immuno-modulator, and carminative. This mini-review attempts to summarize the major important types of phytonutrients and their role in promoting human health and as therapeutic agents along with the current market trend and commercialization.

  1. TACtic- A Multi Behavioral Agent for Trading Agent Competition

    NASA Astrophysics Data System (ADS)

    Khosravi, Hassan; Shiri, Mohammad E.; Khosravi, Hamid; Iranmanesh, Ehsan; Davoodi, Alireza

    Software agents are increasingly being used to represent humans in online auctions. Such agents have the advantages of being able to systematically monitor a wide variety of auctions and then make rapid decisions about what bids to place in what auctions. They can do this continuously and repetitively without losing concentration. To provide a means of evaluating and comparing (benchmarking) research methods in this area the trading agent competition (TAC) was established. This paper describes the design, of TACtic. Our agent uses multi behavioral techniques at the heart of its decision making to make bidding decisions in the face of uncertainty, to make predictions about the likely outcomes of auctions, and to alter the agent's bidding strategy in response to the prevailing market conditions.

  2. Oral contraceptive agents.

    PubMed

    Shearman, R P

    1986-02-17

    The history of the development of oral contraceptives (OCs) has been a progressive reduction in dosage to what is now probably the lowest does that is compatible with the desired therapeutic effect -- to inhibit ovluation. Yet, controversy and argument continue. A table lists the OCs that are available in Australia. Many of these preparations, although having different trade names, have an identical composition. Since the withdrawal of sequential OCs from the Australian market, there are only 2 generic types. These are the progestogen only (mini) OCs, which consist of either 30 mcg of levonorgestrel or 350 mcg of norethisterone given at the same time every day; and the combined OCs, which contain an estrogen and a progestogen. In the last 12 months, some of the older high-dose OCs have been withdrawn, and it seems likely that further withdrawals will follow. Only 2 estrogens are used in the formulation of the OC, but there is a greater variety of progestogens. Ethinyl estradiol is used in most preparations. A small minority of OCs contain mestranol, the 3-methyl ether of ethinyl estradiol. Currently, there are only 4 OC agents that are available in Australia that contain mestranol and 2 of these contain the high doses of 100 mcg. Fundamentally, there are 2 types of progestogens -- those that contain, or are metabolized to, norethisterone and those that contain norgestrel or its close relative, desogestrel. With the exception of the norgestrel group and desogestrel, all other progestins, including norethisterone itself, are effective in vivo after they have been metablized to norethisterone. Mestranol is effective in humans after demethylation to ethinyl estradiol. In the norgesterel group, since d-norgestrel is inert endocrinologically, 250 mcg of levonorgestrel and 500 mcg of dl-norgestrel are equivalent. Levonorgestrel and desogestrel are of approximately equal potency. With the combined OC agents, the overwhelming mechanism of action is by the inhibition of the

  3. 7 CFR 4290.1620 - Functions of agents, including Central Registration Agent, Selling Agent and Fiscal Agent.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... to: (i) Establish performance criteria for Poolers. (ii) Monitor and evaluate the financial markets..., DEPARTMENT OF AGRICULTURE RURAL BUSINESS INVESTMENT COMPANY (âRBICâ) PROGRAM Financial Assistance for RBICs... or cause to be appointed agent(s) to perform functions necessary to market and service Debentures...

  4. 7 CFR 4290.1620 - Functions of agents, including Central Registration Agent, Selling Agent and Fiscal Agent.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... to: (i) Establish performance criteria for Poolers. (ii) Monitor and evaluate the financial markets..., DEPARTMENT OF AGRICULTURE RURAL BUSINESS INVESTMENT COMPANY (âRBICâ) PROGRAM Financial Assistance for RBICs... or cause to be appointed agent(s) to perform functions necessary to market and service Debentures...

  5. Gelled Anti-icing Agents

    NASA Technical Reports Server (NTRS)

    Markles, O. F.; Sperber, H. H.

    1983-01-01

    Pectin added to antifreeze/water mixture. Formulations include water with dimethyl sulfoxide (DMSO) as deicer and pectin as gel former. Without gelling agent, deicer runs off vertical surfaces. Without pectin solution will completely evaporate in far less time. Agents developed have wide potential for ice prevention on runways, highways, bridges and sidewalks.

  6. Field Agent Activities: Level 1.

    ERIC Educational Resources Information Center

    Gussett, James

    One of a series of monographs providing information about the Delaware Model: A Systems Approach to Science Education (Del Mod System), this monograph describes the role of field agents. These agents are responsible for individual teachers who express a desire for involvement in improving teacher effectiveness and to be involved in the teaching of…

  7. Hypersensitivity to antineoplastic agents.

    PubMed

    Castells, M C

    2008-01-01

    The need to offer first line therapy for primary and recurrent cancers has spurred the clinical development of rapid desensitizations for chemotherapy and monoclonal antibodies. Rapid desensitizations allow patients to be treated with medications to which they have presented with hypersensitivity reactions (HSRs), including anaphylaxis. Rapid desensitization achieves temporary tolerization to full therapeutic doses by slow administration of incremental doses of the drug inducing the HSR. Protocols are available for most chemotherapy agents, including taxanes, platins, doxorubicin, monoclonal antibodies, and others. Candidate patients include those who present with type I HSRs, mast cell/IgE dependent, including anaphylaxis, and non-IgE mediated HSRs, during the chemotherapy infusion or shortly after. Idiosyncratic reactions, erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis are not amenable to rapid desensitization. The recommendation for rapid desensitization can only be made by allergy and immunology specialists and can only be performed in settings with one-to-one nurse-patient care and where resuscitation personnel and resources are readily available. Repeated desensitizations can be safely performed in outpatient settings with similar conditions, which allow cancer patients to remain in clinical studies. We have generated a universal 12-step protocol that was applied to 413 cases of intravenous and intraperitoneal rapid desensitizations using taxanes, platins, liposomal doxorubicin, doxorubicin, rituximab, and other chemotherapy drugs. Under this protocol all patients were able to complete their target dose, and 94% of the patients had limited or no reactions. No deaths or codes were reported, indicating that the procedure was safe and effective in delivering first line chemotherapy drugs.

  8. Dialogue Games for Agent Argumentation

    NASA Astrophysics Data System (ADS)

    McBurney, Peter; Parsons, Simon

    The rise of the Internet and the growth of distributed computing have led to a major paradigm shift in software engineering and computer science. Until recently, the notion of computation has been variously construed as numerical calculation, as information processing, or as intelligent symbol analysis, but increasingly, it is now viewed as distributed cognition and interaction between intelligent entities [60]. This new view has major implications for the conceptualization, design, engineering and control of software systems, most profoundly expressed in the concept of systems of intelligent software agents, or multi-agent systems [99]. Agents are software entities with control over their own execution; the design of such agents, and of multi-agent systems of them, presents major research and software engineering challenges to computer scientists.

  9. Transdermal delivery of therapeutic agent

    NASA Technical Reports Server (NTRS)

    Kwiatkowski, Krzysztof C. (Inventor); Hayes, Ryan T. (Inventor); Magnuson, James W. (Inventor); Giletto, Anthony (Inventor)

    2008-01-01

    A device for the transdermal delivery of a therapeutic agent to a biological subject that includes a first electrode comprising a first array of electrically conductive microprojections for providing electrical communication through a skin portion of the subject to a second electrode comprising a second array of electrically conductive microprojections. Additionally, a reservoir for holding the therapeutic agent surrounding the first electrode and a pulse generator for providing an exponential decay pulse between the first and second electrodes may be provided. A method includes the steps of piercing a stratum corneum layer of skin with two arrays of conductive microprojections, encapsulating the therapeutic agent into biocompatible charged carriers, surrounding the conductive microprojections with the therapeutic agent, generating an exponential decay pulse between the two arrays of conductive microprojections to create a non-uniform electrical field and electrokinetically driving the therapeutic agent through the stratum corneum layer of skin.

  10. Intelligent Agents in Physics Education

    NASA Astrophysics Data System (ADS)

    Sánchez-Guzmán, D.; Mora, César

    2010-07-01

    Intelligent Agents are being applied in a wide range of processes and everyday applications. Their development is not new, in recent years they have had an increased attention and design; like learning and mentoring tools. In this work we discuss the definition of what an intelligent agent is; how they are applied; how they look like; recent implementations of agents; agents as support in the learning process, more precisely intelligent tutors; their state in Latin-American countries and future developments and trends that will permit a better communication between people and agents. Also we present an Intelligent Tutor applied as a tool for improving high-school students' skills and reasoning for the first five topics of Mechanics curricula.

  11. Markov Tracking for Agent Coordination

    NASA Technical Reports Server (NTRS)

    Washington, Richard; Lau, Sonie (Technical Monitor)

    1998-01-01

    Partially observable Markov decision processes (POMDPs) axe an attractive representation for representing agent behavior, since they capture uncertainty in both the agent's state and its actions. However, finding an optimal policy for POMDPs in general is computationally difficult. In this paper we present Markov Tracking, a restricted problem of coordinating actions with an agent or process represented as a POMDP Because the actions coordinate with the agent rather than influence its behavior, the optimal solution to this problem can be computed locally and quickly. We also demonstrate the use of the technique on sequential POMDPs, which can be used to model a behavior that follows a linear, acyclic trajectory through a series of states. By imposing a "windowing" restriction that restricts the number of possible alternatives considered at any moment to a fixed size, a coordinating action can be calculated in constant time, making this amenable to coordination with complex agents.

  12. Knowledge focus via software agents

    NASA Astrophysics Data System (ADS)

    Henager, Donald E.

    2001-09-01

    The essence of military Command and Control (C2) is making knowledge intensive decisions in a limited amount of time using uncertain, incorrect, or outdated information. It is essential to provide tools to decision-makers that provide: * Management of friendly forces by treating the "friendly resources as a system". * Rapid assessment of effects of military actions againt the "enemy as a system". * Assessment of how an enemy should, can, and could react to friendly military activities. Software agents in the form of mission agents, target agents, maintenance agents, and logistics agents can meet this information challenge. The role of each agent is to know all the details about its assigned mission, target, maintenance, or logistics entity. The Mission Agent would fight for mission resources based on the mission priority and analyze the effect that a proposed mission's results would have on the enemy. The Target Agent (TA) communicates with other targets to determine its role in the system of targets. A system of TAs would be able to inform a planner or analyst of the status of a system of targets, the effect of that status, adn the effect of attacks on that system. The system of TAs would also be able to analyze possible enemy reactions to attack by determining ways to minimize the effect of attack, such as rerouting traffic or using deception. The Maintenance Agent would scheudle maintenance events and notify the maintenance unit. The Logistics Agent would manage shipment and delivery of supplies to maintain appropriate levels of weapons, fuel and spare parts. The central idea underlying this case of software agents is knowledge focus. Software agents are createad automatically to focus their attention on individual real-world entities (e.g., missions, targets) and view the world from that entities perspective. The agent autonomously monitors the entity, identifies problems/opportunities, formulates solutions, and informs the decision-maker. The agent must be

  13. [Decontamination of chemical and biological warfare agents].

    PubMed

    Seto, Yasuo

    2009-01-01

    Chemical and biological warfare agents (CBWA's) are diverse in nature; volatile acute low-molecular-weight toxic compounds, chemical warfare agents (CWA's, gaseous choking and blood agents, volatile nerve gases and blister agents, nonvolatile vomit agents and lacrymators), biological toxins (nonvolatile low-molecular-weight toxins, proteinous toxins) and microbes (bacteria, viruses, rickettsiae). In the consequence management against chemical and biological terrorism, speedy decontamination of victims, facilities and equipment is required for the minimization of the damage. In the present situation, washing victims and contaminated materials with large volumes of water is the basic way, and additionally hypochlorite salt solution is used for decomposition of CWA's. However, it still remains unsolved how to dispose large volumes of waste water, and the decontamination reagents have serious limitation of high toxicity, despoiling nature against the environments, long finishing time and non-durability in effective decontamination. Namely, the existing decontamination system is not effective, nonspecifically affecting the surrounding non-target materials. Therefore, it is the urgent matter to build up the usable decontamination system surpassing the present technologies. The symposiast presents the on-going joint project of research and development of the novel decontamination system against CBWA's, in the purpose of realizing nontoxic, fast, specific, effective and economical terrorism on-site decontamination. The projects consists of (1) establishment of the decontamination evaluation methods and verification of the existing technologies and adaptation of bacterial organophosphorus hydrolase, (2) development of adsorptive elimination technologies using molecular recognition tools, and (4) development of deactivation technologies using photocatalysis.

  14. EPA Science Matters Newsletter: Chemical Warfare Agent Analytical Standards Facilitate Lab Testing (Published November 2013)

    EPA Pesticide Factsheets

    Learn about the EPA chemists' efforts to develop methods for detecting extremely low concentrations of nerve agents, such as sarin, VX, soman and cyclohexyl sarin, and the blister agent sulfur mustard.

  15. Contrast agents for cardiac angiography: effects of a nonionic agent vs. a standard ionic agent

    SciTech Connect

    Bettmann, M.A.; Bourdillon, P.D.; Barry, W.H.; Brush, K.A.; Levin, D.C.

    1984-12-01

    The effects on cardiac hemodynamics and of a standard contrast agent, sodium methylglucamine diatrizoate (Renografin 76) were compared with the effects of a new nonionic agent (iohexol) in a double-blind study in 51 patietns undergoing coronary angiography and left ventriculography. No significant alteration in measured blood parameters occurred with either contrast agent. Hemodynamic changes occurred with both, but were significantly greater with the standard renografin than with the low-osmolality, nonionic iohexol. After left ventriculography, heart rate increased and peripheral arterial pressure fell with both agents, but less with iohexol. It is concluded that iohexol causes less alteration in cardiac function than does the agent currently most widely used. Nonionic contrast material is likely to improve the safety of coronary angiography, particularly in those patients at greatest risk.

  16. Agent Communications using Distributed Metaobjects

    SciTech Connect

    Goldsmith, Steven Y.; Spires, Shannon V.

    1999-06-10

    There are currently two proposed standards for agent communication languages, namely, KQML (Finin, Lobrou, and Mayfield 1994) and the FIPA ACL. Neither standard has yet achieved primacy, and neither has been evaluated extensively in an open environment such as the Internet. It seems prudent therefore to design a general-purpose agent communications facility for new agent architectures that is flexible yet provides an architecture that accepts many different specializations. In this paper we exhibit the salient features of an agent communications architecture based on distributed metaobjects. This architecture captures design commitments at a metaobject level, leaving the base-level design and implementation up to the agent developer. The scope of the metamodel is broad enough to accommodate many different communication protocols, interaction protocols, and knowledge sharing regimes through extensions to the metaobject framework. We conclude that with a powerful distributed object substrate that supports metaobject communications, a general framework can be developed that will effectively enable different approaches to agent communications in the same agent system. We have implemented a KQML-based communications protocol and have several special-purpose interaction protocols under development.

  17. Requirements Modeling with Agent Programming

    NASA Astrophysics Data System (ADS)

    Dasgupta, Aniruddha; Krishna, Aneesh; Ghose, Aditya K.

    Agent-oriented conceptual modeling notations are highly effective in representing requirements from an intentional stance and answering questions such as what goals exist, how key actors depend on each other, and what alternatives must be considered. In this chapter, we review an approach to executing i* models by translating these into set of interacting agents implemented in the CASO language and suggest how we can perform reasoning with requirements modeled (both functional and non-functional) using i* models. In this chapter we particularly incorporate deliberation into the agent design. This allows us to benefit from the complementary representational capabilities of the two frameworks.

  18. Nuclear magnetic resonance contrast agents

    DOEpatents

    Smith, P.H.; Brainard, J.R.; Jarvinen, G.D.; Ryan, R.R.

    1997-12-30

    A family of contrast agents for use in magnetic resonance imaging and a method of enhancing the contrast of magnetic resonance images of an object by incorporating a contrast agent of this invention into the object prior to forming the images or during formation of the images. A contrast agent of this invention is a paramagnetic lanthanide hexaazamacrocyclic molecule, where a basic example has the formula LnC{sub 16}H{sub 14}N{sub 6}. Important applications of the invention are in medical diagnosis, treatment, and research, where images of portions of a human body are formed by means of magnetic resonance techniques. 10 figs.

  19. Nuclear magnetic resonance contrast agents

    DOEpatents

    Smith, Paul H.; Brainard, James R.; Jarvinen, Gordon D.; Ryan, Robert R.

    1997-01-01

    A family of contrast agents for use in magnetic resonance imaging and a method of enhancing the contrast of magnetic resonance images of an object by incorporating a contrast agent of this invention into the object prior to forming the images or during formation of the images. A contrast agent of this invention is a paramagnetic lanthanide hexaazamacrocyclic molecule, where a basic example has the formula LnC.sub.16 H.sub.14 N.sub.6. Important applications of the invention are in medical diagnosis, treatment, and research, where images of portions of a human body are formed by means of magnetic resonance techniques.

  20. Individual Passive Chemical Sampler Testing Continued Chemical Agent and TIC Performance Validation

    DTIC Science & Technology

    2002-04-01

    chemical warfare munitions by U.S. demolition units resulted in the release of sarin/cyclosarin nerve agents. The Central Intelligence Agency (CIA) and...DOD estimated in September 1997 that the demolition of Iraqi chemical-filled munitions released plumes of nerve agent gas that extended over U.S...testing that involved nerve and blister agents as well as several of the TICs. The Occupational Safety and Health Administration Technical Center at Salt

  1. Probing the role of P dbnd O stretching mode enhancement in nerve-agent sensors: Simulation of the adsorption of diisopropylfluorophosphate on the model MgO and CaO surfaces

    NASA Astrophysics Data System (ADS)

    Kolodziejczyk, Wojciech; Majumdar, D.; Roszak, Szczepan; Leszczynski, Jerzy

    2007-12-01

    The interactions of diisopropylfluorophosphate (DFP) with model MgO and CaO surfaces have been investigated using density functional (DFT) and Møller-Plesset second order perturbation techniques. The geometries were fully optimized at the DFT level. The calculated interaction energies and the corresponding thermodynamic properties show that DFP is physisorbed on these two model oxide surfaces and adsorption on the MgO surface is stronger. Analyses of the calculated IR and Raman spectra point to the enhancement of the P dbnd O stretching mode with respect to the isolated DFP and this property could be used to detect nerve-agents using surface-enhanced Raman spectroscopy.

  2. Agent-based forward analysis

    SciTech Connect

    Kerekes, Ryan A.; Jiao, Yu; Shankar, Mallikarjun; Potok, Thomas E.; Lusk, Rick M.

    2008-01-01

    We propose software agent-based "forward analysis" for efficient information retrieval in a network of sensing devices. In our approach, processing is pushed to the data at the edge of the network via intelligent software agents rather than pulling data to a central facility for processing. The agents are deployed with a specific query and perform varying levels of analysis of the data, communicating with each other and sending only relevant information back across the network. We demonstrate our concept in the context of face recognition using a wireless test bed comprised of PDA cell phones and laptops. We show that agent-based forward analysis can provide a significant increase in retrieval speed while decreasing bandwidth usage and information overload at the central facility. n

  3. Peripheral Neuropathy and Agent Orange

    MedlinePlus

    ... ZIP code here Enter ZIP code here Peripheral Neuropathy and Agent Orange VA presumes Veterans' early-onset ... percent disabling by VA's rating regulations. About peripheral neuropathy Peripheral neuropathy is a condition of the peripheral ...

  4. Diamine curing agents for polyurethanes

    NASA Technical Reports Server (NTRS)

    Bell, V. L.; St. Clair, T. L.

    1975-01-01

    Three aromatic diamines have properties that make them promising candidates as curing agents for converting isocyanates to polyurethanes with higher adhesive strengths, higher softening temperatures, better toughness, and improved abrasion resistance.

  5. Triggered pore-forming agents

    DOEpatents

    Bayley, Hagan; Walker, Barbara J.; Chang, Chung-yu; Niblack, Brett; Panchal, Rekha

    1998-01-01

    An inactive pore-forming agent which is activated to lytic function by a condition such as pH, light, heat, reducing potential, or metal ion concentration, or substance such as a protease, at the surface of a cell.

  6. Tissue Penetration of Antifungal Agents

    PubMed Central

    Felton, Timothy; Troke, Peter F.

    2014-01-01

    SUMMARY Understanding the tissue penetration of systemically administered antifungal agents is critical for a proper appreciation of their antifungal efficacy in animals and humans. Both the time course of an antifungal drug and its absolute concentrations within tissues may differ significantly from those observed in the bloodstream. In addition, tissue concentrations must also be interpreted within the context of the pathogenesis of the various invasive fungal infections, which differ significantly. There are major technical obstacles to the estimation of concentrations of antifungal agents in various tissue subcompartments, yet these agents, even those within the same class, may exhibit markedly different tissue distributions. This review explores these issues and provides a summary of tissue concentrations of 11 currently licensed systemic antifungal agents. It also explores the therapeutic implications of their distribution at various sites of infection. PMID:24396137

  7. AL Amyloidosis and Agent Orange

    MedlinePlus

    ... for survivors' benefits . Research on AL amyloidosis and herbicides The Health and Medicine Division (formally known as ... to the compounds of interest found in the herbicide Agent Orange and AL amyloidosis." VA made a ...

  8. Peripheral Neuropathy and Agent Orange

    MedlinePlus

    ... Z) Hepatitis HIV Mental Health Mental Health Home Suicide Prevention Substance Abuse Military Sexual Trauma PTSD Research ( ... eligible for a free Agent Orange registry health exam . Research on peripheral neuropathy and herbicides The Health ...

  9. AL Amyloidosis and Agent Orange

    MedlinePlus

    ... Z) Hepatitis HIV Mental Health Mental Health Home Suicide Prevention Substance Abuse Military Sexual Trauma PTSD Research ( ... eligible for a free Agent Orange registry health exam . Surviving spouses, dependent children and dependent parents of ...

  10. Launch Commit Criteria Monitoring Agent

    NASA Technical Reports Server (NTRS)

    Semmel, Glenn S.; Davis, Steven R.; Leucht, Kurt W.; Rowe, Dan A.; Kelly, Andrew O.; Boeloeni, Ladislau

    2005-01-01

    The Spaceport Processing Systems Branch at NASA Kennedy Space Center has developed and deployed a software agent to monitor the Space Shuttle's ground processing telemetry stream. The application, the Launch Commit Criteria Monitoring Agent, increases situational awareness for system and hardware engineers during Shuttle launch countdown. The agent provides autonomous monitoring of the telemetry stream, automatically alerts system engineers when predefined criteria have been met, identifies limit warnings and violations of launch commit criteria, aids Shuttle engineers through troubleshooting procedures, and provides additional insight to verify appropriate troubleshooting of problems by contractors. The agent has successfully detected launch commit criteria warnings and violations on a simulated playback data stream. Efficiency and safety are improved through increased automation.

  11. What makes virtual agents believable?

    NASA Astrophysics Data System (ADS)

    Bogdanovych, Anton; Trescak, Tomas; Simoff, Simeon

    2016-01-01

    In this paper we investigate the concept of believability and make an attempt to isolate individual characteristics (features) that contribute to making virtual characters believable. As the result of this investigation we have produced a formalisation of believability and based on this formalisation built a computational framework focused on simulation of believable virtual agents that possess the identified features. In order to test whether the identified features are, in fact, responsible for agents being perceived as more believable, we have conducted a user study. In this study we tested user reactions towards the virtual characters that were created for a simulation of aboriginal inhabitants of a particular area of Sydney, Australia in 1770 A.D. The participants of our user study were exposed to short simulated scenes, in which virtual agents performed some behaviour in two different ways (while possessing a certain aspect of believability vs. not possessing it). The results of the study indicate that virtual agents that appear resource bounded, are aware of their environment, own interaction capabilities and their state in the world, agents that can adapt to changes in the environment and exist in correct social context are those that are being perceived as more believable. Further in the paper we discuss these and other believability features and provide a quantitative analysis of the level of contribution for each such feature to the overall perceived believability of a virtual agent.

  12. Learning in multi-agent systems

    SciTech Connect

    Goldman, C.V.

    1996-12-31

    Learning agents acting in a multi agent environment can improve their performance. These agents might decide upon their course of action by learning about other agents with whom they interact. The learning agents can learn about the others information and rules of behavior. The agents will not need to plan their actions beforehand, each time they are asked to solve the same problem they have already solved or when dealing with similar problems.

  13. Chemical Warfare Agent Degradation and Decontamination

    SciTech Connect

    Talmage, Sylvia Smith; Watson, Annetta Paule; Hauschild, Veronique; Munro, Nancy B; King, J.

    2007-02-01

    The decontamination of chemical warfare agents (CWA) from structures, environmental media, and even personnel has become an area of particular interest in recent years due to increased homeland security concerns. In addition to terrorist attacks, scenarios such as accidental releases of CWA from U.S. stockpile sites or from historic, buried munitions are also subjects for response planning. To facilitate rapid identification of practical and effective decontamination approaches, this paper reviews pathways of CWA degradation by natural means as well as those resulting from deliberately applied solutions and technologies; these pathways and technologies are compared and contrasted. We then review various technologies, both traditional and recent, with some emphasis on decontamination materials used for surfaces that are difficult to clean. Discussion is limited to the major threat CWA, namely sulfur mustard (HD, bis(2-chloroethyl)sulfide), VX (O-ethyl S-(2-diisopropylaminoethyl) methylphosphonothioate), and the G-series nerve agents. The principal G-agents are GA (tabun, ethyl N,N-dimethylphosphoramidocyanidate), GB (sarin, isopropyl methylphosphonofluoridate), and GD (soman, pinacolyl methylphosphonofluoridate). The chemical decontamination pathways of each agent are outlined, with some discussion of intermediate and final degradation product toxicity. In all cases, and regardless of the CWA degradation pathway chosen for decontamination, it will be necessary to collect and analyze pertinent environmental samples during the treatment phase to confirm attainment of clearance levels.

  14. Density functional theory based studies on the nature of Raman and resonance Raman scattering of nerve agent bound to gold and oxide-supported gold clusters: a plausible way of detection.

    PubMed

    Majumdar, D; Roszak, Szczepan; Leszczynski, Jerzy

    2010-04-01

    A detailed theoretical investigation has been carried out at the density functional level of theories to investigate the nature of Raman intensities of the -P=O stretching mode of a model nerve agent DFP (diisopropylfluorophosphate) when bound to different gold (Au(8), Au(20)) and oxide-supported gold (MgO...Au(4), CaO...Au(4), TiO(2)...Au(4), Al(2)O(3)...Au(4), M(16)O(16)...Au(8), and [M(16)O(15)...Au(8)](2+), M = Ca, Mg) clusters. All of these clusters and the DFP-bound clusters are fully optimized, and the computed energetics shows that DFP attaches itself weakly to these clusters. The normal Raman spectra calculations on these clusters show that there is substantial enhancement of the -P=O stretching mode of DFP compared to the isolated species. This enhancement has been found to be due to the polarization of the -P=O bond of DFP when bound to the clusters. Significant enhancement in intensity has been observed in the case of Au(n)...DFP (n = 8, 20), M(16)O(16)...Au(8)...DFP, and [M(16)O(15)...Au(8)](2+)...DFP (M = Ca, Mg) clusters. The resonance Raman calculations on the Au(n)...DFP (n = 8, 20) reveals that this enhancement could be made quite large and selective, which is a feature that is unique to the nerve agents and could be used as a property for detecting them.

  15. A Rapid and Sensitive Strip-Based Quick Test for Nerve Agents Tabun, Sarin, and Soman Using BODIPY-Modified Silica Materials.

    PubMed

    Climent, Estela; Biyikal, Mustafa; Gawlitza, Kornelia; Dropa, Tomáš; Urban, Martin; Costero, Ana M; Martínez-Máñez, Ramón; Rurack, Knut

    2016-08-01

    Test strips that in combination with a portable fluorescence reader or digital camera can rapidly and selectively detect chemical warfare agents (CWAs) such as Tabun (GA), Sarin (GB), and Soman (GD) and their simulants in the gas phase have been developed. The strips contain spots of a hybrid indicator material consisting of a fluorescent BODIPY indicator covalently anchored into the channels of mesoporous SBA silica microparticles. The fluorescence quenching response allows the sensitive detection of CWAs in the μg m(-3) range in a few seconds.

  16. [War and medicine in a culture of peace. 3. Synopsis of chemical warfare agents].

    PubMed

    Piérard, G E

    2002-01-01

    A variety of chemical components can be used as warfare threats directly targeting humans. They can be classified according to their main biological effects as nerve agents, vesicants, lung damaging agents, cyanogen agents and incapacitants. Other chemical agents are water and food contaminants. Still other less aggressive compounds are mainly used to control riots. Smokes, flame materials and herbicides belong to other classes of chemical agents of the warlike armamentum exhibiting a direct effect on man.

  17. Collective behavior of predictive agents

    NASA Astrophysics Data System (ADS)

    Kephart, Jeffrey O.; Hogg, Tad; Huberman, Bernardo A.

    1990-06-01

    We investigate the effect of predictions upon a model of coevolutionary systems which was originally inspired by computational ecosystems. The model incorporates many of the features of distributed resource allocation in systems comprised of many individual agents, including asynchrony, resource contention, and decision-making based upon incomplete knowledge and delayed information. Previous analyses of a similar model of non-predictive agents have demonstrated that periodic or chaotic oscillations in resource allocation can occur under certain conditions, and that these oscillations can affect the performance of the system adversely. In this work, we show that the system performance can be improved if the agents do an adequate job of predicting the current state of the system. We explore two plausible methods for prediction - technical analysis and system analysis. Technical analysts are responsive to the behavior of the system, but suffer from an inability to take their own behavior into account. System analysts perform extremely well when they have very accurate information about the other agents in the system, but can perform very poorly when their information is even slightly inaccurate. By combining the strengths of both methods, we obtain a successful hybrid of the two prediction methods which adapts its model of other agents in response to the observed behavior of the system.

  18. Investigational Antimicrobial Agents of 2013

    PubMed Central

    Pucci, Michael J.

    2013-01-01

    SUMMARY New antimicrobial agents are always needed to counteract the resistant pathogens that continue to be selected by current therapeutic regimens. This review provides a survey of known antimicrobial agents that were currently in clinical development in the fall of 2012 and spring of 2013. Data were collected from published literature primarily from 2010 to 2012, meeting abstracts (2011 to 2012), government websites, and company websites when appropriate. Compared to what was reported in previous surveys, a surprising number of new agents are currently in company pipelines, particularly in phase 3 clinical development. Familiar antibacterial classes of the quinolones, tetracyclines, oxazolidinones, glycopeptides, and cephalosporins are represented by entities with enhanced antimicrobial or pharmacological properties. More importantly, compounds of novel chemical structures targeting bacterial pathways not previously exploited are under development. Some of the most promising compounds include novel β-lactamase inhibitor combinations that target many multidrug-resistant Gram-negative bacteria, a critical medical need. Although new antimicrobial agents will continue to be needed to address increasing antibiotic resistance, there are novel agents in development to tackle at least some of the more worrisome pathogens in the current nosocomial setting. PMID:24092856

  19. Next Generation Remote Agent Planner

    NASA Technical Reports Server (NTRS)

    Jonsson, Ari K.; Muscettola, Nicola; Morris, Paul H.; Rajan, Kanna

    1999-01-01

    In May 1999, as part of a unique technology validation experiment onboard the Deep Space One spacecraft, the Remote Agent became the first complete autonomous spacecraft control architecture to run as flight software onboard an active spacecraft. As one of the three components of the architecture, the Remote Agent Planner had the task of laying out the course of action to be taken, which included activities such as turning, thrusting, data gathering, and communicating. Building on the successful approach developed for the Remote Agent Planner, the Next Generation Remote Agent Planner is a completely redesigned and reimplemented version of the planner. The new system provides all the key capabilities of the original planner, while adding functionality, improving performance and providing a modular and extendible implementation. The goal of this ongoing project is to develop a system that provides both a basis for future applications and a framework for further research in the area of autonomous planning for spacecraft. In this article, we present an introductory overview of the Next Generation Remote Agent Planner. We present a new and simplified definition of the planning problem, describe the basics of the planning process, lay out the new system design and examine the functionality of the core reasoning module.

  20. Dual Rationality and Deliberative Agents

    NASA Astrophysics Data System (ADS)

    Debenham, John; Sierra, Carles

    Human agents deliberate using models based on reason for only a minute proportion of the decisions that they make. In stark contrast, the deliberation of artificial agents is heavily dominated by formal models based on reason such as game theory, decision theory and logic—despite that fact that formal reasoning will not necessarily lead to superior real-world decisions. Further the Nobel Laureate Friedrich Hayek warns us of the ‘fatal conceit’ in controlling deliberative systems using models based on reason as the particular model chosen will then shape the system’s future and either impede, or eventually destroy, the subtle evolutionary processes that are an integral part of human systems and institutions, and are crucial to their evolution and long-term survival. We describe an architecture for artificial agents that is founded on Hayek’s two rationalities and supports the two forms of deliberation used by mankind.

  1. [Anti-influenza virus agent].

    PubMed

    Nakamura, Shigeki; Kohno, Shigeru

    2012-04-01

    The necessity of newly anti-influenza agents is increasing rapidly after the prevalence of pandemic influenza A (H1N1) 2009. In addition to the existing anti-influenza drugs, novel neuraminidase inhibitors such as peramivir (a first intravenous anti-influenza agent) and laninamivir (long acting inhaled anti-influenza agent) can be available. Moreover favipiravir, which shows a novel anti-influenza mechanism acting as RNA polymerase inhibitor, has been developing. These drugs are expected to improve the prognosis of severe cases caused by not only seasonal influenza but pandemic influenza A (H1N1) 2009 virus and H5N1 avian influenza, and also treat oseltamivir-resistant influenza effectively.

  2. Agent review phase one report.

    SciTech Connect

    Zubelewicz, Alex Tadeusz; Davis, Christopher Edward; Bauer, Travis LaDell

    2009-12-01

    This report summarizes the findings for phase one of the agent review and discusses the review methods and results. The phase one review identified a short list of agent systems that would prove most useful in the service architecture of an information management, analysis, and retrieval system. Reviewers evaluated open-source and commercial multi-agent systems and scored them based upon viability, uniqueness, ease of development, ease of deployment, and ease of integration with other products. Based on these criteria, reviewers identified the ten most appropriate systems. The report also mentions several systems that reviewers deemed noteworthy for the ideas they implement, even if those systems are not the best choices for information management purposes.

  3. Learning Agents in Automated Negotiations

    NASA Astrophysics Data System (ADS)

    Chandrashekhar, Hemalatha; Bhasker, Bharat

    In bilateral multi-issue negotiations involving two-sided information uncertainty, selfish agents participating in a distributed search of the solution space need to learn the opponent’s preferences from the on-going negotiation interactions and utilize such knowledge to construct future proposals in order to hope to arrive at efficient outcomes. Besides, negotiation support systems that inhibit strategic misrepresentation of information need to be in place in order to assist the protagonists to obtain truly efficient solutions. To this end, this work suggests an automated negotiation procedure that while protecting the information privacy of the participating agents encourages truthful revelation of information through successive proposals. Further we present an algorithm for proposal construction in the case of two continuous issues. When both the negotiating agents implement the algorithm the negotiation trace shall be confined to the Pareto frontier. The Pareto-optimal deal close to the Nash solution shall be located whenever such a deal exists.

  4. TRPV1 antagonists as potential antitussive agents.

    PubMed

    McLeod, Robbie L; Correll, Craig C; Jia, Yanlin; Anthes, John C

    2008-01-01

    Cough is an important defensive pulmonary reflex that removes irritants, fluids, or foreign materials from the airways. However, when cough is exceptionally intense or when it is chronic and/or nonproductive it may require pharmacologic suppression. For many patients, antitussive therapies consist of OTC products with inconsequential efficacies. On the other hand, the prescription antitussive market is dominated by older opioid drugs such as codeine. Unfortunately, "codeine-like" drugs suppress cough at equivalent doses that also often produce significant ancillary liabilities such as GI constipation, sedation, and respiratory depression. Thus, the discovery of a novel and effective antitussive drug with an improved side effect profile relative to codeine would fulfill an unmet clinical need in the treatment of cough. Afferent pulmonary nerves are endowed with a multitude of potential receptor targets, including TRPV1, that could act to attenuate cough. The evidence linking TRPV1 to cough is convincing. TRPV1 receptors are found on sensory respiratory nerves that are important in the generation of the cough reflex. Isolated pulmonary vagal afferent nerves are responsive to TRPV1 stimulation. In vivo, TRPV1 agonists such as capsaicin elicit cough when aerosolized and delivered to the lungs. Pertinent to the debate on the potential use of TRPV1 antagonist as antitussive agents are the observations that airway afferent nerves become hypersensitive in diseased and inflamed lungs. For example, the sensitivity of capsaicin-induced cough responses following upper respiratory tract infection and in airway inflammatory diseases such as asthma and COPD is increased relative to that of control responses. Indeed, we have demonstrated that TRPV1 antagonism can attenuate antigen-induced cough in the allergic guinea pig. However, it remains to be determined if the emerging pharmacologic profile of TRPV1 antagonists will translate into a novel human antitussive drug. Current

  5. Landslides as agents of diversity

    NASA Astrophysics Data System (ADS)

    Geertsema, Marten

    2016-04-01

    Landslides, often destructive and damaging, are also agents of change that introduce diversity to landscapes. I discuss landslide diversity at three levels: site diversity, soil diversity, and habitat diversity. There are many landslide types involving different materials and rates and styles of movement. Landscape diversity varies with different types of landslides. Landslides, at the same time depositional and erosional agents, influence sites by redistributing materials and changing microtopography. Eroded portions of landslides, with exposed parent material, revert to the initial stages of soil development and ecological succession. Landslides can also alter soil properties including, surface texture, chemistry and porosity. Landslides influence habitat diversity by creating ecosystem mosaics.

  6. Autonomous sensor manager agents (ASMA)

    NASA Astrophysics Data System (ADS)

    Osadciw, Lisa A.

    2004-04-01

    Autonomous sensor manager agents are presented as an algorithm to perform sensor management within a multisensor fusion network. The design of the hybrid ant system/particle swarm agents is described in detail with some insight into their performance. Although the algorithm is designed for the general sensor management problem, a simulation example involving 2 radar systems is presented. Algorithmic parameters are determined by the size of the region covered by the sensor network, the number of sensors, and the number of parameters to be selected. With straight forward modifications, this algorithm can be adapted for most sensor management problems.

  7. Molecular Rotors for the Detection of Chemical Warfare Agent Simulants.

    PubMed

    Kim, Tae-Il; Maity, Shubhra Bikash; Bouffard, Jean; Kim, Youngmi

    2016-09-20

    The fluorogenic probe o-OH is able to detect and quantify organophosphorus nerve agent mimics in solution and in the vapor phase following immobilization on a solid substrate, making the system a suitable candidate for the field detection of chemical warfare agents. Detection is achieved by the suppression of internal rotation upon phosphorylation of a reactive phenolate, resulting in a large fluorescence "turn-on" response.

  8. Topical hemostatic agents for dermatologic surgery.

    PubMed

    Larson, P O

    1988-06-01

    Topical hemostatic agents are very helpful in attaining capillary and small vessel hemostasis in dermatologic surgery. The commonly used topical hemostatic agents, including oxidized cellulose, absorbable gelatin, and thrombin are reviewed, along with newer agents such as microfibrillar collagen, fibrin sealants, and acrylates. Agents best suited for certain situations are recommended.

  9. 13 CFR 120.952 - Fiscal agent.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 13 Business Credit and Assistance 1 2010-01-01 2010-01-01 false Fiscal agent. 120.952 Section 120... Loan Program (504) Debenture Sales and Service Agents § 120.952 Fiscal agent. SBA shall appoint a Fiscal Agent to assess the financial markets, minimize the cost of sales, arrange for the production...

  10. Topical hemostatic agents in otolaryngologic surgery.

    PubMed

    Acar, Baran; Babademez, Mehmet Ali; Karabulut, Hayriye

    2010-01-01

    Topical hemostatic agents are largely used to reduce blood loss during otolaryngologic surgery. These agents play an important role in both keeping the patient's hemodynamic equilibrium and allowing for a better view of the surgical field. These agents can be classified based on their mechanism of action, and include physical or mechanical agents. Most complications of topical hemostatic agents are sustained because of the antigenic reaction of those products. This paper reviews traditional and newer topical hemostatic agents with regard to their chemical properties, their mechanisms of action, and the benefits and complications of topical agents.

  11. Primary screen for potential sheep scab control agents.

    PubMed

    Dunn, J A; Prickett, J C; Collins, D A; Weaver, R J

    2016-07-15

    The efficacy of potential acaricidal agents were assessed against the sheep scab mite Psoroptes ovis using a series of in vitro assays in modified test arenas designed initially to maintain P. ovis off-host. The mortality effects of 45 control agents, including essential oils, detergents, desiccants, growth regulators, lipid synthesis inhibitors, nerve action/energy metabolism disruptors and ecdysteroids were assessed against adults and nymphs. The most effective candidates were the desiccants (diatomaceous earth, nanoclay and sorex), the growth regulators (buprofezin, hexythiazox and teflubenzuron), the lipid synthesis inhibitors (spirodiclofen, spirotetramat and spiromesifen) and the nerve action and energy metabolism inhibitors (fenpyroximate, spinosad, tolfenpyrad, and chlorantraniliprole).

  12. Other Viruses and Viruslike Agents

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The diseases reported under 'Virus and Virus-like Agents' in the first volume of this compendium, with the exception of Cherry rasp leaf virus and Rubus chinese seed-borne virus, should be considered oddities since there are no known type isolates available for these reported viruses. Without a po...

  13. Activity Recognition for Agent Teams

    DTIC Science & Technology

    2007-07-01

    correspond to a real team, but is rather a visual illusion caused by a coincidental configuration of agents. 50 CHAPTER 4. STABR The behavior...each frame-pair were only classified with 76% accuracy, such a method would hallucinate false action transitions at unacceptable rates). Fortunately

  14. Nucleotide cleaving agents and method

    DOEpatents

    Que, Jr., Lawrence; Hanson, Richard S.; Schnaith, Leah M. T.

    2000-01-01

    The present invention provides a unique series of nucleotide cleaving agents and a method for cleaving a nucleotide sequence, whether single-stranded or double-stranded DNA or RNA, using and a cationic metal complex having at least one polydentate ligand to cleave the nucleotide sequence phosphate backbone to yield a hydroxyl end and a phosphate end.

  15. Foodborne illness and microbial agents

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Foodborne illnesses result from the consumption of food containing microbial agents such as bacteria, viruses, parasites or food contaminated by poisonous chemicals or bio-toxins. Pathogen proliferation is due to nutrient composition of foods, which are capable of supporting the growth of microorgan...

  16. An Introduction to Software Agents

    DTIC Science & Technology

    2008-02-01

    applicable to modelling red force entities for VMSA. This paper provides an overview of software agents and represents the first step in the...ordinateur, et que la simulation en cours modélise leurs capteurs , leurs armes et leurs caractéristiques matérielles. vi DRDC Atlantic TM...34 9 Sample Applications

  17. 7 CFR 4290.1620 - Functions of agents, including Central Registration Agent, Selling Agent and Fiscal Agent.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ..., DEPARTMENT OF AGRICULTURE RURAL BUSINESS INVESTMENT COMPANY (âRBICâ) PROGRAM Financial Assistance for RBICs (Leverage) Funding Leverage by Use of Guaranteed Trust Certificates (âtcsâ) § 4290.1620 Functions of agents... to: (i) Establish performance criteria for Poolers. (ii) Monitor and evaluate the financial...

  18. 13 CFR 107.1620 - Functions of agents, including Central Registration Agent, Selling Agent and Fiscal Agent.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... Assistance SMALL BUSINESS ADMINISTRATION SMALL BUSINESS INVESTMENT COMPANIES SBA Financial Assistance for Licensees (Leverage) Funding Leverage by Use of Sba-Guaranteed Trust Certificates (âtcsâ) § 107.1620... Fiscal Agent to: (i) Establish performance criteria for Poolers. (ii) Monitor and evaluate the...

  19. 7 CFR 4290.1620 - Functions of agents, including Central Registration Agent, Selling Agent and Fiscal Agent.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ..., DEPARTMENT OF AGRICULTURE RURAL BUSINESS INVESTMENT COMPANY (âRBICâ) PROGRAM Financial Assistance for RBICs (Leverage) Funding Leverage by Use of Guaranteed Trust Certificates (âtcsâ) § 4290.1620 Functions of agents... to: (i) Establish performance criteria for Poolers. (ii) Monitor and evaluate the financial...

  20. 13 CFR 107.1620 - Functions of agents, including Central Registration Agent, Selling Agent and Fiscal Agent.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... Assistance SMALL BUSINESS ADMINISTRATION SMALL BUSINESS INVESTMENT COMPANIES SBA Financial Assistance for Licensees (Leverage) Funding Leverage by Use of Sba-Guaranteed Trust Certificates (âtcsâ) § 107.1620... Fiscal Agent to: (i) Establish performance criteria for Poolers. (ii) Monitor and evaluate the...

  1. 13 CFR 107.1620 - Functions of agents, including Central Registration Agent, Selling Agent and Fiscal Agent.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... Assistance SMALL BUSINESS ADMINISTRATION SMALL BUSINESS INVESTMENT COMPANIES SBA Financial Assistance for Licensees (Leverage) Funding Leverage by Use of Sba-Guaranteed Trust Certificates (âtcsâ) § 107.1620... Fiscal Agent to: (i) Establish performance criteria for Poolers. (ii) Monitor and evaluate the...

  2. 7 CFR 4290.1620 - Functions of agents, including Central Registration Agent, Selling Agent and Fiscal Agent.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ..., DEPARTMENT OF AGRICULTURE RURAL BUSINESS INVESTMENT COMPANY (âRBICâ) PROGRAM Financial Assistance for RBICs (Leverage) Funding Leverage by Use of Guaranteed Trust Certificates (âtcsâ) § 4290.1620 Functions of agents... to: (i) Establish performance criteria for Poolers. (ii) Monitor and evaluate the financial...

  3. SEM: A Cultural Change Agent

    ERIC Educational Resources Information Center

    Barnes, Bradley; Bourke, Brian

    2015-01-01

    The authors advance the concept that institutional culture is a purposeful framework by which to view SEM's utility, particularly as a cultural change agent. Through the connection of seemingly independent functions of performance and behavior, implications emerge that deepen the understanding of the influence of culture on performance outcomes…

  4. Triggered pore-forming agents

    DOEpatents

    Bayley, H.; Walker, B.J.; Chang, C.Y.; Niblack, B.; Panchal, R.

    1998-07-07

    An inactive pore-forming agent is revealed which is activated to lytic function by a condition such as pH, light, heat, reducing potential, or metal ion concentration, or substance such as a protease, at the surface of a cell. 30 figs.

  5. Voter models with contrarian agents.

    PubMed

    Masuda, Naoki

    2013-11-01

    In the voter and many other opinion formation models, agents are assumed to behave as congregators (also called the conformists); they are attracted to the opinions of others. In this study I investigate linear extensions of the voter model with contrarian agents. An agent is either congregator or contrarian and assumes a binary opinion. I investigate three models that differ in the behavior of the contrarian toward other agents. In model 1, contrarians mimic the opinions of other contrarians and oppose (i.e., try to select the opinion opposite to) those of congregators. In model 2, contrarians mimic the opinions of congregators and oppose those of other contrarians. In model 3, contrarians oppose anybody. In all models, congregators are assumed to like anybody. I show that even a small number of contrarians prohibits the consensus in the entire population to be reached in all three models. I also obtain the equilibrium distributions using the van Kampen small-fluctuation approximation and the Fokker-Planck equation for the case of many contrarians and a single contrarian, respectively. I show that the fluctuation around the symmetric coexistence equilibrium is much larger in model 2 than in models 1 and 3 when contrarians are rare.

  6. Limonene and tetrahydrofurfuryl alcohol cleaning agent

    DOEpatents

    Bohnert, G.W.; Carter, R.D.; Hand, T.E.; Powers, M.T.

    1996-05-07

    The present invention is a tetrahydrofurfuryl alcohol and limonene or terpineol cleaning agent and method for formulating and/or using the cleaning agent. This cleaning agent effectively removes both polar and nonpolar contaminants from various electrical and mechanical parts and is readily used without surfactants, thereby reducing the need for additional cleaning operations. The cleaning agent is warm water rinsable without the use of surfactants. The cleaning agent can be azeotropic, enhancing ease of use in cleaning operations and ease of recycling.

  7. Limonene and tetrahydrofurfuryl alcohol cleaning agent

    DOEpatents

    Bohnert, G.W.; Carter, R.D.; Hand, T.E.; Powers, M.T.

    1997-10-21

    The present invention is a tetrahydrofurfuryl alcohol and limonene cleaning agent and method for formulating and/or using the cleaning agent. This cleaning agent effectively removes both polar and nonpolar contaminants from various electrical and mechanical parts and is readily used without surfactants, thereby reducing the need for additional cleaning operations. The cleaning agent is warm water rinsable without the use of surfactants. The cleaning agent can be azeotropic, enhancing ease of use in cleaning operations and ease of recycling.

  8. Limonene and tetrahydrofurfurly alcohol cleaning agent

    DOEpatents

    Bohnert, George W.; Carter, Richard D.; Hand, Thomas E.; Powers, Michael T.

    1997-10-21

    The present invention is a tetrahydrofurfuryl alcohol and limonene cleaning agent and method for formulating and/or using the cleaning agent. This cleaning agent effectively removes both polar and nonpolar contaminants from various electrical and mechanical parts and is readily used without surfactants, thereby reducing the need for additional cleaning operations. The cleaning agent is warm water rinsable without the use of surfactants. The cleaning agent can be azeotropic, enhancing ease of use in cleaning operations and ease of recycling.

  9. Halide test agent replacement study

    SciTech Connect

    Banks, E.M.; Freeman, W.P.; Kovach, B.J.

    1995-02-01

    The intended phaseout of the chlorofluorocarbons (CFCs) from commercial use required the evaluation of substitute materials for the testing for leak paths through both individual adsorbers and installed adsorbent banks. The American Society of Mechanical Engineers (ASME) Committee on Nuclear Air and Gas Treatment (CONAGT) is in charge of maintaining the standards and codes specifying adsorbent leak test methods for the nuclear safety related air cleaning systems. The currently published standards and codes cite the use of R-11, R-12 and R-112 for leak path test agents. All of these compounds are CFCs. There are other agencies and organizations (USDOE, USDOD and USNRC) also specifying testing for leak paths or in some cases for special life tests using the above compounds. The CONAGT has recently developed criteria for the suitability evaluation of substitute test agents. On the basis of these criteria, several compounds were evaluated for their acceptability as adsorbent bed leak and life test agents. The ASME CONAGT Test Agent Qualification Criteria. The test agent qualification is based on the following parameters: (1) Similar retention times on activated carbons at the same concentration levels as one of the following: R-11, R-12, R-112 or R-112a. (2) Similar lower detection limit sensitivity and precision in the concentration range of use as R-11, R-12, R-112 and R-112a. (3) Gives the same in-place leak test results as R-11, R-12, R-112, or R-112a. (4) Chemical and radiological stability under the use conditions. (5) Causes no degradation of the carbon and its impregnant or of the other NATS components under the use conditions. (6) Is listed in the USEPA Toxic Substances Control Act (TSCA) inventory for commercial use.

  10. Ultraviolet Raman scattering from persistent chemical warfare agents

    NASA Astrophysics Data System (ADS)

    Kullander, Fredrik; Wästerby, Pär.; Landström, Lars

    2016-05-01

    Laser induced Raman scattering at excitation wavelengths in the middle ultraviolet was examined using a pulsed tunable laser based spectrometer system. Droplets of chemical warfare agents, with a volume of 2 μl, were placed on a silicon surface and irradiated with sequences of laser pulses. The Raman scattering from V-series nerve agents, Tabun (GA) and Mustard gas (HD) was studied with the aim of finding the optimum parameters and the requirements for a detection system. A particular emphasis was put on V-agents that have been previously shown to yield relatively weak Raman scattering in this excitation band.

  11. Antidotes and treatments for chemical warfare/terrorism agents: an evidence-based review.

    PubMed

    Rodgers, G C; Condurache, C T

    2010-09-01

    This article reviews the evidence supporting the efficacy of antidotes used or recommended for the potential chemical warfare agents of most concern. Chemical warfare agents considered include cyanide, vesicants, pulmonary irritants such as chlorine and phosgene, and nerve agents. The strength of evidence for most antidotes is weak, highlighting the need for additional research in this area.

  12. Laser interrogation of surface agents (LISA) for chemical agent reconnaissance

    NASA Astrophysics Data System (ADS)

    Higdon, N. S.; Chyba, Thomas H.; Richter, Dale A.; Ponsardin, Patrick L.; Armstrong, Wayne T.; Lobb, C. T.; Kelly, Brian T.; Babnick, Robert D.; Sedlacek, Arthur J., III

    2002-06-01

    Laser Interrogation of Surface Agents (LISA) is a new technique which exploits Raman scattering to provide standoff detection and identification of surface-deposited chemical agents. ITT Industries, Advanced Engineering and Sciences Division is developing the LISA technology under a cost-sharing arrangement with the US Army Soldier and Biological Chemical Command for incorporation on the Army's future reconnaissance vehicles. A field-engineered prototype LISA-Recon system is being designed to demonstrate on-the- move measurements of chemical contaminants. In this article, we will describe the LISA technique, data form proof-of- concept measurements, the LISA-Recon design, and some of the future realizations envisioned for military sensing applications.

  13. Laser-based instrumentation for the detection of chemical agents

    SciTech Connect

    Hartford, A. Jr.; Sander, R.K.; Quigley, G.P.; Radziemski, L.J.; Cremers, D.A.

    1982-01-01

    Several laser-based techniques are being evaluated for the remote, point, and surface detection of chemical agents. Among the methods under investigation are optoacoustic spectroscopy, laser-induced breakdown spectroscopy (LIBS), and synchronous detection of laser-induced fluorescence (SDLIF). Optoacoustic detection has already been shown to be capable of extremely sensitive point detection. Its application to remote sensing of chemical agents is currently being evaluated. Atomic emission from the region of a laser-generated plasma has been used to identify the characteristic elements contained in nerve (P and F) and blister (S and Cl) agents. Employing this LIBS approach, detection of chemical agent simulants dispersed in air and adsorbed on a variety of surfaces has been achieved. Synchronous detection of laser-induced fluorescence provides an attractive alternative to conventional LIF, in that an artificial narrowing of the fluorescence emission is obtained. The application of this technique to chemical agent simulants has been successfully demonstrated. 19 figures.

  14. Onto-Agents-Enabling Intelligent Agents on the Web

    DTIC Science & Technology

    2005-05-01

    concept of the semantic web, but also time- consuming . There has been much research here, but I have not yet seen any public 10 business ...OntoAgents project. 1. Prof. Gio Wiederhold, PhD, Principal Investigator * (Retired) Recalled for active duty to teach the Freshman course: Business on the...Manual annotation is tedious, and often done poorly. Even within the funded DAML project fewer pages were annotated than was hoped. In eCommerce , there

  15. Detoxification of VX and Other V‐Type Nerve Agents in Water at 37 °C and pH 7.4 by Substituted Sulfonatocalix[4]arenes

    PubMed Central

    Schneider, Christian; Bierwisch, Anne; Koller, Marianne; Worek, Franz

    2016-01-01

    Abstract Sulfonatocalix[4]arenes with an appended hydroxamic acid residue can detoxify VX and related V‐type neurotoxic organophosphonates with half‐lives down to 3 min in aqueous buffer at 37 °C and pH 7.4. The detoxification activity is attributed to the millimolar affinity of the calixarene moiety for the positively charged organophosphonates in combination with the correct arrangement of the hydroxamic acid group. The reaction involves phosphonylation of the hydroxamic acid followed by a Lossen rearrangement, thus rendering the mode of action stoichiometric rather than catalytic. Nevertheless, these calixarenes are currently the most efficient low‐molecular‐weight compounds for detoxifying persistent V‐type nerve agents under mild conditions. They thus represent lead structures for novel antidotes that allow treatment of poisonings by these highly toxic chemicals. PMID:27627873

  16. The New Agent: A Qualitative Study to Strategically Adapt New Agent Professional Development

    ERIC Educational Resources Information Center

    Baker, Lauri M.; Hadley, Gregg

    2014-01-01

    The qualitative study reported here assessed the needs of agents related to new agent professional development to improve the current model. Agents who participated in new agent professional development within the last 5 years were selected to participate in focus groups to determine concerns and continued needs. Agents enjoyed networking and…

  17. Does an Agent Matter? The Effects of Animated Pedagogical Agents on Multimedia Environments.

    ERIC Educational Resources Information Center

    Craig, Scotty D.; Gholson, Barry

    Data are presented on the effects of Animated Agents on multimedia learning environments with specific concerns of split attention and modality effects. The study was a 3 (agent properties: agent only, agent with gestures, no agent) x 3 (picture features: static picture, sudden onset, animation) factorial design with outcome measures of mental…

  18. Innovative agents in cancer prevention.

    PubMed

    Manson, Margaret M; Farmer, Peter B; Gescher, Andreas; Steward, William P

    2005-01-01

    There are many facets to cancer prevention: a good diet, weight control and physical activity, a healthy environment, avoidance of carcinogens such as those in tobacco smoke, and screening of populations at risk to allow early detection. But there is also the possibility of using drugs or naturally occurring compounds to prevent initiation of, or to suppress, tumour growth. Only a few such agents have been used to date in the clinic with any success, and these include non-steroidal anti-inflammatory drugs for colon, finasteride for prostate and tamoxifen or raloxifene for breast tumours. An ideal chemopreventive agent would restore normal growth control to a preneoplastic or cancerous cell population by modifying aberrant signalling pathways or inducing apoptosis (or both) in cells beyond repair. Characteristics for such an agent include selectivity for damaged or transformed cells, good bioavailability and more than one mechanism of action to foil redundancy or crosstalk in signalling pathways. As more research effort is being targeted towards this area, the distinction between chemotherapeutic and chemopreventive agents is blurring. Chemotherapeutic drugs are now being designed to target over- or under-active signalling molecules within cancer cells, a philosophy which is just as relevant in chemoprevention. Development of dietary agents is particularly attractive because of our long-standing exposure to them, their relative lack of toxicity, and encouraging indications from epidemiology. The carcinogenic process relies on the cell's ability to proliferate abnormally, evade apoptosis, induce angiogenesis and metastasise to distant sites. In vitro studies with a number of different diet-derived compounds suggest that there are molecules capable of modulating each of these aspects of tumour growth. However, on the negative side many of them have rather poor bioavailability. The challenge is to uncover their multiple mechanisms of action in order to predict their

  19. Neuroprotective "agents" in surgery. Secret "agent" man, or common "agent" machine?

    NASA Technical Reports Server (NTRS)

    Andrews, R. J.

    1999-01-01

    The search for clinically-effective neuroprotective agents has received enormous support in recent years--an estimated $200 million by pharmaceutical companies on clinical trials for traumatic brain injury alone. At the same time, the pathophysiology of brain injury has proved increasingly complex, rendering the likelihood of a single agent "magic bullet" even more remote. On the other hand, great progress continues with technology that makes surgery less invasive and less risky. One example is the application of endovascular techniques to treat coronary artery stenosis, where both the invasiveness of sternotomy and the significant neurological complication rate (due to microemboli showering the cerebral vasculature) can be eliminated. In this paper we review aspects of intraoperative neuroprotection both present and future. Explanations for the slow progress on pharmacologic neuroprotection during surgery are presented. Examples of technical advances that have had great impact on neuroprotection during surgery are given both from coronary artery stenosis surgery and from surgery for Parkinson's disease. To date, the progress in neuroprotection resulting from such technical advances is an order of magnitude greater than that resulting from pharmacologic agents used during surgery. The progress over the last 20 years in guidance during surgery (CT and MRI image-guidance) and in surgical access (endoscopic and endovascular techniques) will soon be complemented by advances in our ability to evaluate biological tissue intraoperatively in real-time. As an example of such technology, the NASA Smart Probe project is considered. In the long run (i.e., in 10 years or more), pharmacologic "agents" aimed at the complex pathophysiology of nervous system injury in man will be the key to true intraoperative neuroprotection. In the near term, however, it is more likely that mundane "agents" based on computers, microsensors, and microeffectors will be the major impetus to improved

  20. Needs, Pains, and Motivations in Autonomous Agents.

    PubMed

    Starzyk, Janusz A; Graham, James; Puzio, Leszek

    2016-08-17

    This paper presents the development of a motivated learning (ML) agent with symbolic I/O. Our earlier work on the ML agent was enhanced, giving it autonomy for interaction with other agents. Specifically, we equipped the agent with drives and pains that establish its motivations to learn how to respond to desired and undesired events and create related abstract goals. The purpose of this paper is to explore the autonomous development of motivations and memory in agents within a simulated environment. The ML agent has been implemented in a virtual environment created within the NeoAxis game engine. Additionally, to illustrate the benefits of an ML-based agent, we compared the performance of our algorithm against various reinforcement learning (RL) algorithms in a dynamic test scenario, and demonstrated that our ML agent learns better than any of the tested RL agents.