Blaptica dubia as sentinels for exposure to chemical warfare agents - a pilot study.

PubMed

Worek, Franz; Seeger, Thomas; Neumaier, Katharina; Wille, Timo; Thiermann, Horst

2016-11-16

The increased interest of terrorist groups in toxic chemicals and chemical warfare agents presents a continuing threat to our societies. Early warning and detection is a key component for effective countermeasures against such deadly agents. Presently available and near term solutions have a number of major drawbacks, e.g. lack of automated, remote warning and detection of primarily low volatile chemical warfare agents. An alternative approach is the use of animals as sentinels for exposure to toxic chemicals. To overcome disadvantages of vertebrates the present pilot study was initiated to investigate the suitability of South American cockroaches (Blaptica dubia) as warning system for exposure to chemical warfare nerve and blister agents. Initial in vitro experiments with nerve agents showed an increasing inhibitory potency in the order tabun - cyclosarin - sarin - soman - VX of cockroach cholinesterase. Exposure of cockroaches to chemical warfare agents resulted in clearly visible and reproducible reactions, the onset being dependent on the agent and dose. With nerve agents the onset was related to the volatility of the agents. The blister agent lewisite induced signs largely comparable to those of nerve agents while sulfur mustard exposed animals exhibited a different sequence of events. In conclusion, this first pilot study indicates that Blaptica dubia could serve as a warning system to exposure of chemical warfare agents. A cockroach-based system will not detect or identify a particular chemical warfare agent but could trigger further actions, e.g. specific detection and increased protective status. By designing appropriate boxes with (IR) motion sensors and remote control (IR) camera automated off-site warning systems could be realized. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Worek, Franz, E-mail: franzworek@bundeswehr.org; Wille, Timo; Aurbek, Nadine

Treatment of poisoning by highly toxic organophosphorus compounds (OP, nerve agents) is a continuous challenge. Standard treatment with atropine and a clinically used oxime, obidoxime or pralidoxime is inadequate against various nerve agents. For ethical reasons testing of oxime efficacy has to be performed in animals. Now, it was tempting to investigate the reactivation kinetics of MMB-4, a candidate oxime to replace pralidoxime, with nerve agent-inhibited acetylcholinesterase (AChE) from human and animal origin in order to provide a kinetic basis for the proper assessment of in vivo data. By applying a modified kinetic approach, allowing the use of necessary highmore » MMB-4 concentrations, it was possible to determine the reactivation constants with sarin-, cyclosarin-, VX-, VR- and tabun-inhibited AChE. MMB-4 exhibited a high reactivity and low affinity towards OP-inhibited AChE, except of tabun-inhibited enzyme where MMB-4 had an extremely low reactivity. Species differences between human and animal AChE were low (Cynomolgus) to moderate (swine, guinea pig). Due to the high reactivity of MMB-4 a rapid reactivation of inhibited AChE can be anticipated at adequate oxime concentrations which are substantially higher compared to HI-6. Additional studies are necessary to determine the in vivo toxicity, tolerability and pharmacokinetics of MMB-4 in humans in order to enable a proper assessment of the value of this oxime as an antidote against nerve agent poisoning.« less

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. Published by Elsevier Ireland Ltd.

Reactivation of organophosphate-inhibited human, Cynomolgus monkey, swine and guinea pig acetylcholinesterase by MMB-4: a modified kinetic approach.

PubMed

Worek, Franz; Wille, Timo; Aurbek, Nadine; Eyer, Peter; Thiermann, Horst

2010-12-15

Treatment of poisoning by highly toxic organophosphorus compounds (OP, nerve agents) is a continuous challenge. Standard treatment with atropine and a clinically used oxime, obidoxime or pralidoxime is inadequate against various nerve agents. For ethical reasons testing of oxime efficacy has to be performed in animals. Now, it was tempting to investigate the reactivation kinetics of MMB-4, a candidate oxime to replace pralidoxime, with nerve agent-inhibited acetylcholinesterase (AChE) from human and animal origin in order to provide a kinetic basis for the proper assessment of in vivo data. By applying a modified kinetic approach, allowing the use of necessary high MMB-4 concentrations, it was possible to determine the reactivation constants with sarin-, cyclosarin-, VX-, VR- and tabun-inhibited AChE. MMB-4 exhibited a high reactivity and low affinity towards OP-inhibited AChE, except of tabun-inhibited enzyme where MMB-4 had an extremely low reactivity. Species differences between human and animal AChE were low (Cynomolgus) to moderate (swine, guinea pig). Due to the high reactivity of MMB-4 a rapid reactivation of inhibited AChE can be anticipated at adequate oxime concentrations which are substantially higher compared to HI-6. Additional studies are necessary to determine the in vivo toxicity, tolerability and pharmacokinetics of MMB-4 in humans in order to enable a proper assessment of the value of this oxime as an antidote against nerve agent poisoning. Copyright © 2010 Elsevier Inc. All rights reserved.

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. © 2014 The Authors. Chirality published by John Wiley Periodicals, Inc.

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

The Fate of Chemical Warfare Agents in the Environment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Talmage, Sylvia Smith; Munro, Nancy B; Watson, Annetta Paule

2007-01-01

Chemical Warfare Agents, Second Edition has been totally revised since the successful first edition and expanded to about three times the length, with many new chapters and much more in-depth consideration of all the topics. The chapters have been written by distinguished international experts in various aspects of chemical warfare agents and edited by an experienced team to produce a clear review of the field. The book now contains a wealth of material on the mechanisms of action of the major chemical warfare agents, including the nerve agent cyclosarin, formally considered to be of secondary importance, as well as ricinmore » and abrin. Chemical Warfare Agents, Second Edition discusses the physico-chemical properties of chemical warfare agents, their dispersion and fate in the environment, their toxicology and management of their effects on humans, decontamination and protective equipment. New chapters cover the experience gained after the use of sarin to attack travelers on the Tokyo subway and how to deal with the outcome of the deployment of riot control agents such as CS gas. This book provides a comprehensive review of chemical warfare agents, assessing all available evidence regarding the medical, technical and legal aspects of their use. It is an invaluable reference work for physicians, public health planners, regulators and any other professionals involved in this field.« less

Theoretical Studies Applied to the Evaluation of the DFPase Bioremediation Potential against Chemical Warfare Agents Intoxication

PubMed Central

Soares, Flávia V.; de Castro, Alexandre A.; Pereira, Ander F.; Leal, Daniel H. S.; Mancini, Daiana T.; da Cunha, Elaine F. F.; Kuca, Kamil

2018-01-01

Organophosphorus compounds (OP) are part of a group of compounds that may be hazardous to health. They are called neurotoxic agents because of their action on the nervous system, inhibiting the acetylcholinesterase (AChE) enzyme and resulting in a cholinergic crisis. Their high toxicity and rapid action lead to irreversible damage to the nervous system, drawing attention to developing new treatment methods. The diisopropyl fluorophosphatase (DFPase) enzyme has been considered as a potent biocatalyst for the hydrolysis of toxic OP and has potential for bioremediation of this kind of intoxication. In order to investigate the degradation process of the nerve agents Tabun, Cyclosarin and Soman through the wild-type DFPase, and taking into account their stereochemistry, theoretical studies were carried out. The intermolecular interaction energy and other parameters obtained from the molecular docking calculations were used to construct a data matrix, which were posteriorly treated by statistical analyzes of chemometrics, using the PCA (Principal Components Analysis) multivariate analysis. The analyzed parameters seem to be quite important for the reaction mechanisms simulation (QM/MM). Our findings showed that the wild-type DFPase enzyme is stereoselective in hydrolysis, showing promising results for the catalytic degradation of the neurotoxic agents under study, with the degradation mechanism performed through two proposed pathways. PMID:29690585

Theoretical Studies Applied to the Evaluation of the DFPase Bioremediation Potential against Chemical Warfare Agents Intoxication.

PubMed

Soares, Flávia V; de Castro, Alexandre A; Pereira, Ander F; Leal, Daniel H S; Mancini, Daiana T; Krejcar, Ondrej; Ramalho, Teodorico C; da Cunha, Elaine F F; Kuca, Kamil

2018-04-23

Organophosphorus compounds (OP) are part of a group of compounds that may be hazardous to health. They are called neurotoxic agents because of their action on the nervous system, inhibiting the acetylcholinesterase (AChE) enzyme and resulting in a cholinergic crisis. Their high toxicity and rapid action lead to irreversible damage to the nervous system, drawing attention to developing new treatment methods. The diisopropyl fluorophosphatase (DFPase) enzyme has been considered as a potent biocatalyst for the hydrolysis of toxic OP and has potential for bioremediation of this kind of intoxication. In order to investigate the degradation process of the nerve agents Tabun, Cyclosarin and Soman through the wild-type DFPase, and taking into account their stereochemistry, theoretical studies were carried out. The intermolecular interaction energy and other parameters obtained from the molecular docking calculations were used to construct a data matrix, which were posteriorly treated by statistical analyzes of chemometrics, using the PCA (Principal Components Analysis) multivariate analysis. The analyzed parameters seem to be quite important for the reaction mechanisms simulation (QM/MM). Our findings showed that the wild-type DFPase enzyme is stereoselective in hydrolysis, showing promising results for the catalytic degradation of the neurotoxic agents under study, with the degradation mechanism performed through two proposed pathways.

Health effects in Army Gulf War veterans possibly exposed to chemical munitions destruction at Khamisiyah, Iraq: Part I. Morbidity associated with potential exposure.

PubMed

Mahan, Clare M; Page, William F; Bullman, Tim A; Kang, Han K

2005-11-01

In March 1991, U.S. troops detonated the Khamisiyah, Iraq, ammunition depot, possibly releasing two chemical warfare agents, sarin and cyclosarin. The long-term health effects associated with possible exposure to these chemical warfare agents are unknown. This study was undertaken to investigate whether possible exposure was associated with morbidity among Army Gulf War veterans using morbidity data for 5,555 Army veterans who were deployed to the Gulf region. Responses to 86 self-assessed health measures, as reported in the 1995 Department of Veterans Affairs National Health Survey of Gulf War Era Veterans, were evaluated. We found little association between potential exposure and health, after adjustment for demographic variables, and conclude that potential exposure to sarin or cyclosarin at Khamisiyah does not seem to have adversely affected self-perceived health status, as evidenced by a wide range of health measures.

Reactivation of organophosphate-inhibited human acetylcholinesterase by isonitrosoacetone (MINA): a kinetic analysis.

PubMed

Worek, Franz; Thiermann, Horst

2011-11-15

Treatment of poisoning by highly toxic organophosphorus compounds (OP) with atropine and an acetylcholinesterase (AChE) reactivator (oxime) is of limited effectiveness in case of different nerve agents and pesticides. One challenge is the reactivation of OP-inhibited brain AChE which shows inadequate success with charged pyridinium oximes. Recent studies with high doses of the tertiary oxime isonitrosoacetone (MINA) indicated a beneficial effect on central and peripheral AChE and on survival in nerve agent poisoned guinea pigs. Now, an in vitro study was performed to determine the reactivation kinetics of MINA with tabun-, sarin-, cyclosarin-, VX- and paraoxon-inhibited human AChE. MINA showed an exceptionally low affinity to inhibited AChE but, with the exception of tabun-inhibited AChE, a moderate to high reactivity. In comparison to the pyridinium oximes obidoxime, 2-PAM and HI-6 the affinity and reactivity of MINA was in most cases lower and in relation to the most effective reactivators, the second order reactivation constant of MINA was 500 to 3400-fold lower. Hence, high in vivo MINA concentrations would be necessary to achieve at least partial reactivation. This assumption corresponds to in vivo data showing a dose-dependent effect on reactivation and survival in animals. In view, of the toxic potential of MINA in animals human studies would be necessary to determine the tolerability and pharmacokinetics of MINA in order to enable a proper assessment of the value of this oxime as an antidote in OP poisoning. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Reprogramming cells from Gulf War veterans into neurons to study Gulf War illness.

PubMed

Qiang, Liang; Rao, Anand N; Mostoslavsky, Gustavo; James, Marianne F; Comfort, Nicole; Sullivan, Kimberly; Baas, Peter W

2017-05-16

Gulf War illness (GWI), which afflicts at least 25% of veterans who served in the 1990-1991 war in the Persian Gulf, is thought to be caused by deployment exposures to various neurotoxicants, including pesticides, anti-nerve gas pills, and low-level nerve agents including sarin/cyclosarin. GWI is a multisymptom disorder characterized by fatigue, joint pain, cognitive problems, and gastrointestinal complaints. The most prominent symptoms of GWI (memory problems, poor attention/concentration, chronic headaches, mood alterations, and impaired sleep) suggest that the disease primarily affects the CNS. Development of urgently needed treatments depends on experimental models appropriate for testing mechanistic hypotheses and for screening therapeutic compounds. Rodent models have been useful thus far, but are limited by their inability to assess the contribution of genetic or epigenetic background to the disease, and because disease-vulnerable proteins and pathways may be different in humans relative to rodents. As of yet, no postmortem tissue from the veterans has become available for research. We are moving forward with a paradigm shift in the study of GWI, which utilizes contemporary stem cell technology to convert somatic cells from Gulf War veterans into pluripotent cell lines that can be differentiated into various cell types, including neurons, glia, muscle, or other relevant cell types. Such cell lines are immortal and will be a resource for GWI researchers to pursue mechanistic hypotheses and therapeutics. © 2017 American Academy of Neurology.

Reprogramming cells from Gulf War veterans into neurons to study Gulf War illness

PubMed Central

Qiang, Liang; Rao, Anand N.; Mostoslavsky, Gustavo; James, Marianne F.; Comfort, Nicole; Sullivan, Kimberly

2017-01-01

Gulf War illness (GWI), which afflicts at least 25% of veterans who served in the 1990–1991 war in the Persian Gulf, is thought to be caused by deployment exposures to various neurotoxicants, including pesticides, anti–nerve gas pills, and low-level nerve agents including sarin/cyclosarin. GWI is a multisymptom disorder characterized by fatigue, joint pain, cognitive problems, and gastrointestinal complaints. The most prominent symptoms of GWI (memory problems, poor attention/concentration, chronic headaches, mood alterations, and impaired sleep) suggest that the disease primarily affects the CNS. Development of urgently needed treatments depends on experimental models appropriate for testing mechanistic hypotheses and for screening therapeutic compounds. Rodent models have been useful thus far, but are limited by their inability to assess the contribution of genetic or epigenetic background to the disease, and because disease-vulnerable proteins and pathways may be different in humans relative to rodents. As of yet, no postmortem tissue from the veterans has become available for research. We are moving forward with a paradigm shift in the study of GWI, which utilizes contemporary stem cell technology to convert somatic cells from Gulf War veterans into pluripotent cell lines that can be differentiated into various cell types, including neurons, glia, muscle, or other relevant cell types. Such cell lines are immortal and will be a resource for GWI researchers to pursue mechanistic hypotheses and therapeutics. PMID:28507260

Catalytic soman scavenging by Y337A/F338A acetylcholinesterase mutant assisted with novel site-directed aldoximes

PubMed Central

Kovarik, Zrinka; Hrvat, Nikolina Maček; Katalinić, Maja; Sit, Rakesh K.; Paradyse, Alexander; Žunec, Suzana; Musilek, Kamil; Fokin, Valery V.; Taylor, Palmer; Radić, Zoran

2016-01-01

Exposure to the nerve agent soman is difficult to treat due to the rapid dealkylation of soman-acetylcholinesterase (AChE) conjugate known as aging. Oxime antidotes commonly used to reactivate organophosphate inhibited AChE are ineffective against soman, while the efficacy of the recommended nerve agent bioscavenger butyrylcholinesterase is limited by strictly stoichiometric scavenging. To overcome this limitation, we tested ex vivo, in human blood, and in vivo, in soman exposed mice, the capacity of aging-resistant human AChE mutant Y337A/F338A in combination with oxime HI-6 to act as a catalytic bioscavenger of soman. HI-6 was previously shown in vitro to efficiently reactivate this mutant upon soman, as well as VX, cyclosarin, sarin and paraoxon inhibition. We here demonstrate that ex vivo, in whole human blood, 1 μM soman was detoxified within 30 minutes when supplemented with 0.5 μM Y337A/F338A AChE and 100 μM HI-6. This combination was further tested in vivo. Catalytic scavenging of soman in mice improved the therapeutic outcome and resulted in the delayed onset of toxicity symptoms. Furthermore, in a preliminary in vitro screen we identified an even more efficacious oxime than HI-6, in a series of forty-two pyridinium aldoximes, and five imidazole 2-aldoxime N-propyl pyridinium derivatives. One of the later imidazole aldoximes, RS-170B, was a 2–3 –fold more effective reactivator of Y337A/F338A AChE than HI-6 due to the smaller imidazole ring, as indicated by computational molecular models, that affords a more productive angle of nucleophilic attack. PMID:25835984

Effects of low-level sarin and cyclosarin exposure on hippocampal microstructure in Gulf War Veterans.

PubMed

Chao, Linda L; Zhang, Yu

2018-05-04

In early March 1991, shortly after the end of the Gulf War (GW), a munitions dump was destroyed at Khamisiyah, Iraq. Later, in 1996, the dump was found to have contained the organophosphorus (OP) nerve agents sarin and cyclosarin. We previously reported evidence of smaller hippocampal volumes in GW veterans with predicted exposure to the Khamisiyah plume compared to unexposed GW veterans. To investigate whether these macroscopic hippocampal volume changes are accompanied by microstructural alterations in the hippocampus, the current study acquired diffusion-tensor imaging (DTI), T1-, and T2-weighted images from 170 GW veterans (mean age: 53 ± 7 years), 81 of whom had predicted exposure to the Khamisiyah plume according to Department of Defense (DOD) plume modeling. We examined fractional anisotropy (FA), mean diffusivity (MD), and grey matter (GM) density from a hippocampal region of interest (ROI). Results indicate that, even after accounting for total hippocampal GM density (or hippocampal volume), age, sex, apolipoprotein ε4 genotype, and potential confounding OP pesticide exposures, hippocampal MD significantly predicted Khamisiyah exposure status (model p = 0.005, R 2  = 0.215, standardized coefficient β = 0.26, t = 2.85). Hippocampal MD was also inversely correlated with verbal memory learning performance in the entire study sample (p = 0.001). There were no differences in hippocampal FA or GM density; however, veterans with predicted Khamisiyah exposure had smaller hippocampal volumes compared to unexposed veterans. Because MD is sensitive to general microstructural disruptions that lead to increased extracellular spaces due to neuronal death, inflammation and gliosis, and/or to axonal loss or demyelination, these findings suggest that low-level exposure to the Khamisiyah plume has a detrimental, lasting effects on both macro- and micro-structure of the hippocampus. Copyright © 2018. Published by Elsevier Inc.

Recent research on Gulf War illness and other health problems in veterans of the 1991 Gulf War: Effects of toxicant exposures during deployment.

PubMed

White, Roberta F; Steele, Lea; O'Callaghan, James P; Sullivan, Kimberly; Binns, James H; Golomb, Beatrice A; Bloom, Floyd E; Bunker, James A; Crawford, Fiona; Graves, Joel C; Hardie, Anthony; Klimas, Nancy; Knox, Marguerite; Meggs, William J; Melling, Jack; Philbert, Martin A; Grashow, Rachel

2016-01-01

Veterans of Operation Desert Storm/Desert Shield - the 1991 Gulf War (GW) - are a unique population who returned from theater with multiple health complaints and disorders. Studies in the U.S. and elsewhere have consistently concluded that approximately 25-32% of this population suffers from a disorder characterized by symptoms that vary somewhat among individuals and include fatigue, headaches, cognitive dysfunction, musculoskeletal pain, and respiratory, gastrointestinal and dermatologic complaints. Gulf War illness (GWI) is the term used to describe this disorder. In addition, brain cancer occurs at increased rates in subgroups of GW veterans, as do neuropsychological and brain imaging abnormalities. Chemical exposures have become the focus of etiologic GWI research because nervous system symptoms are prominent and many neurotoxicants were present in theater, including organophosphates (OPs), carbamates, and other pesticides; sarin/cyclosarin nerve agents, and pyridostigmine bromide (PB) medications used as prophylaxis against chemical warfare attacks. Psychiatric etiologies have been ruled out. This paper reviews the recent literature on the health of 1991 GW veterans, focusing particularly on the central nervous system and on effects of toxicant exposures. In addition, it emphasizes research published since 2008, following on an exhaustive review that was published in that year that summarizes the prior literature (RACGWI, 2008). We conclude that exposure to pesticides and/or to PB are causally associated with GWI and the neurological dysfunction in GW veterans. Exposure to sarin and cyclosarin and to oil well fire emissions are also associated with neurologically based health effects, though their contribution to development of the disorder known as GWI is less clear. Gene-environment interactions are likely to have contributed to development of GWI in deployed veterans. The health consequences of chemical exposures in the GW and other conflicts have been called "toxic wounds" by veterans. This type of injury requires further study and concentrated treatment research efforts that may also benefit other occupational groups with similar exposure-related illnesses. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Recent research on Gulf War illness and other health problems in veterans of the 1991 Gulf War: Effects of toxicant exposures during deployment

PubMed Central

White, Roberta F.; Steele, Lea; O’Callaghan, James P.; Sullivan, Kimberly; Binns, James H.; Golomb, Beatrice A.; Bloom, Floyd E.; Bunker, James A.; Crawford, Fiona; Graves, Joel C.; Hardie, Anthony; Klimas, Nancy; Knox, Marguerite; Meggs, William J.; Melling, Jack; Philbert, Martin A.; Grashow, Rachel

2015-01-01

Veterans of Operation Desert Storm/Desert Shield – the 1991 Gulf War (GW) – are a unique population who returned from theater with multiple health complaints and disorders. Studies in the U.S. and elsewhere have consistently concluded that approximately 25–32% of this population suffers from a disorder characterized by symptoms that vary somewhat among individuals and include fatigue, headaches, cognitive dysfunction, musculoskeletal pain, and respiratory, gastrointestinal and dermatologic complaints. Gulf War illness (GWI) is the term used to describe this disorder. In addition, brain cancer occurs at increased rates in subgroups of GW veterans, as do neuropsychological and brain imaging abnormalities. Chemical exposures have become the focus of etiologic GWI research because nervous system symptoms are prominent and many neurotoxicants were present in theater, including organophosphates (OPs), carbamates, and other pesticides; sarin/cyclosarin nerve agents, and pyridostigmine bromide (PB) medications used as prophylaxis against chemical warfare attacks. Psychiatric etiologies have been ruled out. This paper reviews the recent literature on the health of 1991 GW veterans, focusing particularly on the central nervous system and on effects of toxicant exposures. In addition, it emphasizes research published since 2008, following on an exhaustive review that was published in that year that summarizes the prior literature (RACGWI, 2008). We conclude that exposure to pesticides and/or to PB are causally associated with GWI and the neurological dysfunction in GW veterans. Exposure to sarin and cyclosarin and to oil well fire emissions are also associated with neurologically based health effects, though their contribution to development of the disorder known as GWI is less clear. Gene-environment interactions are likely to have contributed to development of GWI in deployed veterans. The health consequences of chemical exposures in the GW and other conflicts have been called “toxic wounds” by veterans. This type of injury requires further study and concentrated treatment research efforts that may also benefit other occupational groups with similar exposure-related illnesses. PMID:26493934

Metal-Organic Framework Modified Glass Substrate for Analysis of Highly Volatile Chemical Warfare Agents by Paper Spray Mass Spectrometry.

PubMed

Dhummakupt, Elizabeth S; Carmany, Daniel O; Mach, Phillip M; Tovar, Trenton M; Ploskonka, Ann M; Demond, Paul S; DeCoste, Jared B; Glaros, Trevor

2018-03-07

Paper spray mass spectrometry has been shown to successfully analyze chemical warfare agent (CWA) simulants. However, due to the volatility differences between the simulants and real G-series (i.e., sarin, soman) CWAs, analysis from an untreated paper substrate proved difficult. To extend the analytical lifetime of these G-agents, metal-organic frameworks (MOFs) were successfully integrated onto the paper spray substrates to increase adsorption and desorption. In this study, several MOFs and nanoparticles were tested to extend the analytical lifetimes of sarin, soman, and cyclosarin on paper spray substrates. It was found that the addition of either UiO-66 or HKUST-1 to the paper substrate increased the analytical lifetime of the G-agents from less than 5 min detectability to at least 50 min.

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) for detection and identification of albumin phosphylation by organophosphorus pesticides and G- and V-type nerve agents.

PubMed

John, Harald; Breyer, Felicitas; Thumfart, Jörg Oliver; Höchstetter, Hans; Thiermann, Horst

2010-11-01

Toxic organophosphorus compounds (OPC), e.g., pesticides and nerve agents (NA), are known to phosphylate distinct endogenous proteins in vivo and in vitro. OPC adducts of butyrylcholinesterase and albumin are considered to be valuable biomarkers for retrospective verification of OPC exposure. Therefore, we have detected and identified novel adducts of human serum albumin (HSA) by means of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Pure albumin and plasma were incubated with numerous pesticides and NA of the V- and G-type in different molar ratios. Samples were prepared either by sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by in-gel enzymatic cleavage using endoproteinase Glu-C (Glu-C) or by combining highly albumin-selective affinity extraction with ultrafiltration followed by reduction, carbamidomethylation, and enzymatic cleavage (Glu-C) prior to MALDI-TOF MS analysis. Characteristic mass shifts for phosphylation revealed tyrosine adducts at Y(411) (Y(401)KFQNALLVRY(411)TKKVPQVSTPTLVE(425)), Y(148) and Y(150) (I(142)ARRHPY(148)FY(150)APE(153), single and double labeled), and Y(161) (L(154)LFFAKRY(161)KAAFTE(167)) produced by original NA (tabun, sarin, soman, cyclosarin, VX, Chinese VX, and Russian VX) as well as by chlorpyrifos-oxon, diisopropyl fluorophosphate (DFP), paraoxon-ethyl (POE), and profenofos. MALDI-MS/MS of the single-labeled I(142)-E(153) peptide demonstrated that Y(150) was phosphylated with preference to Y(148). Aged albumin adducts were not detected. The procedure described was reproducible and feasible for detection of adducts at the most reactive Y(411)-residue (S/N ≥ 3) when at least 1% of total albumin was labeled. This was achieved by incubating plasma with molar HSA/OPC ratios ranging from approximately 1:0.03 (all G-type NA, DFP, and POE) to 1:3 (V-type NA, profenofos). Relative signal intensity of the Y(411) adduct correlated well with the spotted relative molar amount underlining the usefulness for quantitative adduct determination. In conclusion, the current analytical design exhibits potential as a verification tool for high-dose exposure.

Evaluation of RSDL, M291 SDK, 0.5% Bleach, 1% Soapy Water and SERPACWA. Part 12: Challenge with EA1212 (GF, cyclosarin)

DTIC Science & Technology

2016-01-01

products in the haired guinea pig model following exposure to GF (EA1212). 15. SUBJECT TERMS decontamination, delayed decontamination, Reactive Skin...the four listed decontamination products in the haired guinea pig model following exposure to GF (EA1212). In all experiments, guinea pigs were close...the four listed decontamination products and SERPACWA in the haired guinea pig model following exposure to GF [cyclosarin, EA1212, Cyclohexyl

Department of Defense Chemical, Biological, Defense Program, Annual Report to Congress, March 2005

DTIC Science & Technology

2005-03-01

nerve agents ( GA , GB, GD, and GF), V type nerve agents , and H (mustard) type blister agents . M8 paper can identify agents through...The M21 RSCAAL is an automatic scanning, passive infrared sensor that detects nerve ( GA , GB, and GD) and blister (H and L) agent vapor clouds...Chief of Staff for Programs GA – tabun, a nerve agent GAO – General Accounting Office GB – sarin, a nerve agent GD – soman, a nerve

United States Army Biomedical Research and Development Laboratory Annual Progress Report FY90

DTIC Science & Technology

1991-01-01

pesticide . Parallel and follow-on studies will include hydrolysis products of nerve agents , vesicants, and agents of...Division FO Fog oil FORSCOM U.S. Army Forces Command FY Fiscal year 249 GA The nerve agent tabun GB The nerve agent soman GD The nerve agent sarin GLP... Nerve Agents , Industrial Hygiene Sampling, Microbiology, Combustion Products, Liquid Gun Propellant, Organic Chemistry, Inorganic

Symptoms of Gulf War veterans possibly exposed to organophosphate chemical warfare agents at Khamisiyah, Iraq.

PubMed

McCauley, L A; Rischitelli, G; Lambert, W E; Lasarev, M; Sticker, D L; Spencer, P S

2001-01-01

During the 1991 Gulf War, some Allied troops were potentially exposed to sarin/cyclosarin as the result of the destruction of Iraqi munitions at Khamisiyah. To evaluate the prevalence of past and current symptoms known to be associated with exposure to these chemical warfare agents, the authors conducted a computer-assisted telephone survey of 2,918 U.S. Gulf War veterans. Veterans who had participated in or witnessed the demolition in 1991 were more likely to report historical or extant symptoms than were veterans from other military units. These results should be viewed cautiously because they are based on symptoms recalled nine years after the event without precise characterization of exposure. Nonetheless, the findings suggest that symptoms consistent with low-level sarin exposure may have initially occurred, and health effects may have persisted in the veterans who were nearest to the demolition activity. Further research is warranted.

Reliable Prescreening of Candidate NerveAgent Prophylaxes via 3D QSAR

DTIC Science & Technology

2005-12-31

recognize and predict prospective toxicity among covalent -binding AChE inhibitors of potential application to nerve agent prophylaxis and...is below since many authors do not follow the 200 word limit 14. SUBJECT TERMS nerve agents , acetylcholinesterase, prophylaxis, QSAR, virtual...Report: Reliable Prescreening of Candidate NerveAgent Prophylaxes via 3D QSAR Report Title ABSTRACT Organophosphorus (OP) nerve agents are among the

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

DTIC Science & Technology

2016-05-09

Analysis of Nerve Agent Metabolites from Hair for Long-Term Verification of Nerve Agent Exposure Amanda S. Appel,† John H. McDonough,‡ Joseph D...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

Metal organic frameworks for the catalytic detoxification of chemical warfare nerve agents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hupp, Joseph T.; Farha, Omar K.; Katz, Michael J.

A method of using a metal organic framework (MOF) comprising a metal ion and an at least bidendate organic ligand to catalytically detoxify chemical warfare nerve agents including exposing the metal-organic-framework (MOF) to the chemical warfare nerve agent and catalytically decomposing the nerve agent with the MOF.

Symposium on Toxic Substance Control: Decontamination, April 22 - 24, 1980, Columbus, Ohio.

DTIC Science & Technology

1981-06-01

standard decontaminants is used. TABLE 1. Standard Chemical Decontaminants Decontaminant Agents Used On STB Blister and nerve agents DS-2 All chemical... agents M258 Kit Sodium Hydroxide, Ethanol, G-Series nerve agents Phenol, Water Chloramine B, ZnCI2, Blister ana V-Series Ethanol, Water nerve agents A...is a point source alarm that actively samples ambient air and reacts to low concentrations of nerve agents . The M-8 alarm detector also detects several

Effects of low-level sarin and cyclosarin exposure on hippocampal subfields in Gulf War Veterans.

PubMed

Chao, Linda L; Kriger, Stephen; Buckley, Shannon; Ng, Peter; Mueller, Susanne G

2014-09-01

More than 100,000 US troops were potentially exposed to chemical warfare agents sarin (GB) and cyclosarin (GF) when an ammunition dump at Khamisiyah, Iraq was destroyed during the 1991 Gulf War (GW). We previously reported reduced hippocampal volume in GW veterans with suspected GB/GF exposure relative to matched, unexposed GW veterans estimated from 1.5T magnetic resonance images (MRI). Here we investigate, in a different cohort of GW veterans, whether low-level GB/GF exposure is associated with structural alterations in specific hippocampal subfields, estimated from 4T MRI. The Automatic Segmentation of Hippocampal Subfields (ASHS) technique was used to quantify CA1, CA2, CA3 and dentate gyrus (DG), and subiculum (SUB) subfields volumes from high-resolution T2-weighted images acquired on a 4T MR scanner in 56 GW veterans with suspected GB/GF exposure and 56 "matched" unexposed GW veterans (mean age 49±7 years). GB/GF exposed veterans had smaller CA2 (p=0.003) and CA3/DG (p=0.01) subfield volumes compared to matched, unexposed GW veterans. There were no group difference in total hippocampal volume, quantified with FreeSurfer, and no dose-response relationship between estimated levels of GB/GF exposure and total hippocampal or subfield volume. These findings extend our previous report of structural alterations in the hippocampi of GW veterans with suspected GB/GF exposure to volume changes in the CA2, CA3, and DG hippocampal subfields in a different cohort of GW veterans with suspected GB/GF exposure. Published by Elsevier B.V.

GC-MS and LC-MS analysis of nerve agents in body fluids: intra-laboratory verification test using spiked plasma and urine samples.

PubMed

Koller, Marianne; Becker, Christian; Thiermann, Horst; Worek, Franz

2010-05-15

The purpose of this study was to check the applicability of different analytical methods for the identification of unknown nerve agents in human body fluids. Plasma and urine samples were spiked with nerve agents (plasma) or with their metabolites (urine) or were left blank. Seven random samples (35% of all samples) were selected for the verification test. Plasma was worked up for unchanged nerve agents and for regenerated nerve agents after fluoride-induced reactivation of nerve agent-inhibited butyrylcholinesterase. Both extracts were analysed by GC-MS. Metabolites were extracted from plasma and urine, respectively, and were analysed by LC-MS. The urinary metabolites and two blank samples could be identified without further measurements, plasma metabolites and blanks were identified in six of seven samples. The analysis of unchanged nerve agent provided five agents/blanks and the sixth agent after further investigation. The determination of the regenerated agents also provided only five clear findings during the first screening because of a rather noisy baseline. Therefore, the sample preparation was extended by a size exclusion step performed before addition of fluoride which visibly reduced baseline noise and thus improved identification of the two missing agents. The test clearly showed that verification should be performed by analysing more than one biomarker to ensure identification of the agent(s). Copyright (c) 2010 Elsevier B.V. All rights reserved.

Cranial nerve contrast using nerve-specific fluorophores improved by paired-agent imaging with indocyanine green as a control agent

NASA Astrophysics Data System (ADS)

Torres, Veronica C.; Vuong, Victoria D.; Wilson, Todd; Wewel, Joshua; Byrne, Richard W.; Tichauer, Kenneth M.

2017-09-01

Nerve preservation during surgery is critical because damage can result in significant morbidity. This remains a challenge especially for skull base surgeries where cranial nerves (CNs) are involved because visualization and access are particularly poor in that location. We present a paired-agent imaging method to enhance identification of CNs using nerve-specific fluorophores. Two myelin-targeting imaging agents were evaluated, Oxazine 4 and Rhodamine 800, and coadministered with a control agent, indocyanine green, either intravenously or topically in rats. Fluorescence imaging was performed on excised brains ex vivo, and nerve contrast was evaluated via paired-agent ratiometric data analysis. Although contrast was improved among all experimental groups using paired-agent imaging compared to conventional, solely targeted imaging, Oxazine 4 applied directly exhibited the greatest enhancement, with a minimum 3 times improvement in CNs delineation. This work highlights the importance of accounting for nonspecific signal of targeted agents, and demonstrates that paired-agent imaging is one method capable of doing so. Although staining, rinsing, and imaging protocols need to be optimized, these findings serve as a demonstration for the potential use of paired-agent imaging to improve contrast of CNs, and consequently, surgical outcome.

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

2014-03-01

for Biotechnology, Gurgaon, India (Sep, 2013) by Joel L. Sussman, title: “Molecular Basis of How Nerve Agents through anti- Alzheimer Drugs Function...Molecular Basis of How Nerve Agents through anti- Alzheimer Drugs Function: 3D Structure of Acetylcholinesterase • Florida International University...FIU), Miami, FL (Dec 2013) - Invited Lecture by Joel L. Sussman, title: “Molecular Basis of anti- Alzheimer Drugs & Nerve Agents: 3D Structure of

Differential sensitivity of plasma carboxylesterase-null mice to parathion, chlorpyrifos and chlorpyrifos oxon, but not to diazinon, dichlorvos, diisopropylfluorophosphate, cresyl saligenin phosphate, cyclosarin thiocholine, tabun thiocholine, and carbofuran

PubMed Central

Duysen, Ellen G.; Cashman, John R.; Schopfer, Lawrence M.; Nachon, Florian; Masson, Patrick; Lockridge, Oksana

2012-01-01

Mouse blood contains four esterases that detoxify organophosphorus compounds: carboxylesterase, butyrylcholinesterase, acetylcholinesterase, and paraoxonase-1. In contrast human blood contains the latter three enzymes but not carboxylesterase. Organophosphorus compound toxicity is due to inhibition of acetylcholinesterase. Symptoms of intoxication appear after approximately 50% of the acetylcholinesterase is inhibited. However, complete inhibition of carboxylesterase and butyrylcholinesterase has no known effect on an animal’s well being. Paraoxonase hydrolyzes organophosphorus compounds and is not inhibited by them. Our goal was to determine the effect of plasma carboxylesterase deficiency on response to sublethal doses of 10 organophosphorus toxicants and one carbamate pesticide. Homozygous plasma carboxylesterase deficient ES1−/− mice and wild-type littermates were observed for toxic signs and changes in body temperature after treatment with a single sublethal dose of toxicant. Inhibition of plasma acetylcholinesterase, butyrylcholinesterase, and plasma carboxylesterase was measured. It was found that wild-type mice were protected from the toxicity of 12.5 mg/kg parathion applied subcutaneously. However, both genotypes responded similarly to paraoxon, cresyl saligenin phosphate, diisopropylfluorophosphate, diazinon, dichlorvos, cyclosarin thiocholine, tabun thiocholine, and carbofuran. An unexpected result was the finding that transdermal application of chlorpyrifos at 100 mg/kg and chlorpyrifos oxon at 14 mg/kg was lethal to wild-type but not to ES1−/− mice, showing that with this organochlorine, the presence of carboxylesterase was harmful rather than protective. It was concluded that carboxylesterase in mouse plasma protects from high toxicity agents, but the amount of carboxylesterase in plasma is too low to protect from low toxicity compounds that require high doses to inhibit acetylcholinesterase. PMID:22209767

Effects of low-level exposure to sarin and cyclosarin during the 1991 Gulf War on brain function and brain structure in US veterans

PubMed Central

Chao, Linda L.; Rothlind, Johannes C.; Cardenas, Valerie A.; Meyerhoff, Dieter J.; Weiner, Michael W.

2010-01-01

Background Potentially more than 100,000 US troops may have been exposed to the organophosphate chemical warfare agents sarin (GB) and cyclosarin (GF) when a munitions dump at Khamisiyah, Iraq was destroyed during the Gulf War (GW) in 1991. Although little is known about the long-term neurobehavioral or neurophysiological effects of low-dose exposure to GB/GF in humans, recent studies of GW veterans from the Devens Cohort suggest decrements in certain cognitive domains and atrophy in brain white matter occur individuals with higher estimated levels of presumed GB/GF exposure. The goal of the current study is to determine the generalizability of these findings in another cohort of GW veterans with suspected GB/GF exposure. Methods Neurobehavioral and imaging data collected in a study on Gulf War Illness between 2002–2007 were used in this study. We focused on the data of 40 GW-deployed veterans categorized as having been exposed to GB/GF at Khamisiyah, Iraq and 40 matched controls. Magnetic resonance images (MRI) of the brain were analyzed using automated and semi-automated image processing techniques that produced volumetric measurements of gray matter (GM), white matter (WM), cerebrospinal fluid (CSF) and hippocampus. Results GW veterans with suspected GB/GF exposure had reduced total GM and hippocampal volumes compared to their unexposed peers (p≤0.01). Although there were no group differences in measures of cognitive function or total WM volume, there were significant, positive correlations between total WM volume and measures of executive function and visuospatial abilities in veterans with suspected GB/GF exposure. Conclusions These findings suggest that low-level exposure to GB/GF can have deleterious effects on brain structure and brain function more than decade later. PMID:20580739

Cholinesterase Structure: Identification of Mechanisms and Residues Involved in Organophosphate Inhibition and Enzyme Reactivation

DTIC Science & Technology

2005-05-01

nerve agents , soman is the great- terrorist acts. At the same time, OP pesticides , such as est challenge since both the rapid aging of the soman- paraoxon...also from enzyme very slowly (requiring hours, days, or weeks used as nerve warfare agents . Similar to pesticides , nerve for complete dissociation...TERMS acetylcholinesterase, nerve agent antidotes and propylaxis, organophosphate scavenging , oxime reactivation fluorescence spectroscopy, exposure

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

Evaluating mice lacking serum carboxylesterase as a behavioral model for nerve agent intoxication.

PubMed

Dunn, Emily N; Ferrara-Bowens, Teresa M; Chachich, Mark E; Honnold, Cary L; Rothwell, Cristin C; Hoard-Fruchey, Heidi M; Lesyna, Catherine A; Johnson, Erik A; Cerasoli, Douglas M; McDonough, John H; Cadieux, C Linn

2018-06-07

Mice and other rodents are typically utilized for chemical warfare nerve agent research. Rodents have large amounts of carboxylesterase in their blood, while humans do not. Carboxylesterase nonspecifically binds to and detoxifies nerve agent. The presence of this natural bioscavenger makes mice and other rodents poor models for studies identifying therapeutics to treat humans exposed to nerve agents. To obviate this problem, a serum carboxylesterase knockout (Es1 KO) mouse was created. In this study, Es1 KO and wild type (WT) mice were assessed for differences in gene expression, nerve agent (soman; GD) median lethal dose (MLD) values, and behavior prior to and following nerve agent exposure. No expression differences were detected between Es1 KO and WT mice in more than 34 000 mouse genes tested. There was a significant difference between Es1 KO and WT mice in MLD values, as the MLD for GD-exposed WT mice was significantly higher than the MLD for GD-exposed Es1 KO mice. Behavioral assessments of Es1 KO and WT mice included an open field test, a zero maze, a Barnes maze, and a sucrose preference test (SPT). While sex differences were observed in various measures of these tests, overall, Es1 KO mice behaved similarly to WT mice. The two genotypes also showed virtually identical neuropathological changes following GD exposure. Es1 KO mice appear to have an enhanced susceptibility to GD toxicity while retaining all other behavioral and physiological responses to this nerve agent, making the Es1 KO mouse a more human-like model for nerve agent research.

Chemicals of military deployments: revisiting Gulf War Syndrome in light of new information.

PubMed

Brimfield, A A

2012-01-01

Despite the amount of hard work that has gone into elucidating a toxicological basis for Gulf War Illness, we do not appear to have reached a mechanistic understanding. Investigation of long-term low-level exposure as a basis does not seem to have provided an answer. Nor does the deployment-related toxic soup idea, where exposure to a mixture of toxic chemicals not usually encountered in the same physical vicinity, seems to have explained the symptoms developed by Gulf War Veterans. The idea that an overabundance of CNS acetylcholine leftover from excessive cholinesterase inhibition is at the basis of this syndrome is intellectually appealing and offers a level of neurochemical complexity that may be just beyond the reach of our technical understanding. But no one has yet assembled a coherent mechanism from it either. It seems reasonable that chemical warfare agents were involved. They were not included in early work because it was felt that the toxicant plumes produced during the destruction of stockpiled Iraqi chemical weapons had not been large enough to cause an exposure of US forces and those of our allies. That misconception was disproven, and it is now accepted that people could very well have been exposed to low levels of massive quantities of sarin, cyclosarin, and sulfur mustard. It also seems reasonable that excess acetylcholine or neurological consequences of its presence that we do not fully understand were involved. The combination of nerve agents and the insecticidal anticholinesterases plus the pyridostigmine bromide given prophylactically were probably sufficient to cause the problem. However, the most notable thing is the result of recent work on the toxic mechanism of sulfur mustard showing that it can inhibit the microsomal electron transport chain as a result of sulfonium ion reduction to carbon free radicals by NADPH-cytochrome P450 reductase. This information was not available during the work on Gulf War Illness. So this provides an opportunity to discuss the effects of the general inhibition of the cytochrome P450 system superimposed on the conditions encountered by the participants in Desert Storm and Desert Shield as an approach to the toxicology of mixtures. Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical Warfare Agent Operational Exposure Hazard Assessment Research: FY07 Report and Analysis

DTIC Science & Technology

2010-07-01

of the nerve agents sarin, soman, cyclohexylsarin, VX, and Russian VX in human urine using isotope-dilution gas chromatography-tandem mass...Needham L.L.; Barr, D.B. Quantitation of organophosphorous nerve agent metabolites in human urine using isotope dilution gas chromatography-tandem mass... nerve agents , VX, GB, or GF, and to determine lethal percutaneous (PC) levels of VX. Calibration of Physiologically-based pharmacokinetic biomarkers

Neuroprotective Effects of Galantamine on Nerve Agent-Induced Neuroglial and Biochemical Changes.

PubMed

Golime, RamaRao; Palit, Meehir; Acharya, J; Dubey, D K

2018-05-01

Neuroprotection from nerve agent such as soman-induced neural damage is a major challenge for existing drugs. Nerve agent exposure can cause many neural effects in survivors arising mainly due to acetylcholinesterase (AChE) inhibition or death within minutes. Unraveling the mechanisms underlying the nerve agent-induced multiple neurological effects is useful to develop better and safe drugs. The present study aimed to understand the molecular response during soman exposure and to evaluate the neuroprotective efficacy of galantamine on nerve agent-induced neurotoxic changes. mRNA expression studies using quantitative real-time PCR revealed significant changes in S-100β, Gfap, c-fos, and Bdnf in the hippocampus and piriform cortex after soman (90 μg/kg, s.c) exposure. Immunoblot analysis showed acute soman exposure significantly increased the protein levels of neuroglial markers (S100-β and GFAP); c-Fos and protein oxidation in discrete rat brain areas indicate their role in nerve agent-induced neurotoxicity. Induction of BDNF levels during soman exposure may indicate the recovery mechanisms activation. AChE was inhibited in the blood and brain up to 82% after soman exposure. Antidotal treatment with galantamine alone (3 mg/kg) and galantamine plus atropine (10 mg/kg) has protected animals from nerve agent-induced intoxication, death, and soman-inhibited AChE up to 45% in the blood and brain. Animal received galantamine displayed increased levels of neuroprotective genes (nAChRα-7, Bcl-2, and Bdnf) in the brain suggest the neuroprotective value of galantamine. Neuroglial changes, c-Fos, and protein oxidation levels significantly reduced after galantamine and galantamine plus atropine treatment indicate their potential antidotal value in nerve agent treatment.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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 tomore » 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.« less

ARO in Review 2010

DTIC Science & Technology

2010-01-01

develop a fundamental understanding of the key recognition elements in various nerve agents , pesticides , and simulants. Using this knowledge, these groups...SCIENCES DIVISION 29 ARO IN REVIEW 2010 1. Low-power Nerve Agent Detector. Three Phase I CBD-SBIR contracts were awarded to Identizyme Defense...Technologies, Inc., Luna Innovations, Inc., and Lynntech, Inc. to develop a nerve agent detection system that requires little to no operating power

Improved identification of cranial nerves using paired-agent imaging: topical staining protocol optimization through experimentation and simulation

NASA Astrophysics Data System (ADS)

Torres, Veronica C.; Wilson, Todd; Staneviciute, Austeja; Byrne, Richard W.; Tichauer, Kenneth M.

2018-03-01

Skull base tumors are particularly difficult to visualize and access for surgeons because of the crowded environment and close proximity of vital structures, such as cranial nerves. As a result, accidental nerve damage is a significant concern and the likelihood of tumor recurrence is increased because of more conservative resections that attempt to avoid injuring these structures. In this study, a paired-agent imaging method with direct administration of fluorophores is applied to enhance cranial nerve identification. Here, a control imaging agent (ICG) accounts for non-specific uptake of the nerve-targeting agent (Oxazine 4), and ratiometric data analysis is employed to approximate binding potential (BP, a surrogate of targeted biomolecule concentration). For clinical relevance, animal experiments and simulations were conducted to identify parameters for an optimized stain and rinse protocol using the developed paired-agent method. Numerical methods were used to model the diffusive and kinetic behavior of the imaging agents in tissue, and simulation results revealed that there are various combinations of stain time and rinse number that provide improved contrast of cranial nerves, as suggested by optimal measures of BP and contrast-to-noise ratio.

The role of genetic background in susceptibility to chemical warfare nerve agents across rodent and non-human primate models.

PubMed

Matson, Liana M; McCarren, Hilary S; Cadieux, C Linn; Cerasoli, Douglas M; McDonough, John H

2018-01-15

Genetics likely play a role in various responses to nerve agent exposure, as genetic background plays an important role in behavioral, neurological, and physiological responses to environmental stimuli. Mouse strains or selected lines can be used to identify susceptibility based on background genetic features to nerve agent exposure. Additional genetic techniques can then be used to identify mechanisms underlying resistance and sensitivity, with the ultimate goal of developing more effective and targeted therapies. Here, we discuss the available literature on strain and selected line differences in cholinesterase activity levels and response to nerve agent-induced toxicity and seizures. We also discuss the available cholinesterase and toxicity literature across different non-human primate species. The available data suggest that robust genetic differences exist in cholinesterase activity, nerve agent-induced toxicity, and chemical-induced seizures. Available cholinesterase data suggest that acetylcholinesterase activity differs across strains, but are limited by the paucity of carboxylesterase data in strains and selected lines. Toxicity and seizures, two outcomes of nerve agent exposure, have not been fully evaluated for genetic differences, and thus further studies are required to understand baseline strain and selected line differences. Published by Elsevier B.V.

Development and Structural Modifications of Cholinesterase Reactivators against Chemical Warfare Agents in Last Decade: A Review.

PubMed

Sharma, Rahul; Gupta, Bhanushree; Singh, Namrata; Acharya, J R; Musilek, Kamil; Kuca, Kamil; Ghosh, Kallol Kumar

2015-01-01

Organophosphate (OP) pesticides and nerve agents are responsible for suicidal and accidental poisonings. The acute toxicity of nerve agents leads to progressive inhibition of the enzyme acetylcholinesterase (AChE) by phosphylation of serine residue at the active site of gorge. The recent massive destruction of Syrian civilians by nerve gas sarin, has again renewed the research attention of global science fraternity towards nerve agents, their mode of action and most prominently their therapeutic treatment. This review is principally focused on nerve agent intoxication. The common approach to deal with OP-intoxication is, application of antimuscarinic drug (atropine), anticonvulsant drug (diazepam) and clinically used oximes (pralidoxime, trimedoxime, obidoxime and asoxime). However, the existing therapeutic approach is arguable and has several failings to cure all kinds of nerve agent poisonings. Considering this issue, numerous oximes have been synthesized and screened through various in-vitro and in-vivo studies in last decade to overcome the downsides. At present, only a few oximes (bis pyridinum-oximes) exhibit sound efficacy against selective OPs. In spite of extensive efforts, till date no oxime is available as a universal antidote against all the classes of OPs. This review is centered on the recent developments and structural modification of AChE reactivators against nerve agent toxicity. In particular, a deeper look has been taken into chemical modifications of the reactivators by incorporation of different structural moieties targeted towards the increased reactivation affinity and improved blood brain barrier (BBB) penetration.

Conference on Receptor-Based Biosensors (3rd) Held in Aberdeen Proving Ground, Maryland, September 1987

DTIC Science & Technology

1988-07-01

agents throughout the world had mode the threat to U.S. forces an urgent reality, perhaps more so now than ever. The use of blister and nerve agents ...today we have no capability to detect biological organism, toxins, or anything other then the traditional nerve , blood, and blister type agents . For...anticholinesterase. This kind of result was duplicated by Dr. Valdes at his lab at Edgewood. All the nerve agents that we looked at produced this result

The effects of hemostatic agents on peripheral nerve function: an experimental study.

PubMed

Alkan, Alper; Inal, Samet; Yildirim, Mehmet; Baş, Burcu; Ağar, Erdal

2007-04-01

In the practice of oral and maxillofacial surgery, hemostatic agents are sometimes placed in close proximity to peripheral nerves. In the present study, we evaluated immediate and delayed effects of 4 hemostatic agents (oxidized regenerated cellulose, 5% colloid silver-added gelatine sponge, bovine collagen, bone wax) on peripheral nerve function. A total of 25 rat sciatic nerves were prepared, and the amplitudes were recorded with a physiological data acquisition system. Animals were randomly assigned to 5 groups: control, oxidized regenerated cellulose, gelatine sponge, bone wax, and bovine collagen. The first hour records are defined as immediate effects of these hemostatic agents on nerve function. The animals were then allowed to recover for 4 weeks. At the end of this period, the same surgical and recording procedures were performed. These final records are defined as delayed effects of hemostatic agents on nerve function. According to nerve conduction velocity (NCV) and compound action potential (CAP) values of the experimental groups, early and delayed effects of each hemostatic agent were statistically compared with Bonferroni corrected test (P < .05). Statistically, NCV was significantly reduced, and the CAP was significantly increased 1 hour after surgery (P < .05) in the group of oxidized regenerated cellulose. However, there were no significant differences after 4 weeks compared with the first records. In the gelatine sponge group, CAP was significantly increased 4 weeks after the application. In the bovine collagen and bone wax groups, NCV and CAP values (1 hour and 4 weeks after the application) were not statistically significant compared with initial control records. The present study shows that bovine collagen is the most suitable hemostatic agent applicable for peripheral nerves.

Recent Advances in the Development of Chromophore-Based Chemosensors for Nerve Agents and Phosgene.

PubMed

Chen, Liyan; Wu, Di; Yoon, Juyoung

2018-01-26

The extreme toxicity and ready accessibility of nerve agents and phosgene has caused an increase in the demand to develop effective systems for the detection of these substances. Among the traditional platforms utilized for this purpose, chemosensors including surface acoustic wave (SAW) sensors, enzymes, carbon nanotubes, nanoparticles, and chromophore based sensors have attracted increasing attention. In this review, we describe in a comprehensive manner recent progress that has been made on the development of chromophore-based chemosensors for detecting nerve agents (mimic) and phosgene. This review comprises two sections focusing on studies of the development of chemosensors for nerve agents (mimic) and phosgene. In each of the sections, the discussion follows a format which concentrates on different reaction sites/mechanisms involved in the sensing processes. Finally, chemosensors uncovered in these efforts are compared with those based on other sensing methods and challenges facing the design of more effective chemosensors for the detection of nerve agents (mimic) and phosgene are discussed.

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.

Increasing nerve agent treatment efficacy by P-glycoprotein inhibition.

PubMed

Joosen, Marloes J A; Vester, Stefanie M; Hamelink, Jouk; Klaassen, Steven D; van den Berg, Roland M

2016-11-25

One of the shortcomings of current treatment of nerve agent poisoning is that not all drugs effectively penetrate the blood-brain barrier (BBB), whereas most nerve agents easily do. P-glycoprotein (Pgp) efflux transporters at the BBB may contribute to this aspect. It was previously shown that Pgp inhibition by tariquidar enhanced the efficacy of nerve agent treatment when administered as a pretreatment. In the present study soman-induced seizures were also substantially prevented when the animals were intravenously treated with tariquidar post-poisoning, in addition to HI-6 and atropine. In these animals, approximately twice as much AChE activity was present in their brain as compared to control rats. The finding that tariquidar did not affect distribution of soman to the brain indicates that the potentiating effects were a result of interactions of Pgp inhibition with drug distribution. In line with this, atropine appeared to be a substrate for Pgp in in vitro studies in a MDR1/MDCK cell model. This indicates that tariquidar might induce brain region specific effects on atropine distribution, which could contribute to the therapeutic efficacy increase found. Furthermore, the therapeutic enhancement by tariquidar was compared to that of the less specific and less potent Pgp inhibitor cyclosporine A. This compound appeared to induce a protective effect similar to tariquidar. In conclusion, treatment with a Pgp inhibitor resulted in enhanced therapeutic efficacy of HI-6 and atropine in a soman-induced seizure model in the rat. The mechanism underlying these effects should be further investigated. To that end, the potentiating effect of nerve agent treatment should be addressed against a broader range of nerve agents, for oximes and atropine separately, and for those at lower doses. In particular when efficacy against more nerve agents is shown, a Pgp inhibitor such as tariquidar might be a valid addition to nerve agent antidotes. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

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.

A Gas Chromotographic-Mass Spectrometric Approach to Examining Stereoselective Interaction of Human Plasma Proteins with Soman

DTIC Science & Technology

2008-02-01

ABSTRACT See reprint. 15. SUBJECT TERMS Human plasma proteins, soman, nerve agent , bioscavenger, gas chromatography, mass spectrometry 16. SECURITY...usually referred to as nerve agents ) are tabun (ethyl dimethylamidocyanophosphate, or GA ), sarin (iso- propyl methylfluorophosphonate, or GB), soman...Pharmacology and toxicology of chemical warfare agents Ann. Acad. Med. Singapore 2&: 104-107 (1997). 11. C Macilwain. Study proves Iraq used nerve gas . Nature 3

Proceedings of the Annual Chemical Defense Bioscience Review (5th) Held at Columbia, Maryland on 29-31 May 1985. Appendix 2

DTIC Science & Technology

1985-06-01

biocompatible enzyme-like catalyst for the rapid and specific deactivation of sys- temically sorbed nerve agents . We plan to introduce catalytic groups (thiol...mustard, seizures, respiratory failure, atropine, 2-PAM chloride, neurobehavioral effects, nerve agents , soman, cyanide, animal models, chemical casualties...Animal Model ........ .. A-541 Dr. H.L. Williams Effects of Nerve Agents on the Respiratory and e Cardiovascular Systems

Degradation of Toxic Chemicals by Zero-Valent Metal Nanoparticles - A Literature Review

DTIC Science & Technology

2005-11-01

oxidative reactions. Oxidative reactions are of primary interest to us as they have the potential to degrade organophosphorous nerve agents as well...a) mustard and b) nerve agent (general structure). To decontaminate mustard there are two approaches, dechlorination or oxidation of the sulfur, the...later of which is preferable due to the reversibility of the former. To decontaminate the nerve agents oxidation is required to replace X2, X3 and

The Toxicity of Soman in the African Green Monkey (Chlorocebus aethiops)

DTIC Science & Technology

2007-01-01

M., and Mestries, 1. C. 1998. Nerve agent poisoning in primates: antilethal, anti -epileptic and neuroprotective effects of GK-11. Arch. Toxico/. 72...toxicity in African green monkeys (Chlorocebus aethiops) and is the first step in exploring the suitability of this species as a model for nerve agent ...rhesus monkey (Macaca mulatta) has traditionally served as the NHP research species of choice to assess nerve agent toxicity and the effectiveness of

Quantification of VX Nerve Agent in Various Food Matrices by Solid-Phase Extraction Ultra-Performance Liquid ChromatographyTime-of-Flight Mass Spectrometry

DTIC Science & Technology

2016-04-01

QUANTIFICATION OF VX NERVE AGENT IN VARIOUS FOOD MATRICES BY SOLID-PHASE EXTRACTION ULTRA-PERFORMANCE...TITLE AND SUBTITLE Quantification of VX Nerve Agent in Various Food Matrices by Solid-Phase Extraction Ultra-Performance Liquid Chromatography... food matrices. The mixed-mode cation exchange (MCX) sorbent and Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) methods were used for

Department of Defense Chemical and Biological Defense Program. Volume I: Annual Report to Congress

DTIC Science & Technology

2002-04-01

The M21 RSCAAL is an automatic scanning, passive infrared sensor that detects nerve ( GA , GB, and GD) and blister (H and L) agent vapor clouds based on...Point Detection GA - tabun, a nerve agent System GAO - General Accounting Office IPE - Individual Protective Equipment GAS - Group A Streptococcus...IPR - In-Process Review GB - sarin , a nerve agent IPT - Integrated Product Team GC - gas chromatography IR&D - Independent Research & Development GD

Evaluation of ADD392124 for the Delayed Treatment of Nerve Agent-Induced Status Epilepticus Seizures

DTIC Science & Technology

2011-09-01

Induced Status Epilepticus Seizures John H. McDonough Kerry E. Van Shura Megan E. Lyman Claire G. Eisner Amelia Mazza Robert K. Kan Tsung...TITLE AND SUBTITLE 5a. CONTRACT NUMBER Evaluation of ADD392124 for the delayed treatment of nerve agent-induced status epilepticus seizures 5b... status epilepticus seizures. We evaluated the ability of ADD392124 to control seizures induced by the nerve agent soman. Rats were exposed to a

Nerve Agents: What They Are, How They Work, How to Counter Them.

PubMed

Costanzi, Stefano; Machado, John-Hanson; Mitchell, Moriah

2018-05-16

Nerve agents are organophosphorus chemical warfare agents that exert their action through the irreversible inhibition of acetylcholinesterase, with a consequent overstimulation of cholinergic transmission followed by its shutdown. Beyond warfare, they have notoriously been employed in acts of terrorism as well as high profile assassinations. After a brief historical introduction on the development and deployment of nerve agents, this review provides a survey of their chemistry, the way they affect cholinergic transmission, the available treatment options, and the current directions for their improvement. As the review illustrates, despite their merits, the currently available treatment options present several shortcomings. Current research directions involve the search for improved antidotes, antagonists of the nicotinic receptors, small-molecule pretreatment options, as well as bioscavengers as macromolecular pretreatment options. These efforts are making good progress in many different directions and, hopefully, will lead to a lower target susceptibility, thus reducing the appeal of nerve agents as chemical weapons.

Neurosteroids for the potential protection of humans against organophosphate toxicity.

PubMed

Reddy, Doodipala Samba

2016-08-01

This article describes the therapeutic potential of neurosteroids as anticonvulsant antidotes for chemical intoxication caused by organophosphate pesticides and nerve agents or gases like sarin and soman. Toxic manifestations following nerve agent exposure, as evident in chemical attacks in Japan and Syria, include hypersecretion, respiratory distress, tremors, convulsions leading to status epilepticus (SE), and death. Benzodiazepines, such as diazepam, are the current anticonvulsants of choice for controlling nerve agent-induced life-threatening seizures, SE, and brain injury. Benzodiazepines can control acute seizures when given early, but they are less effective for delayed treatment of SE, which is characterized by rapid desensitization of synaptic GABA A receptors, benzodiazepine resistance, and brain injury. Neurosteroid-sensitive extrasynaptic GABA A receptors, however, remain unaffected by such events. Thus, anticonvulsant neurosteroids may produce more effective protection than benzodiazepines against a broad spectrum of chemical agents, even when given late after nerve agent exposure. © 2016 New York Academy of Sciences.

In Search of an Effective in vivo Reactivator for Organophosphorus Nerve Agent-Inhibited Acetylcholinesterase in the Central Nervous System

DTIC Science & Technology

2012-01-01

monoisonitrosoacetone (MINA) crossed BBB, provided some degree of CNS AChE reactivation, enhanced survival, and mitigated the seizure activity following nerve agent...tissues (brain regions, diaphragm, heart, skeletal muscle) were collected. AChE activity was measured using the Ellman assay. In GB exposure, pro...therapy. Protecting and/or restoring AChE activity in the brain is a major goal in the treatment of nerve agent intoxication. Our long-term goal is to

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.

Effects of low-level exposure to sarin and cyclosarin during the 1991 Gulf War on brain function and brain structure in US veterans.

PubMed

Chao, Linda L; Rothlind, Johannes C; Cardenas, Valerie A; Meyerhoff, Dieter J; Weiner, Michael W

2010-09-01

Potentially more than 100,000 US troops may have been exposed to the organophosphate chemical warfare agents sarin (GB) and cyclosarin (GF) when a munitions dump at Khamisiyah, Iraq was destroyed during the Gulf War (GW) in 1991. Although little is known about the long-term neurobehavioral or neurophysiological effects of low-dose exposure to GB/GF in humans, recent studies of GW veterans from the Devens Cohort suggest decrements in certain cognitive domains and atrophy in brain white matter occur individuals with higher estimated levels of presumed GB/GF exposure. The goal of the current study is to determine the generalizability of these findings in another cohort of GW veterans with suspected GB/GF exposure. Neurobehavioral and imaging data collected in a study on Gulf War Illness between 2002 and 2007 were used in this study. We focused on the data of 40 GW-deployed veterans categorized as having been exposed to GB/GF at Khamisiyah, Iraq and 40 matched controls. Magnetic resonance images (MRI) of the brain were analyzed using automated and semi-automated image processing techniques that produced volumetric measurements of gray matter (GM), white matter (WM), cerebrospinal fluid (CSF) and hippocampus. GW veterans with suspected GB/GF exposure had reduced total GM and hippocampal volumes compared to their unexposed peers (p< or =0.01). Although there were no group differences in measures of cognitive function or total WM volume, there were significant, positive correlations between total WM volume and measures of executive function and visuospatial abilities in veterans with suspected GB/GF exposure. These findings suggest that low-level exposure to GB/GF can have deleterious effects on brain structure and brain function more than decade later. Copyright © 2010 Elsevier Inc. All rights reserved.

Polymeric Sorbent with Controlled Surface Polarity: An Alternate for Solid-Phase Extraction of Nerve Agents and Their Markers from Organic Matrix.

PubMed

Roy, Kanchan Sinha; Purohit, Ajay Kumar; Chandra, Buddhadeb; Goud, D Raghavender; Pardasani, Deepak; Dubey, Devendra Kumar

2018-06-05

Extraction and identification of lethal nerve agents and their markers in complex organic background have a prime importance from the forensic and verification viewpoint of the Chemical Weapons Convention (CWC). Liquid-liquid extraction with acetonitrile and commercially available solid phase silica cartridges are extensively used for this purpose. Silica cartridges exhibit limited applicability for relatively polar analytes, and acetonitrile extraction shows limited efficacy toward relatively nonpolar analytes. The present study describes the synthesis of polymeric sorbents with tunable surface polarity, their application as a solid-phase extraction (SPE) material against nerve agents and their polar as well as nonpolar markers from nonpolar organic matrices. In comparison with the acetonitrile extraction and commercial silica cartridges, the new sorbent showed better extraction efficiency toward analytes of varying polarity. The extraction parameters were optimized for the proposed method, which included ethyl acetate as an extraction solvent and n-hexane as a washing solvent. Under optimized conditions, method linearity ranged from 0.10 to 10 μg mL -1 ( r 2 = 0.9327-0.9988) for organophosphorus esters and 0.05-20 μg mL -1 ( r 2 = 0.9976-0.9991) for nerve agents. Limits of detection (S:N = 3:1) in the SIM mode were found in the range of 0.03-0.075 μg mL -1 for organophosphorus esters and 0.015-0.025 μg mL -1 for nerve agents. Limits of quantification (S:N = 10:1) were found in the range of 0.100-0.25 μg mL -1 for organophosphorus esters and 0.05-0.100 μg mL -1 for nerve agents in the SIM mode. The recoveries of the nerve agents and their markers ranged from 90.0 to 98.0% and 75.0 to 95.0% respectively. The repeatability and reproducibility (with relative standard deviations (RSDs) %) for organophosphorus esters were found in the range of 1.35-8.61% and 2.30-9.25% respectively. For nerve agents, the repeatability range from 1.00 to 7.75% and reproducibility were found in the range of 2.17-6.90%.

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.

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

Proceedings of the Army Science Conference (15th) Held at West Point, New York on 17-19 June 1986. Volume 2. Principal Authors H through L.

DTIC Science & Technology

1986-06-20

Page Leonard, Joseph M. See Seiders, Barbara A. B. V 189 Linden, Carol D. See Canonico, Peter G. 1 127 Little, James S. A Potential Nerve Agent II 271...Semi-Automated System for Testing 11 235 Waring, Paul P. the Efficacy of Nerve Agent Hawkins, George S. Protection/Decontamination Powanda, Michael...potential uses. Among them are: 1) detection of organofluoro- phosphate chemicals, 2) non-corrosive decontamination of nerve agent mate- rials

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 yielded two types of adducts, one of which was thiomethyl phosphonate, a modification not found after treatment with authentic soman and sarin.

Changes in Extracellular Striatal Acetylcholine and Brain Seizure Activity Following Acute Exposure to Nerve Against in Freely Moving Guinea Pigs

DTIC Science & Technology

2010-01-01

Literature 3. DATES COVERED (From - To) 4. TITLE AND SUBTITLE Changes in extracellular striatal acetylcholine and brain seizure activity following...Acetylcholine, acetylcholinesterase, choline, guinea pig, in vivo microdialysis, nerve agents, organophosphorus compounds, sarin, seizure activity ...RESEARCH ARTICLE Changes in extracellular striatal acetylcholine and brain seizure activity following acute exposure to nerve agents in freely

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Collombet, Jean-Marc, E-mail: jmcollombet@imassa.fr

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 increasedmore » 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.« less

Neurosciences and research on chemical weapons of mass destruction in Nazi Germany.

PubMed

Schmaltz, Florian

2006-09-01

As a side-product of industrial research, new chemical nerve agents (Tabun, Sarin, Soman) superior to those available to the Allied Forces were discovered in Nazi Germany. These agents were never used by Germany, even though they were produced at a large scale. This article explores the toxicological and physiological research into the mechanisms of action of these novel nerve agents, and the emergence of military research objectives in neurophysiological and neurotoxicological research. Recently declassified Allied military intelligence files document secret nerve agent research, leading to intensified research on anticholinesterase agents in the peripheral and the central nervous system. The article discusses the involvement of IG Farben scientists, educational, medical and military institutions, and of Nobel Prize laureate Richard Kuhn, director of the Kaiser Wilhelm Institute for Medical Research.

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...

Post-exposure therapy with recombinant human BuChE following percutaneous VX challenge in guinea-pigs

PubMed Central

Mumford, Helen; Troyer, John K.

2011-01-01

Poisoning by nerve agents via the percutaneous (p.c.) route is an issue because the slow absorption of agent could result in poisoning which outlasts the protection provided by conventional pharmacological therapy. The bioscavenger approach is based on the concept of binding nerve agent in the bloodstream, thus preventing nerve agent from reaching the target tissues and inhibiting acetylcholinesterase activity. One bioscavenger that has been extensively studied is human butyrylcholinesterase (huBuChE). Protexia® is a pegylated form of recombinant huBuChE. We used a guinea-pig model of p.c. nerve agent poisoning, using an implanted telemetry system to collect physiological data. Guinea-pigs were poisoned with the nerve agent VX (0.74 mg/kg) (~2.5×LD50). Two hours following VX exposure, Protexia (72 mg/kg) or saline control was administered intramuscularly. All guinea-pigs treated with Protexia (n=8) survived, compared to no survivors in a saline-treated control group (n=8). Survival following VX and Protexia treatment was associated with minimal incapacitation and observable signs of poisoning, and the mitigation or prevention of the detrimental physiological changes (e.g. seizure, bradycardia and hypothermia) observed in control animals. The opportunity for post-exposure treatment may have utility in both civilian and military scenarios, and this is a promising indication for the use of a bioscavenger. PMID:21620937

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.

Crystal Structures of Human Carboxylesterase 1 in Covalent Complexes with the Chemical Warfare Agents Soman and Tabun†,‡

PubMed Central

Fleming, Christopher D.; Edwards, Carol C.; Kirby, Stephen D.; Maxwell, Donald M.; Potter, Philip M.; Cerasoli, Douglas M.; Redinbo, Matthew R.

2008-01-01

The organophosphorus nerve agents sarin, soman, tabun, and VX exert their toxic effects by inhibiting the action of human acetylcholinesterase, a member of the serine hydrolase superfamily of enzymes. The current treatments for nerve agent exposure must be administered quickly to be effective and they often do not eliminate long-term toxic side effects associated with organophosphate poisoning. Thus, there is significant need for effective prophylactic methods to protect at-risk personnel from nerve agent exposure, and protein-based approaches have emerged as promising candidates. We present the 2.7 Å resolution crystal structures of the serine hydrolase human carboxylesterase 1 (hCE1), a broad-spectrum drug metabolism enzyme, in covalent acyl-enzyme intermediate complexes with the chemical weapons soman and tabun. The structures reveal that hCE1 binds stereoselectively to these nerve agents; for example, hCE1 appears to react preferentially with the 104-fold more lethal PS stereoisomer of soman relative to the PR form. In addition, structural features of the hCE1 active site indicate that the enzyme may be resistant to dead-end organophosphate aging reactions that permanently inactivate other serine hydrolases. Taken together, these data provide important structural details toward the goal of engineering hCE1 into an organophosphate hydrolase and protein-based therapeutic for nerve agent exposure. PMID:17407327

Best time window for the use of calcium-modulating agents to improve functional recovery in injured peripheral nerves-An experiment in rats.

PubMed

Yan, Yuhui; Shen, Feng-Yi; Agresti, Michael; Zhang, Lin-Ling; Matloub, Hani S; LoGiudice, John A; Havlik, Robert; Li, Jifeng; Gu, Yu-Dong; Yan, Ji-Geng

2017-09-01

Peripheral nerve injury can have a devastating effect on daily life. Calcium concentrations in nerve fibers drastically increase after nerve injury, and this activates downstream processes leading to neuron death. Our previous studies showed that calcium-modulating agents decrease calcium accumulation, which aids in regeneration of injured peripheral nerves; however, the optimal therapeutic window for this application has not yet been identified. In this study, we show that calcium clearance after nerve injury is positively correlated with functional recovery in rats suffering from a crushed sciatic nerve injury. After the nerve injury, calcium accumulation increased. Peak volume is from 2 to 8 weeks post injury; calcium accumulation then gradually decreased over the following 24-week period. The compound muscle action potential (CMAP) measurement from the extensor digitorum longus muscle recovered to nearly normal levels in 24 weeks. Simultaneously, real-time polymerase chain reaction results showed that upregulation of calcium-ATPase (a membrane protein that transports calcium out of nerve fibers) mRNA peaked at 12 weeks. These results suggest that without intervention, the peak in calcium-ATPase mRNA expression in the injured nerve occurs after the peak in calcium accumulation, and CMAP recovery continues beyond 24 weeks. Immediately using calcium-modulating agents after crushed nerve injury improved functional recovery. These studies suggest that a crucial time frame in which to initiate effective clinical approaches to accelerate calcium clearance and nerve regeneration would be prior to 2 weeks post injury. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Stabilizing Acetylcholinesterase on Carbon Electrodes Using Peptide Nanotubes to Produce Effective Biosensors

DTIC Science & Technology

2012-03-22

of pesticide . Plans for the cleanup of nerve gas attacks involve hosing affected areas down with bleach and water, which may also lead to water...They have been widely used in agriculture as pesticides and are also used as deadly nerve agents in chemical weapons. Chromatography and...Amperometric Detection of Organophosphorus Pesticides and Nerve Agents ,” Electroanalysis 16, Nos. 1-2: 145-149 (2004). Norouzi, Parviz, Farnoush

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

DTIC Science & Technology

2010-01-01

hese findings support previous reports that protection of ChE nzyme activity in the brain as well as in peripheral tissues with entrally acting... activity . Animals were injected s.c. with either saline (0.5ml/kg) or a 1.0× LD50 dose of GB (42.0g/kg), GF (57.0g/kg), or VX (8.0g/kg). The severity...of toxic signs of each animal was scored at 13min after nerve agent. Fifteen minutes after nerve agent injection, when the inhibition of ChE activity

Toxicity of the Organophosphate Chemical Warfare Agents GA, GB, and VX: Implications for Public Protection.

PubMed Central

Munro, N

1994-01-01

The nerve agents, GA, GB, and VX are organophosphorus esters that form a major portion of the total agent volume contained in the U.S. stockpile of unitary chemical munitions. Congress has mandated the destruction of these agents, which is currently slated for completion in 2004. The acute, chronic, and delayed toxicity of these agents is reviewed in this analysis. The largely negative results from studies of genotoxicity, carcinogenicity, developmental, and reproductive toxicity are also presented. Nerve agents show few or delayed effects. At supralethal doses, GB can cause delayed neuropathy in antidote-protected chickens, but there is no evidence that it causes this syndrome in humans at any dose. Agent VX shows no potential for inducing delayed neuropathy in any species. In view of their lack of genotoxcity, the nerve agents are not likely to be carcinogens. The overreaching concern with regard to nerve agent exposure is the extraordinarily high acute toxicity of these substances. Furthermore, acute effects of moderate exposure such as nausea, diarrhea, inability to perform simple mental tasks, and respiratory effects may render the public unable to respond adequately to emergency instructions in the unlikely event of agent releaase, making early warning and exposure avoidance important. Likewise, exposure or self-contamination of first responders and medical personnel must be avoided. Control limits for exposure via surface contact of drinking water are needed, as are detection methods for low levels in water or foodstuffs. Images Figure 2. PMID:9719666

Stoichiometric and catalytic scavengers as protection against nerve agent toxicity: a mini review.

PubMed

Lenz, David E; Yeung, David; Smith, J Richard; Sweeney, Richard E; Lumley, Lucille A; Cerasoli, Douglas M

2007-04-20

Currently fielded treatments for nerve agent intoxication promote survival, but do not afford complete protection against either nerve agent-induced motor and cognitive deficits or neuronal pathology. The use of human plasma-derived butyrylcholinesterase (HuBuChE) to neutralize the toxic effects of nerve agents in vivo has been shown to both aid survival and protect against decreased cognitive function after nerve agent exposure. Recently, a commercially produced recombinant form of human butyrylcholinesterase (r-HuBuChE; PharmAthene Inc.) expressed in the milk of transgenic goats has become available. This material is biochemically similar to plasma-derived HuBuChE in in vitro assays. The pharmacokinetic characteristics of a polyethylene glycol coated (pegylated) form of r-HuBuChE were determined in guinea pigs; the enzyme was rapidly bioavailable with a half-life (t(1/2)) and pharmacokinetic profile that resembled that of plasma-derived huBuChE. Guinea pigs were injected with 140mg/kg (i.m.) of pegylated r-HuBuChE 18h prior to exposure (sc) to 5.5xLD(50) VX or soman. VX and soman were administered in a series of three injections of 1.5xLD(50), 2.0xLD(50), and 2.0xLD(50), respectively, with injections separated by 2h. Pretreatment with pegylated r-HuBuChE provided 100% survival against multiple lethal doses of VX and soman. Guinea pigs displayed no signs of nerve agent toxicity following exposure. Assessments of motor activity, coordination, and acquisition of spatial memory were performed for 2 weeks following nerve agent exposure. There were no measurable decreases in motor or cognitive function during this period. In contrast, animals receiving 1.5xLD(50) challenges of soman or VX and treated with standard atropine, 2-PAM, and diazepam therapy showed 50 and 100% survival, respectively, but exhibited marked decrements in motor function and, in the case of GD, impaired spatial memory acquisition. The advances in this field have resulted in the decision to select both the plasma-derived and the recombinant form of BuChE for advanced development and transition to clinical trials. Efforts have now been expanded to identify a catalytic protein capable of not only binding, but also rapidly hydrolyzing the standard threat nerve agents. Recent work has focused on paraoxonase-1 (PON1), a naturally occurring human serum enzyme with the capacity to catalyze the hydrolysis of nerve agents, albeit too slowly to afford dramatic protection. Using rational design, several amino acids involved in substrate binding have been identified and site-directed mutations have revealed that residue H115 plays an important role in binding. In addition, the stereospecificity of PON1 for the catalytic hydrolysis of soman has been examined. The enzyme exhibits a slight stereospecificity for the C+P+ isomer of soman, which is due more to preferential binding than to selective hydrolysis of this isomer. The results suggest that it may be possible to engineer a mutant form of PON1 with enhanced activity and stereospecificity for the most toxic nerve agent isoforms.

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...

Soman increases neuronal COX-2 levels: possible link between seizures and protracted neuronal damage.

PubMed

Angoa-Pérez, Mariana; Kreipke, Christian W; Thomas, David M; Van Shura, Kerry E; Lyman, Megan; McDonough, John H; Kuhn, Donald M

2010-12-01

Nerve agent-induced seizures cause neuronal damage in brain limbic and cortical circuits leading to persistent behavioral and cognitive deficits. Without aggressive anticholinergic and benzodiazepine therapy, seizures can be prolonged and neuronal damage progresses for extended periods of time. The objective of this study was to determine the effects of the nerve agent soman on expression of cyclooxygenase-2 (COX-2), the initial enzyme in the biosynthetic pathway of the proinflammatory prostaglandins and a factor that has been implicated in seizure initiation and propagation. Rats were exposed to a toxic dose of soman and scored behaviorally for seizure intensity. Expression of COX-2 was determined throughout brain from 4h to 7 days after exposure by immunohistochemistry and immunoblotting. Microglial activation and astrogliosis were assessed microscopically over the same time-course. Soman increased 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 induced in neurons, and not in microglia or astrocytes, and remained elevated through 7 days. The magnitude of COX-2 induction was correlated with seizure intensity. COX-1 expression was not changed by soman. Increased expression of neuronal COX-2 by soman is a late-developing response relative to other signs of acute physiological distress caused by nerve agents. COX-2-mediated production of prostaglandins is a consequence of the seizure-induced neuronal damage, even after survival of the initial cholinergic crisis is assured. COX-2 inhibitors should be considered as adjunct therapy in nerve agent poisoning to minimize nerve agent-induced seizure activity. Published by Elsevier B.V.

Acute toxicity of organophosphorus compounds in guinea pigs is sex- and age-dependent and cannot be solely accounted for by acetylcholinesterase inhibition.

PubMed

Fawcett, William P; Aracava, Yasco; Adler, Michael; Pereira, Edna F R; Albuquerque, Edson X

2009-02-01

This study was designed to test the hypothesis that the acute toxicity of the nerve agents S-[2-(diisopropylamino)ethyl]-O-ethyl methylphosphonothioate (VX), O-pinacolyl methylphosphonofluoridate (soman), and O-isopropyl methylphosphonofluoridate (sarin) in guinea pigs is age- and sex-dependent and cannot be fully accounted for by the irreversible inhibition of acetylcholinesterase (AChE). The subcutaneous doses of nerve agents needed to decrease 24-h survival of guinea pigs by 50% (LD(50) values) were estimated by probit analysis. In all animal groups, the rank order of LD(50) values was sarin > soman > VX. The LD(50) value of soman was not influenced by sex or age of the animals. In contrast, the LD(50) values of VX and sarin were lower in adult male than in age-matched female or younger guinea pigs. A colorimetric assay was used to determine the concentrations of nerve agents that inhibit in vitro 50% of AChE activity (IC(50) values) in guinea pig brain extracts, plasma, red blood cells, and whole blood. A positive correlation between LD(50) values and IC(50) values for AChE inhibition would support the hypothesis that AChE inhibition is a major determinant of the acute toxicity of the nerve agents. However, such a positive correlation was found only between LD(50) values and IC(50) values for AChE inhibition in brain extracts from neonatal and prepubertal guinea pigs. These results demonstrate for the first time that the lethal potencies of some nerve agents in guinea pigs are age- and sex-dependent. They also support the contention that mechanisms other than AChE inhibition contribute to the lethality of nerve agents.

Zirconium Hydroxide-coated Nanofiber Mats for Nerve Agent Decontamination.

PubMed

Kim, Sohee; Ying, Wu Bin; Jung, Hyunsook; Ryu, Sam Gon; Lee, Bumjae; Lee, Kyung Jin

2017-03-16

Diverse innovative fabrics with specific functionalities have been developed for requirements such as self-decontamination of chemical/biological pollutants and toxic nerve agents. In this work, Zr(OH) 4 -coated nylon-6,6 nanofiber mats were fabricated for the decontamination of nerve agents. Nylon-6,6 fabric was prepared via the electrospinning process, followed by coating with Zr(OH) 4 , which was obtained by the hydrolysis of Zr(OBu) 4 by a sol-gel reaction on nanofiber surfaces. The reaction conditions were optimized by varying the amounts of Zr(OBu) 4 ,the reaction time, and the temperature of the sol-gel reaction. The composite nanofibers show high decontamination efficiency against diisopropylfluorophosphate, which is a nerve agent analogue, due to its high nucleophilicity that aids in the catalysis of the hydrolysis of the phosphonate ester bonds. Composite nanofiber mats have a large potential and can be applied in specific fields such as military and medical markets. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Vesicants and nerve agents in chemical warfare. Decontamination and treatment strategies for a changed world.

PubMed

Devereaux, Asha; Amundson, Dennis E; Parrish, J S; Lazarus, Angeline A

2002-10-01

Vesicants and nerve agents have been used in chemical warfare for ages. They remain a threat in today's altered political climate because they are relatively simple to produce, transport, and deploy. Vesicants, such as mustard and lewisite, can affect the skin, eyes, respiratory system, and gastrointestinal system. They leave affected persons at risk for long-term effects. Nerve agents, such as tabun, sarin, soman, and VX, hyperstimulate the muscarinic and nicotinic receptors of the nervous system. Physicians need to familiarize themselves with the clinical findings of such exposures and the decontamination and treatment strategies necessary to minimize injuries and deaths.

Midazolam: An Improved Anticonvulsant Treatment for Nerve Agent-Induced Seizures

DTIC Science & Technology

2002-01-01

variety of compounds that different authors had championed as being capable of stopping or moderating nerve agent seizures (e.g., memantine , clonidine...e.g., memantine , neuroactive steroids; EEG seizures were still evident) or required such a narrow dose range or specific treatment conditions that

Army Science Conference Proceedings, 12-15 June 1990, Volume 2: Principal Authors G-M

DTIC Science & Technology

1990-07-30

The Excitatory Amino Acid Antagonist MK-801 Prevents Nerve Agent -induced Neuropathology Even When Given After the Onset of Convulsions See Johnson...Smejkal, Ruthann M. See Sharp, Edward J. See O’Neill, Timothy R. See Coffee, Terence P. Oxidative Decontamination of the Chemical Nerve Agent See...190, 1955. 5 Hoskin, F. C. G.,and Roush, A. H. "Hydrolysis of Nerve Gas by Squid Type Diisopropylphosphorofluoridate Hydrolyzing Enzyme on Agarose

[Perspectives in the treatments of poisonings by organophosphorus insecticides and warfare nerve agents].

PubMed

Sogorb-Sánchez, M A; Vilanova-Gisbert, E; Carrera-González, V

Organophosphorus compounds are worldwide employed as insecticides and are yearly responsible of several millions of poisonings. The chemical structure of most of the warfare nerve agents also corresponds with an organophosphorus compound. Organophosphorus insecticides and warfare nerve agents exert their main toxicological effects through inhibition of acetylcholinesterase. Current treatments of patients poisoned with organophosphorus compounds include atropine (in order to protect muscarinic receptors), oximes (in order to accelerate the reactivation of the inhibited acetylcholinesterase) and benzodiazepines (in order to avoid convulsions). The administration of phosphotriesterases (enzymes involved in the detoxication of organophosphorus compounds through hydrolysis) is a very effective treatment against poisonings by organophosphorus insecticides and warfare nerve agents. There are experimental preventive treatments based on the simultaneous administration of carbamates and certain antimuscarinic drugs, different from atropine, which notably improve the efficacy of the classical treatments applied after poisonings by warfare nerve agents. The treatments based in the administration of phosphotriesterases might be the response to the call of the World Health Organization for searching new treatments with capability to reduce the high mortality recorded in the cases of poisonings by organophosphorus compounds. These treatments can be applied in a preventive way without the intrinsic neurotoxicity associated to the preventive treatments based on carbamates and antimuscarinic drugs. Therefore, these treatments are specially interesting for people susceptible to suffer severe exposures, i.e. sprayers in the farms.

Department of Defense Chemical, Biological, Radiological, and Nuclear Defense Program, Annual Report to Congress, 2004

DTIC Science & Technology

2004-05-01

foldable/ portable emergency smoke hoods with extended gas sorption capabilities and regenerable, biological pathogen-destroying and gas-sorbing...traditional agents. • Cyanide Countermeasures – Potential pretreatment compounds (e.g., methemoglobin formers and sulfide donors) and regimen are being...evaluated for safety and efficacy as pretreatments. • Nerve agent antidotes – New nerve agent antidote compounds that are water soluble, have a broader

Identification and Characterization of Novel Catalytic Bioscavengers of Organophosphorus Nerve Agents

DTIC Science & Technology

2013-01-01

hydrolase activity . These strains are Ammoniphilus oxalaticus, Haloarcula sp., and Micromonospora aurantiaca. Lysates from A. oxalaticus had...warfare agents [1–3]. OP nerve agents readily bind covalently to the active site serine in acetylcho- linesterase (AChE), thereby inhibiting the ability...muscarinic receptors, whereas 2-pralidoxime chloride, an oxime nucleophile, reactivates AChE by displacing the phospho- nyl group left on the active site

Toxicology of organophosphorus compounds in view of an increasing terrorist threat.

PubMed

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

2016-09-01

The implementation of the Chemical Weapon Convention (CWC), prohibiting the development, production, storage and use of chemical weapons by 192 nations and the ban of highly toxic OP pesticides, especially class I pesticides according to the WHO classification, by many countries constitutes a great success of the international community. However, the increased interest of terrorist groups in toxic chemicals and chemical warfare agents presents new challenges to our societies. Almost seven decades of research on organophosphorus compound (OP) toxicology was mainly focused on a small number of OP nerve agents despite the fact that a huge number of OP analogues, many of these agents having comparable toxicity to classical nerve agents, were synthesized and published. Only limited physicochemical, toxicological and medical information on nerve agent analogues is available in the open literature. This implies potential gaps of our capabilities to detect, to decontaminate and to treat patients if nerve agent analogues are disseminated and may result in inadequate effectiveness of newly developed countermeasures. In summary, our societies may face new, up to now disregarded, threats by toxic OP which calls for increased awareness and appropriate preparedness of military and civilian CBRN defense, a broader approach for new physical and medical countermeasures and an integrated system of effective detection, decontamination, physical protection and treatment.

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 ...

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...

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

USDA-ARS?s Scientific Manuscript database

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 ...

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

USDA-ARS?s Scientific Manuscript database

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 ...

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....

Using Nanotechnology to Detect Nerve Agents

DTIC Science & Technology

2011-01-01

56 | Air & Space Power Journal Air Force Institute of Technology Using Nanotechnology to Detect Nerve Agents Lt Col Mark N. Goltz , PhD, USAF...Retired Dr. Dong Shik Kim Maj LeeAnn Racz, PhD, USAF* *Lieutenant Colonel Goltz and Major Racz are faculty members in the Department of Systems and

Proceedings of the U.S. Army Chemical Research, Development and Engineering Center Scientific Conference on Chemical Defense Research Held in Aberdeen Proving Ground, Maryland on 14-17 November 1989

DTIC Science & Technology

1990-08-01

to react in a similar electrochemical manner to the agent 2,21- dichlorodiethylsulfide (Mustard gas or HD). As a simulant for the nerve agents ...attack which may permit effective discrimination of pesticides from nerve agents in a chemical agent detector. Table 1 shows the results of film badge...amount of CASARM agent ( GA , GB, HD or VX) was placed into a 5 mm O.D. Pyrex NMR tube and 1.0 ml of the decontaminating solution was added. The tube was

Polarimetry and infrared spectroscopy in the detection of low-volatility chemical threats

NASA Astrophysics Data System (ADS)

Petryk, Michael W. P.; Marenco, Armando J.

2011-05-01

The polarization modulation infrared reflection absorption spectroscopy (PMIRRAS) spectra of the nerve agents GB (O-isopropyl methylphosphonofluoridate) and GF (cyclohexyl methylphoshonofluoridate) were recorded for the first time. A comparison of these spectra with the nerve agent VX (ethyl S-2-diisopropylaminoethyl methylphosphonothiolate) and the spectra of some trialkyl phosphates indicates that it is easy to distinguish between chemical warfare agents and simulants on militarily-relevant surfaces using PMIRRAS.

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

DTIC Science & Technology

2014-08-01

chemical warfare nerve agents (CWNA). Enzymes identified in these screens should be capable of catalytically neutralizing the target agent under...soluble form. 4. Large-scale production of selected enzyme candidates, and their kinetic, structural and pharmacological evaluation 6...employed, with an enzyme protein concentration of 0.5-2 mM in the assay cuvette, the activity measured was indistinguishable from the rate of

Effects of low-level sarin and cyclosarin exposure and Gulf War Illness on brain structure and function: a study at 4T.

PubMed

Chao, Linda L; Abadjian, Linda; Hlavin, Jennifer; Meyerhoff, Deiter J; Weiner, Michael W

2011-12-01

More than 100,000 US troops were potentially exposed to chemical warfare agents sarin (GB) and cyclosarin (GF) when an ammunition dump at Khamisiyah, Iraq was destroyed during the 1991 Persian Gulf War (GW). We previously found reduced total gray matter (GM) volume in 40 GW veterans with suspected GB/GF exposure relative to 40 matched, unexposed GW veterans on a 1.5T MR scanner. In this study, we reexamine the relationship between GB/GF exposure and volumetric measurements of gross neuroanatomical structures in a different cohort of GW veterans on a 4T MR scanner. Neuropsychological and magnetic resonance imaging (MRI) data from a cross sectional study on Gulf War Illness performed between 2005 and 2010 were used in this study. 4T MRI data were analyzed using automated image processing techniques that produced volumetric measurements of gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF). Binary comparisons of 64 GB/GF exposed veterans and 64 'matched', unexposed veterans revealed reduced GM (p=0.03) and WM (p=0.03) volumes in the exposed veterans. Behaviorally, exposed veterans committed more errors of omission (p=0.02) and tended to have slower responses (p=0.05) than unexposed veterans on the Continuous Performance Test (CPT), a measure sustained and selective attention. Regression analyses confirmed that GB/GF exposure status predicted GM (β=-0.11, p=0.02) and WM (β=-0.14, p=0.03) volumes, and number of CPT omission errors (β=0.22, p=0.02) over and above potentially confounding demographic, clinical, and psychosocial variables. There was no dose-response relationship between estimated levels of GB/GF exposure and brain volume. However, we did find an effect of Gulf War Illness/Chronic Multisymptom Illness on both GM and WM volume in the GB/GF exposed veterans. These findings confirm previous reports by our group and others of central nervous system pathology in GW veterans with suspected exposure to low levels of GB/GF two decades after the exposure. Copyright © 2011 Elsevier Inc. All rights reserved.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Samanta, Uttamkumar; Kirby, Stephen D.; Srinivasan, Prabhavathi

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{submore » 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.« less

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

PubMed

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

2009-08-15

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(R) and P(S) stereoisomers at the P-chiral center. The tabun complex displayed only the P(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.

Evolution of and perspectives on therapeutic approaches to nerve agent poisoning.

PubMed

Masson, Patrick

2011-09-25

After more than 70 years of considerable efforts, research on medical defense against nerve agents has come to a standstill. Major progress in medical countermeasures was achieved between the 50s and 70s with the development of anticholinergic drugs and carbamate-based pretreatment, the introduction of pyridinium oximes as antidotes, and benzodiazepines in emergency treatments. These drugs ensure good protection of the peripheral nervous system and mitigate the acute effects of exposure to lethal doses of nerve agents. However, pyridostigmine and cholinesterase reactivators currently used in the armed forces do not protect/reactivate central acetylcholinesterases. Moreover, other drugs used are not sufficiently effective in protecting the central nervous system against seizures, irreversible brain damages and long-term sequelae of nerve agent poisoning.New developments of medical counter-measures focus on: (a) detoxification of organophosphorus molecules before they react with acetylcholinesterase and other physiological targets by administration of stoichiometric or catalytic scavengers; (b) protection and reactivation of central acetylcholinesterases, and (c) improvement of neuroprotection following delayed therapy.Future developments will aim at treatment of acute and long-term effects of low level exposure to nerve agents, research on alternative routes for optimizing drug delivery, and therapies. Though gene therapy for in situ generation of bioscavengers, and cell therapy based on neural progenitor engraftment for neuronal regeneration have been successfully explored, more studies are needed before practical medical applications can be made of these new approaches. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

History and perspectives of bioanalytical methods for chemical warfare agent detection.

PubMed

Black, Robin M

2010-05-15

This paper provides a short historical overview of the development of bioanalytical methods for chemical warfare (CW) agents and their biological markers of exposure, with a more detailed overview of methods for organophosphorus nerve agents. Bioanalytical methods for unchanged CW agents are used primarily for toxicokinetic/toxicodynamic studies. An important aspect of nerve agent toxicokinetics is the different biological activity and detoxification pathways for enantiomers. CW agents have a relatively short lifetime in the human body, and are hydrolysed, metabolised, or adducted to nucleophilic sites on macromolecules such as proteins and DNA. These provide biological markers of exposure. In the past two decades, metabolites, protein adducts of nerve agents, vesicants and phosgene, and DNA adducts of sulfur and nitrogen mustards, have been identified and characterized. Sensitive analytical methods have been developed for their detection, based mainly on mass spectrometry combined with gas or liquid chromatography. Biological markers for sarin, VX and sulfur mustard have been validated in cases of accidental and deliberate human exposures. The concern for terrorist use of CW agents has stimulated the development of higher throughput analytical methods in support of homeland security. Copyright (c) 2010. Published by Elsevier B.V.

Detection of nerve gases using surface-enhanced Raman scattering substrates with high droplet adhesion

NASA Astrophysics Data System (ADS)

Hakonen, Aron; Rindzevicius, Tomas; Schmidt, Michael Stenbæk; Andersson, Per Ola; Juhlin, Lars; Svedendahl, Mikael; Boisen, Anja; Käll, Mikael

2016-01-01

Threats from chemical warfare agents, commonly known as nerve gases, constitute a serious security issue of increasing global concern because of surging terrorist activity worldwide. However, nerve gases are difficult to detect using current analytical tools and outside dedicated laboratories. Here we demonstrate that surface-enhanced Raman scattering (SERS) can be used for sensitive detection of femtomol quantities of two nerve gases, VX and Tabun, using a handheld Raman device and SERS substrates consisting of flexible gold-covered Si nanopillars. The substrate surface exhibits high droplet adhesion and nanopillar clustering due to elasto-capillary forces, resulting in enrichment of target molecules in plasmonic hot-spots with high Raman enhancement. The results may pave the way for strategic life-saving SERS detection of chemical warfare agents in the field.Threats from chemical warfare agents, commonly known as nerve gases, constitute a serious security issue of increasing global concern because of surging terrorist activity worldwide. However, nerve gases are difficult to detect using current analytical tools and outside dedicated laboratories. Here we demonstrate that surface-enhanced Raman scattering (SERS) can be used for sensitive detection of femtomol quantities of two nerve gases, VX and Tabun, using a handheld Raman device and SERS substrates consisting of flexible gold-covered Si nanopillars. The substrate surface exhibits high droplet adhesion and nanopillar clustering due to elasto-capillary forces, resulting in enrichment of target molecules in plasmonic hot-spots with high Raman enhancement. The results may pave the way for strategic life-saving SERS detection of chemical warfare agents in the field. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr06524k

Developmental Toxic Effects of Exposure to Chemical Warfare Nerve Agents in Rats: Effects on Brain and Behavior

DTIC Science & Technology

2015-03-01

Analysis of seizure activity and dendritic spine density following exposure to sarin during puberty Methods Female rats were surgically implanted...effects were observed in rats exposed to GB on PND 7 or 21. This study shows that nerve agent exposure during puberty results in severe and life

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...XX-01-2016 2. REPORT TYPE Final 3. DATES COVERED (From - To) Jan – Jun 2015 4. TITLE AND SUBTITLE Using NMR Spectroscopy to Investigate the...MOLECULAR MOTIONS AND NMR SPECTROSCOPY ...................................................................................................3 4. THE

Chemical warfare and the Gulf War: a review of the impact on Gulf veterans' health.

PubMed

Riddle, James R; Brown, Mark; Smith, Tyler; Ritchie, Elspeth Cameron; Brix, Kelley Ann; Romano, James

2003-08-01

It is unlikely that Gulf War veterans are suffering chronic effects from illnesses caused by chemical warfare nerve agent exposure. Extensive investigation and review by several expert panels have determined that no evidence exists that chemical warfare nerve agents were used during the Gulf War. At no time before, during, or after the war was there confirmation of symptoms among anyone, military or civilian, caused by chemical warfare nerve agent exposure. However, studies of Gulf War veterans have found belief that chemical weapons were used, significantly associated with both severe and mild-moderate illnesses. The psychological impact of a chemical warfare attack, either actual or perceived, can result in immediate and long-term health consequences. The deployment or war-related health impact from life-threatening experiences of the Gulf War, including the perceived exposure to chemical warfare agents, should be considered as an important cause of morbidity among Gulf War veterans.

Modification of human serum albumin by the nerve agent VX: microbore liquid chromatography/electrospray ionization high-resolution time-of-flight tandem mass spectrometry method for detection of phosphonylated tyrosine and novel cysteine containing disulfide adducts.

PubMed

Kranawetvogl, Andreas; Worek, Franz; Thiermann, Horst; John, Harald

2016-10-15

Organophosphorus nerve agents still constitute a considerable threat to the health of military personnel and the civilian population. Long-term biomarkers are crucial for reliable verification of exposure to banned substances. Therefore, current research focuses on identification of endogenous protein targets showing covalent modifications by organophosphorus nerve agents (adducts). Purified human serum albumin and human plasma were incubated with the nerve agent VX followed by enzymatic proteolysis with pronase. Resulting peptide cleavage products were separated by microbore liquid chromatography (μLC) online coupled to positive electrospray ionization (ESI) with subsequent high-resolution time-of-flight tandem mass spectrometry (HR MS/MS) allowing identification of known and novel adducts. In addition to known phosphonylation of various tyrosine residues, albumin was found to be modified at diverse cysteine residues by covalent attachment of the leaving group of VX. These novel disulfide adducts were cleaved from at least two regions of the intact protein as dipeptides containing cysteine and proline either as CP or PC. A rapid and sensitive method was developed for simultaneous detection of the diverse covalent modifications of human albumin by VX. Identification of the novel leaving group adducts with human albumin expands the basic knowledge on molecular toxicology of the nerve agent VX. Furthermore, the presented μLC/ESI HR MS/MS method might be of relevance for verification of VX poisoning. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

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.

The efficacy of HI-6 DMS in a sustained infusion against percutaneous VX poisoning in the guinea-pig.

PubMed

Whitmore, C; Cook, A R; Mann, T; Price, M E; Emery, E; Roughley, N; Flint, D; Stubbs, S; Armstrong, S J; Rice, H; Tattersall, J E H

2018-09-01

Post-exposure nerve agent treatment usually includes administration of an oxime, which acts to restore function of the enzyme acetylcholinesterase (AChE). For immediate treatment of military personnel, this is usually administered with an autoinjector device, or devices containing the oxime such as pralidoxime, atropine and diazepam. In addition to the autoinjector, it is likely that personnel exposed to nerve agents, particularly by the percutaneous route, will require further treatment at medical facilities. As such, there is a need to understand the relationship between dose rate, plasma concentration, reactivation of AChE activity and efficacy, to provide supporting evidence for oxime infusions in nerve agent poisoning. Here, it has been demonstrated that intravenous infusion of HI-6, in combination with atropine, is efficacious against a percutaneous VX challenge in the conscious male Dunkin-Hartley guinea-pig. Inclusion of HI-6, in addition to atropine in the treatment, improved survival when compared to atropine alone. Additionally, erythrocyte AChE activity following poisoning was found to be dose dependent, with an increased dose rate of HI-6 (0.48mg/kg/min) resulting in increased AChE activity. As far as we are aware, this is the first study to correlate the pharmacokinetic profile of HI-6 with both its pharmacodynamic action of reactivating nerve agent inhibited AChE and with its efficacy against a persistent nerve agent exposure challenge in the same conscious animal. Copyright © 2017 Crown Copyright. Published by Elsevier B.V. All rights reserved.

Human Metabolism and Interactions of Deployment-Related Chemicals

DTIC Science & Technology

2003-08-01

with individual test compounds (final concentration, 100 PM), agent pyridostigmine bromide to protect against possible nerve gas NADPH-generating system...an insect repellent (N,N-diethyl-m- toluamide) a nerve gas prophyllactic (pyridostigmine bromide) did not cause the inhibition of trans-permethrin...mechanism of organophosphorus anticholinesterase agents , namely; covalent modification of the active site of the esterases in question. Carbaryl, another

Nerve Agent Sensing Biopolymer Wipe

DTIC Science & Technology

2003-04-01

3. Urease and BChE (at two concentrations) activity as function of pH. ..... 10 Figure 4. Reaction scheme Agentase nerve agent sensor...11 Figure 5. Signal development in Agentase’s Traffic Light Sensor Construct.......... 11 Figure 6. Effect of BChE/ urease ...between two competing enzyme reactions. BChE catalyzed butyrylcholine hydrolysis results in the production of acid (decreasing pH) while urease - catalyzed

Effective countermeasure against poisoning by organophosphorus insecticides and nerve agents.

PubMed

Albuquerque, Edson X; Pereira, Edna F R; Aracava, Yasco; Fawcett, William P; Oliveira, Maristela; Randall, William R; Hamilton, Tracey A; Kan, Robert K; Romano, James A; Adler, Michael

2006-08-29

The nerve agents soman, sarin, VX, and tabun are deadly organophosphorus (OP) compounds chemically related to OP insecticides. Most of their acute toxicity results from the irreversible inhibition of acetylcholinesterase (AChE), the enzyme that inactivates the neurotransmitter acetylcholine. The limitations of available therapies against OP poisoning are well recognized, and more effective antidotes are needed. Here, we demonstrate that galantamine, a reversible and centrally acting AChE inhibitor approved for treatment of mild to moderate Alzheimer's disease, protects guinea pigs from the acute toxicity of lethal doses of the nerve agents soman and sarin, and of paraoxon, the active metabolite of the insecticide parathion. In combination with atropine, a single dose of galantamine administered before or soon after acute exposure to lethal doses of soman, sarin, or paraoxon effectively and safely counteracted their toxicity. Doses of galantamine needed to protect guinea pigs fully against the lethality of OPs were well tolerated. In preventing the lethality of nerve agents, galantamine was far more effective than pyridostigmine, a peripherally acting AChE inhibitor, and it was less toxic than huperzine, a centrally acting AChE inhibitor. Thus, a galantamine-based therapy emerges as an effective and safe countermeasure against OP poisoning.

Effective countermeasure against poisoning by organophosphorus insecticides and nerve agents

PubMed Central

Albuquerque, Edson X.; Pereira, Edna F. R.; Aracava, Yasco; Fawcett, William P.; Oliveira, Maristela; Randall, William R.; Hamilton, Tracey A.; Kan, Robert K.; Romano, James A.; Adler, Michael

2006-01-01

The nerve agents soman, sarin, VX, and tabun are deadly organophosphorus (OP) compounds chemically related to OP insecticides. Most of their acute toxicity results from the irreversible inhibition of acetylcholinesterase (AChE), the enzyme that inactivates the neurotransmitter acetylcholine. The limitations of available therapies against OP poisoning are well recognized, and more effective antidotes are needed. Here, we demonstrate that galantamine, a reversible and centrally acting AChE inhibitor approved for treatment of mild to moderate Alzheimer’s disease, protects guinea pigs from the acute toxicity of lethal doses of the nerve agents soman and sarin, and of paraoxon, the active metabolite of the insecticide parathion. In combination with atropine, a single dose of galantamine administered before or soon after acute exposure to lethal doses of soman, sarin, or paraoxon effectively and safely counteracted their toxicity. Doses of galantamine needed to protect guinea pigs fully against the lethality of OPs were well tolerated. In preventing the lethality of nerve agents, galantamine was far more effective than pyridostigmine, a peripherally acting AChE inhibitor, and it was less toxic than huperzine, a centrally acting AChE inhibitor. Thus, a galantamine-based therapy emerges as an effective and safe countermeasure against OP poisoning. PMID:16914529

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.

Research in Progress 1 July 1990 - 30 June 1991

DTIC Science & Technology

1991-06-30

that encountered for diequatorial ring place- warfare agents , pesticides . explosives, etc. In addi- ment. In a more general sense both the theoretical...mustards but also for chlorodinitromethane was the major product. Nitration nerve agents . The advantages (and one disadvantage) of vinylidene chloride gave...resolution capillary gas The membrane potential of cultured rat sciatic nerve chromatography-mass spectrometry to obtain infor- Schwann cells was determined

Toxicity studies on agent GA (Phase 2): 90 day subchronic study of GA (Tabun) in cd rats. Appendices. Final report, July 1985-August 1991

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

1992-03-01

The purpose of the report is to provide essential toxicologic information on Tabun administration over a 90 day period. This toxicologic information may be used to adjust the maximum-tolerated dose for subsequent dominant-lethal and two-generation reproduction studies. The objectives were to determine the toxic effects of nerve agent exposure (e.g., target organs); and to determine the effects of nerve agent GA on sperm morphology and motility and vaginal cytology.

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.

Hazards of chemical weapons release during war: new perspectives.

PubMed Central

Reutter, S

1999-01-01

The two major threat classes of chemical weapons are mustard gas and the nerve agents, and this has not changed in over 50 years. Both types are commonly called gases, but they are actually liquids that are not remarkably volatile. These agents were designed specifically to harm people by any route of exposure and to be effective at low doses. Mustard gas was used in World War I, and the nerve agents were developed shortly before, during, and after World War II. Our perception of the potency of chemical weapons has changed, as well as our concern over potential effects of prolonged exposures to low doses and potential target populations that include women and children. Many of the toxicologic studies and human toxicity estimates for both mustard and nerve agents were designed for the purpose of quickly developing maximal casualties in the least sensitive male soldier. The "toxicity" of the chemical weapons has not changed, but our perception of "toxicity" has. PMID:10585902

Letterman Army Institute of Research Annual Research Progress Report, FY 1981.

DTIC Science & Technology

1981-10-01

with physiology and mech- anisms of skin damage and repair. The mechanisms by which nerve agents and vesicants produce physiologic aberration and...enzyme vital for nerve function. Organophos- phates react rapidly and covalently with the enzyme to produce an in- active enzyme. Reactivation of the...warfare agents . These organic molecules may also alter the natural defense mechanism by activating or deactivating enzymes in the skin that destroy

Characterisation of a Cell Culture System for Investigating Nerve Agent Neurotoxicology. Part 1

DTIC Science & Technology

2012-03-01

eds. CRC Press), pp. 1-24. Sawyer,T.W., Weiss,M.T., and Unger,R.J. (1992). Anticholinesterase activity of organophosphate nerve agents in neuronal...were confirmed. The presence of muscarinic receptors and acetylcholinesterase activity was determined. Importantly, differential acetylcholinesterase... activity assays that will provide the basis for an ongoing research programme. The neuroblastoma cell lines chosen can potentially be used as a

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.

Toxicity of the organophosphate chemical warfare agents GA, GB, and VX: Implications for public protection

DOE Office of Scientific and Technical Information (OSTI.GOV)

Munro, N.B.; Ambrose, K.R.; Watson, A.P.

1994-01-01

The nerve agents, GA, GB, and VX are organophosphorus esters that form a major portion of the total agent volume contained in the U.S. stockpile of unitary chemical munitions. Congress has mandated the destruction of these agents, which is currently slated for completion in 2004. The acute, chronic, and delayed toxicity of these agents is reviewed in this analysis. The largely negative results from studies of genotoxicity, carcinogenicity, developmental, and reproductive toxicity are also presented. Nerve agents show few or delayed effects. At supralethal doses, GB can cause delayed neuropathy in antidote-protected chickens, but there is not evidence that itmore » causes this syndrome in humans at any dose. Agent VX shows no potential for inducing delayed neuropathy in any species. In view of their lack of genotoxicity, the nerve agent exposure is the extraordinarily high acute toxicity of these substances. Futhermore, acute effects of moderate exposure such as nausea, diarrhea, inability to perform simple mental tasks, and respiratory effects may render the public unable to respond adequately to emergency instructions in the unlikely event of agent release, making early warning and exposure avoidance important. Likewise, exposure or self-contamination of first responders and medical personnel must be avoided. Control limits for exposure via surface contact of drinking water are needed, as are detection methods for low levels in water or foodstuffs. 187 refs., 3 figs., 7 tabs.« less

X-Ray Crystallographic Studies on Acetylcholinesterase and Related Enzymes.

DTIC Science & Technology

1999-10-01

nerve gas intoxication, as well as of insecticide poisoning. Such structures can yield direct information concerning the functional groups and steric...Glyll7His mutant (48). Recent solution of the 3D structures of conjugates of the nerve agents , sarin, soman, DFP and VX with 7cAChE (49, 50) has revealed... pesticides and chemical warfare agents is a topic of considerable environmental and toxicological importance. Hence, a substantial research effort is being

Acute Toxicity Estimation and Operational Risk Management of Chemical Warfare Agent Exposures

DTIC Science & Technology

2004-05-01

Following absorption into the body, nerve agents bind with and inhibit the activity of cholinesterases (ChE) that are present in the blood and...other tissues. Blood ChE activity depression by itself is not considered an adverse effect but (particularly red blood cell cholinesterase (RBC-ChE...chemical, such as an organophosphate , that blocks nerve impulses by inhibiting the activity of the enzyme cholinesterase (adapted from University of

The Limitations of Diazepam as a Treatment for Nerve Agent-Induced Seizures and Neuropathology in Rats: Comparison with UBP302

DTIC Science & Technology

2014-11-01

to nerve agents induces prolonged status epilepticus (SE), causing brain damage or death. Diazepam (DZP) is the cur- rent US Food and Drug... status epilepticus (SE), which are initiated by the excessive stimulation of cholinergic receptors. If immediate death is prevented by adequate...5-yl)ethyl] decahydroisoquinoline-3-carboxylic acid; PBS, phosphate-buffered saline; SE, status epilepticus ; UBP302, (S)-3-(2-carboxybenzyl

Effects of subacute pretreatment with carbamate together with acute adjunct pretreatment against nerve agent exposure. (Reannouncement with new availability information)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Anderson, D.R.; Harris, L.W.; Lennox, W.J.

1991-12-31

Acute carbamate pretreatment, in conjunction with atropine pretreatment or followed by atropine and oxime therapy has been shown to protect rabbits, rats, guinea pigs and monkeys against multiple lethal doses of soman. In those experiments, pretreated animals were usually challenged with soman at the time of peak whole blood acetylcholinesterase (AChE) inhibition by the carbamate or when the concentration of carbamate in the blood was expected to be rapidly diminishing. However, soldiers in a chemical environment, having taken carbamate orally might well be exposed to nerve agent shortly thereafter. Thus, both active carbamate and nerve agent would be entering themore » blood simultaneously. In a recent study it was reported that subacute administration of physostigmine (Phy), via subcutaneously implanted 28 day osmotic minipump, afforded protection against an iv challenge of soman on the 27th day.« less

Hydrolysis of Nerve Agents by Model Nucleophiles: A Computational Study

PubMed Central

Beck, Jeremy M.

2008-01-01

Density functional theory calculations were employed to study the reaction of five nerve agents with model nucleophiles, including EtX− and EtXH (X = O, S, Se) for serine, cysteine and selenocysteine, respectively. Calculations at the B3LYP/6-311++G(2d,p) level of theory predict an exothermic reaction between ethoxide and all of the nerve agents studied. As compared to EtO− as a nucleophile, these reactions become ~30 kcal/mol more endothermic for EtS−, and by ~40 kcal/mol for EtSe−. The equivalent reactions with the neutral nucleophiles (EtXH) were more endothermic. The effect of solvation on the reaction thermochemistry was determined using a polarizable continuum model simulating the dielectric constant of chloroform. While there was a large exothermic shift for reactions involving charged nucleophiles with solvation modeling, the corresponding shift was minimal for the reaction with neutral nucleophiles. PMID:18538754

A common-path optical coherence tomography based electrode for structural imaging of nerves and recording of action potentials

NASA Astrophysics Data System (ADS)

Islam, M. Shahidul; Haque, Md. Rezuanul; Oh, Christian M.; Wang, Yan; Park, B. Hyle

2013-03-01

Current technologies for monitoring neural activity either use different variety of electrodes (electrical recording) or require contrast agents introduced exogenously or through genetic modification (optical imaging). Here we demonstrate an optical method for non-contact and contrast agent free detection of nerve activity using phase-resolved optical coherence tomography (pr-OCT). A common-path variation of the pr-OCT is recently implemented and the developed system demonstrated the capability to detect rapid transient structural changes that accompany neural spike propagation. No averaging over multiple trials was required, indicating its capability of single-shot detection of individual impulses from functionally stimulated Limulus optic nerve. The strength of this OCT-based optical electrode is that it is a contactless method and does not require any exogenous contrast agent. With further improvements in accuracy and sensitivity, this optical electrode will play a complementary role to the existing recording technologies in future.

Screening of nerve agent degradation products by MALDI-TOFMS.

PubMed

Shu, You-Ren; Su, An-Kai; Liu, Ju-Tsung; Lin, Cheng-Huang

2006-07-01

A novel method for the rapid screening of degradation products derived from nerve agents by matrix-assisted laser desorption ionization time-of-flight mass spectrometry is described. Five standard products were selected as model compounds, including isopropyl methylphosphonic acid (IMPA), pinacolyl methylphosphonic acid (PMPA), ethyl methylphosphonic acid (EMPA), isobutyl methylphosphonic acid (i-BuMPA), and cyclohexyl methylphosphonic acid (CHMPA), which are degradation products of Sarin (GB), Soman (GD), VX, Russian VX (RVX), and GF, respectively. For comparison, CHCA (alpha-cyano-4-hydroxycinnamic acid) and DCCA (7-(diethylamino)coumarin-3-carboxylic acid) were used as the MALDI-matrix when the third harmonic generation (355 nm) of a Nd:YAG laser and a hydrogen Raman laser (multifrequency laser) were used, respectively. The method permitted the five nerve agent degradation products to be screened rapidly and successfully, suggesting that it has the potential for use as a routine monitoring tool.

Potent 3-Hydroxy-2-Pyridine Aldoxime Reactivators of Organophosphate-Inhibited Cholinesterases with Predicted Blood-Brain Barrier Penetration.

PubMed

Zorbaz, Tamara; Braïki, Anissa; Maraković, Nikola; Renou, Julien; de la Mora, Eugenio; Maček Hrvat, Nikolina; Katalinić, Maja; Silman, Israel; Sussman, Joel L; Mercey, Guillaume; Gomez, Catherine; Mougeot, Romain; Pérez, Belén; Baati, Rachid; Nachon, Florian; Weik, Martin; Jean, Ludovic; Kovarik, Zrinka; Renard, Pierre-Yves

2018-04-19

A new series of 3-hydroxy-2-pyridine aldoxime compounds have been designed, synthesised and tested in vitro, in silico, and ex vivo as reactivators of human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) inhibited by organophosphates (OPs), for example, VX, sarin, cyclosarin, tabun, and paraoxon. The reactivation rates of three oximes (16-18) were determined to be greater than that of 2-PAM and comparable to that of HI-6, two pyridinium aldoximes currently used by the armies of several countries. The interactions important for a productive orientation of the oxime group within the OP-inhibited enzyme have been clarified by molecular-modelling studies, and by the resolution of the crystal structure of the complex of oxime 17 with Torpedo californica AChE. Blood-brain barrier penetration was predicted for oximes 15-18 based on their physicochemical properties and an in vitro brain membrane permeation assay. Among the evaluated compounds, two morpholine-3-hydroxypyridine aldoxime conjugates proved to be promising reactivators of OP-inhibited cholinesterases. Moreover, efficient ex vivo reactivation of phosphylated native cholinesterases by selected oximes enabled significant hydrolysis of VX, sarin, paraoxon, and cyclosarin in whole human blood, which indicates that the oximes have scavenging potential. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Molecular and dissociative adsorption of DMMP, Sarin and Soman on dry and wet TiO2(110) using density functional theory

NASA Astrophysics Data System (ADS)

Quintero, Yenny Cardona; Nagarajan, Ramanathan

2018-09-01

Titania, among the metal oxides, has shown promising characteristics for the adsorption and decontamination of chemical warfare nerve agents, due to its high stability and rapid decomposition rates. In this study, the adsorption energy and geometry of the nerve agents Sarin and Soman, and their simulant dimethyl methyl phosphonate (DMMP) on TiO2 rutile (110) surface were calculated using density functional theory. The molecular and dissociative adsorption of the agents and simulant on dry as well as wet metal oxide surfaces were considered. For the wet system, computations were done for the cases of both molecularly adsorbed water (hydrated conformation) and dissociatively adsorbed water (hydroxylated conformation). DFT calculations show that dissociative adsorption of the agents and simulant is preferred over molecular adsorption for both dry and wet TiO2. The dissociative adsorption on hydrated TiO2 shows higher stability among the different configurations considered. The dissociative structure of DMMP on hydrated TiO2 (the most stable one) was identified as the dissociation of a methyl group and its adsorption on the TiO2 surface. For the nerve agents Sarin and Soman on hydrated TiO2 the dissociative structure was by the dissociation of the F atom from the molecule and its interaction with a Ti atom from the surface, which could indicate a reduction in the toxicity of the products. This study shows the relevance of water adsorption on the metal oxide surface for the stability and dissociation of the simulant DMMP and the nerve agents Sarin and Soman on TiO2.

Sarin Exposures in A Cohort of British Military Participants in Human Experimental Research at Porton Down 1945-1987.

PubMed

Keegan, Thomas J; Carpenter, Lucy M; Brooks, Claire; Langdon, Toby; Venables, Katherine M

2017-12-15

The effects of exposure to chemical warfare agents in humans are topical. Porton Down is the UK's centre for research on chemical warfare where, since WWI, a programme of experiments involving ~30000 participants drawn from the UK armed services has been undertaken. Our aim is to report on exposures to nerve agents, particularly sarin, using detailed exposure data not explored in a previous analysis. In this paper, we have used existing data on exposures to servicemen who attended the human volunteer programme at Porton Down to examine exposures to nerve agents in general and to sarin in particular. Six principal nerve agents were tested on humans between 1945 and 1987. Of all 4299 nerve agent tests recorded, 3511 (82%) were with sarin, most commonly in an exposure chamber, with inhalation being the commonest exposure route (85%). Biological response to sarin exposure was expressed as percentage change in cholinesterase activity and, less commonly, change in pupil size. For red blood cell cholinesterase, median inhibition for inhalation tests was 41% (interquartile range 28-51%), with a maximum of 87%. For dermal exposures the maximum inhibition recorded was 99%. There was a clear association between increasing exposure to sarin and depression of cholinesterase activity but the strength and direction of the association varied by exposure route and the presence of chemical or physical protection. Pupil size decreased with increased exposure but this relationship was less clear when modifiers, such as atropine drops, were present. These results, drawn from high quality experimental data, offer a unique insight into the effects of these chemical agents on humans. © The Author 2017. Published by Oxford University Press on behalf of the British Occupational Hygiene Society.

Fluorescent sensors for the detection of chemical warfare agents.

PubMed

Burnworth, Mark; Rowan, Stuart J; Weder, Christoph

2007-01-01

Along with biological and nuclear threats, chemical warfare agents are some of the most feared weapons of mass destruction. Compared to nuclear weapons they are relatively easy to access and deploy, which makes them in some aspects a greater threat to national and global security. A particularly hazardous class of chemical warfare agents are the nerve agents. Their rapid and severe effects on human health originate in their ability to block the function of acetylcholinesterase, an enzyme that is vital to the central nervous system. This article outlines recent activities regarding the development of molecular sensors that can visualize the presence of nerve agents (and related pesticides) through changes of their fluorescence properties. Three different sensing principles are discussed: enzyme-based sensors, chemically reactive sensors, and supramolecular sensors. Typical examples are presented for each class and different fluorescent sensors for the detection of chemical warfare agents are summarized and compared.

Nerve Agent Induced Status Epilepticus: From Seizure Onset to Long Lasting Pathology

DTIC Science & Technology

2014-01-31

of oximes in the treatment of nerve agent poisoning in civilian casualties. Toxicol Rev 25:297-323 168. Martin LF, Kem WR, Freedman R. 2004. Alpha-7...Pharmacol 82:931-42 220. Paxinos G, Watson C. 2005. The Rat Brain in Stereotaxic Coordinates. New York NY: Elsevier 221. Petras JM. 1981. Soman...neurotoxicity. Fundam Appl Toxicol 1 :242 222. Petras JM. 1994. Neurology and neuropathology of Soman-induced brain injury: an overview. J Exp Anal

Tertiary Oximes on Brain Acetylcholinesterase and Central Excitatory Effects of Nerve Agents

DTIC Science & Technology

2012-01-01

5 test doses of the oxime. Animals were euthanized 45 min after oxime treatment when blood and target tissues were collected. AChE activity was...the ability of MINA and DHAP to block or terminate nerve agent-induced electroencephalographic (EEG) seizure activity was evaluated. Animals...instrumented to record brain EEG activity were challenged with a seizure-inducing dose (2.0 x LD50) of GB, GF, or VX, and oxime was administered one min

In Vivo Microdialysis and Electroencephalographic Activity in Freely Moving Guinea Pigs Exposed to Organophosphorus Nerve Agents Sarin and VX: Analysis of Acetylcholine and Glutamate

DTIC Science & Technology

2011-01-01

3. DATES COVERED (From - To) 4. TITLE AND SUBTITLE In vivo microdialysis and electroencephalographic activity in freely moving guinea pigs 5a...microdialysis and electroencephalographic activity in freely moving guinea pigs exposed to organophosphorus nerve agents sarin and VX: analysis of...brain seizure activity . This robust double multi- variate design provides greater fidelity when comparing data while also reducing the required number

Examination of plasma PON1 paraoxonase activity and genotype in Gulf War veterans

DTIC Science & Technology

2017-10-01

cholinergic” effects (e.g., personal pesticide use, exposure to OP nerve agents) in subgroups of veterans with different PON1192 genotype. (2...associations between GWI and GW-related exposures with the potential for “cholinergic” effects (e.g., personal pesticide use, exposure to OP nerve agents) in...learning and careers in science, technology, and the humanities . What do you plan to do during the next reporting period to accomplish the goals

The application of single particle aerosol mass spectrometry for the detection and identification of high explosives and chemical warfare agents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Martin, Audrey Noreen

2006-01-01

Single Particle Aerosol Mass Spectrometry (SPAMS) was evaluated as a real-time detection technique for single particles of high explosives. Dual-polarity time-of-flight mass spectra were obtained for samples of 2,4,6-trinitrotoluene (TNT), 1,3,5-trinitro-1,3,5-triazinane (RDX), and pentaerythritol tetranitrate (PETN); peaks indicative of each compound were identified. Composite explosives, Comp B, Semtex 1A, and Semtex 1H were also analyzed, and peaks due to the explosive components of each sample were present in each spectrum. Mass spectral variability with laser fluence is discussed. The ability of the SPAMS system to identify explosive components in a single complex explosive particle (~1 pg) without the need formore » consumables is demonstrated. SPAMS was also applied to the detection of Chemical Warfare Agent (CWA) simulants in the liquid and vapor phases. Liquid simulants for sarin, cyclosarin, tabun, and VX were analyzed; peaks indicative of each simulant were identified. Vapor phase CWA simulants were adsorbed onto alumina, silica, Zeolite, activated carbon, and metal powders which were directly analyzed using SPAMS. The use of metal powders as adsorbent materials was especially useful in the analysis of triethyl phosphate (TEP), a VX stimulant, which was undetectable using SPAMS in the liquid phase. The capability of SPAMS to detect high explosives and CWA simulants using one set of operational conditions is established.« less

The postwar hospitalization experience of Gulf War Veterans possibly exposed to chemical munitions destruction at Khamisiyah, Iraq.

PubMed

Gray, G C; Smith, T C; Knoke, J D; Heller, J M

1999-09-01

Using Department of Defense hospital data, the authors examined the postwar hospitalization experience from March 1991 through September 1995 of US Gulf War veterans who were near Khamisiyah, Iraq, during nerve agent munition destruction in March 1991. Multiple sources of meteorologic, munition, and toxicology data were used to circumscribe geographic areas of low level, vaporized nerve agent for 4 days after the destruction. Plume estimates were overlaid on military unit positions, and exposure was estimated for the 349,291 US Army Gulf War veterans. Exposure was classified as not exposed (n = 224,804), uncertain low dose exposure (n = 75,717), and specific estimated subclinical exposure (n = 48,770) categorized into three groups for dose-response evaluation. Using Cox proportional hazard modeling, the authors compared the postwar experiences of these exposure groups for hospitalization due to any cause, for diagnoses in 15 unique categories, and for specific diagnoses an expert panel proposed as most likely to reflect latent disease from such subclinical exposure. There was little evidence that veterans possibly exposed to the nerve agent plumes experienced unusual postwar morbidity. While there were several differences in hospitalization risk, none of the models suggested a dose-response relation or neurologic sequelae. These data, having a number of limitations, do not support the hypothesis that Gulf War veterans are suffering postwar morbidity from subclinical nerve agent exposure.

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.

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.

High-sensitivity, high-selectivity detection of chemical warfare agents

NASA Astrophysics Data System (ADS)

Pushkarsky, Michael B.; Webber, Michael E.; Macdonald, Tyson; Patel, C. Kumar N.

2006-01-01

We report high-sensitivity detection of chemical warfare agents (nerve gases) with very low probability of false positives (PFP). We demonstrate a detection threshold of 1.2ppb (7.7μg/m3 equivalent of Sarin) with a PFP of <1:106 in the presence of many interfering gases present in an urban environment through the detection of diisopropyl methylphosphonate, an accepted relatively harmless surrogate for the nerve agents. For the current measurement time of ˜60s, a PFP of 1:106 corresponds to one false alarm approximately every 23months. The demonstrated performance satisfies most current homeland and military security requirements.

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

PubMed

RamaRao, Golime; Afley, Prachiti; Acharya, Jyothiranjan; Bhattacharya, Bijoy Krishna

2014-04-04

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. 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. 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 molecular and biochemical changes and subsequent long term neurological effects induced by nerve agents.

Evaluation of Chemical Warfare Agent Wipe Sampling ...

EPA Pesticide Factsheets

Report This investigation tested specific (CWAs), including sarin (GB), soman (GD), cyclosarin (GF), sulfur mustard (HD), and O-ethyl-S-(2-diisopropylaminoethyl) methylphosphonothioate (VX) on the non-ideal (e.g., porous and permeable) surfaces of drywall, vinyl tile, wood, laminate, and coated glass. Pesticides (diazinon and malathion) were used so that a comparison is possible with existing literature data (1). Experiments included testing with coupons having surface areas of 10 cm2 and 100 cm2. The 10-cm2 coupons were of a size that could easily be extracted in a 2 oz jar (to provide comparative data for CWA recoveries generated by direct extraction) and the 100-cm2 coupons better represented the area of a surface that might typically be sampled by wipe extraction. In addition, CWA, at a normalized surface concentration of 0.1 µg per cm2 surface area, were spiked on coupons of the tested surfaces. Wipes were wetted with either dichloromethane (DCM) or isopropanol (IPA) before sampling for CWA. Experimental parameters include multiple wipe types, porous/permeable surfaces, coupon surface area, solvent used to wet the wipe (i.e., wetting solvent), and the utility of VX-d14 as an extracted internal standard.

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

Naturally Occurring Genetic Variants of Human Acetylcholinesterase and Butyrylcholinesterase and Their Potential Impact on the Risk of Toxicity from Cholinesterase Inhibitors

PubMed Central

2016-01-01

Acetylcholinesterase (AChE) is the physiologically important target for organophosphorus toxicants (OP) including nerve agents and pesticides. Butyrylcholinesterase (BChE) in blood serves as a bioscavenger that protects AChE in nerve synapses from inhibition by OP. Mass spectrometry methods can detect exposure to OP by measuring adducts on the active site serine of plasma BChE. Genetic variants of human AChE and BChE do exist, but loss of function mutations have been identified only in the BCHE gene. The most common AChE variant, His353Asn (H322N), also known as the Yt blood group antigen, has normal AChE activity. The most common BChE variant, Ala567Thr (A539T) or the K-variant in honor of Werner Kalow, has 33% reduced plasma BChE activity. The genetic variant most frequently associated with prolonged response to muscle relaxants, Asp98Gly (D70G) or atypical BChE, has reduced activity and reduced enzyme concentration. Early studies in young, healthy males, performed at a time when it was legal to test nerve agents in humans, showed that individuals responded differently to the same low dose of sarin with toxic symptoms ranging in severity from minimal to moderate. Additionally, animal studies indicated that BChE protects from toxicants that have a higher reactivity with AChE than with BChE (e.g., nerve agents) but not from toxicants that have a higher reactivity with BChE than with AChE (e.g., OP pesticides). As a corollary, we hypothesize that individuals with genetic variants of BChE may be at increased risk of toxicity from nerve agents but not from OP pesticides. PMID:27551784

Naturally Occurring Genetic Variants of Human Acetylcholinesterase and Butyrylcholinesterase and Their Potential Impact on the Risk of Toxicity from Cholinesterase Inhibitors.

PubMed

Lockridge, Oksana; Norgren, Robert B; Johnson, Rudolph C; Blake, Thomas A

2016-09-19

Acetylcholinesterase (AChE) is the physiologically important target for organophosphorus toxicants (OP) including nerve agents and pesticides. Butyrylcholinesterase (BChE) in blood serves as a bioscavenger that protects AChE in nerve synapses from inhibition by OP. Mass spectrometry methods can detect exposure to OP by measuring adducts on the active site serine of plasma BChE. Genetic variants of human AChE and BChE do exist, but loss of function mutations have been identified only in the BCHE gene. The most common AChE variant, His353Asn (H322N), also known as the Yt blood group antigen, has normal AChE activity. The most common BChE variant, Ala567Thr (A539T) or the K-variant in honor of Werner Kalow, has 33% reduced plasma BChE activity. The genetic variant most frequently associated with prolonged response to muscle relaxants, Asp98Gly (D70G) or atypical BChE, has reduced activity and reduced enzyme concentration. Early studies in young, healthy males, performed at a time when it was legal to test nerve agents in humans, showed that individuals responded differently to the same low dose of sarin with toxic symptoms ranging in severity from minimal to moderate. Additionally, animal studies indicated that BChE protects from toxicants that have a higher reactivity with AChE than with BChE (e.g., nerve agents) but not from toxicants that have a higher reactivity with BChE than with AChE (e.g., OP pesticides). As a corollary, we hypothesize that individuals with genetic variants of BChE may be at increased risk of toxicity from nerve agents but not from OP pesticides.

Activity Based Protein Profiling Leads to Identification of Novel Protein Targets for Nerve Agent VX.

PubMed

Carmany, Dan; Walz, Andrew J; Hsu, Fu-Lian; Benton, Bernard; Burnett, David; Gibbons, Jennifer; Noort, Daan; Glaros, Trevor; Sekowski, Jennifer W

2017-04-17

Organophosphorus (OP) nerve agents continue to be a threat at home and abroad during the war against terrorism. Human exposure to nerve agents such as VX results in a cascade of toxic effects relative to the exposure level including ocular miosis, excessive secretions, convulsions, seizures, and death. The primary mechanism behind these overt symptoms is the disruption of cholinergic pathways. While much is known about the primary toxicity mechanisms of nerve agents, there remains a paucity of information regarding impacts on other pathways and systemic effects. These are important for establishing a comprehensive understanding of the toxic mechanisms of OP nerve agents. To identify novel proteins that interact with VX, and that may give insight into these other mechanisms, we used activity-based protein profiling (ABPP) employing a novel VX-probe on lysates from rat heart, liver, kidney, diaphragm, and brain tissue. By making use of a biotin linked VX-probe, proteins covalently bound by the probe were isolated and enriched using streptavidin beads. The proteins were then digested, labeled with isobarically distinct tandem mass tag (TMT) labels, and analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Quantitative analysis identified 132 bound proteins, with many proteins found in multiple tissues. As with previously published ABPP OP work, monoacylglycerol lipase associated proteins and fatty acid amide hydrolase (FAAH) were shown to be targets of VX. In addition to these two and other predicted neurotransmitter-related proteins, a number of proteins involved with energy metabolism were identified. Four of these enzymes, mitochondrial isocitrate dehydrogenase 2 (IDH2), isocitrate dehydrogenase 3 (IDH3), malate dehydrogenase (MDH), and succinyl CoA (SCS) ligase, were assayed for VX inhibition. Only IDH2 NADP+ activity was shown to be inhibited directly. This result is consistent with other work reporting animals exposed to OP compounds exhibit reduced IDH activity. Though clearly a secondary mechanism for toxicity, this is the first time VX has been shown to directly interfere with energy metabolism. Taken together, the ABPP work described here suggests the discovery of novel protein-agent interactions, which could be useful for the development of novel diagnostics or potential adjuvant therapeutics.

Limitations and challenges in treatment of acute chemical warfare agent poisoning.

PubMed

Thiermann, Horst; Worek, Franz; Kehe, Kai

2013-12-05

Recent news from Syria on a possible use of chemical warfare agents made the headlines. Furthermore, the motivation of terrorists to cause maximal harm shifts these agents into the public focus. For incidents with mass casualties appropriate medical countermeasures must be available. At present, the most important threats arise from nerve agents and sulfur mustard. At first, self-protection and protection of medical units from contamination is of utmost importance. Volatile nerve agent exposure, e.g. sarin, results in fast development of cholinergic crisis. Immediate clinical diagnosis can be confirmed on-site by assessment of acetylcholinesterase activity. Treatment with autoinjectors that are filled with 2mg atropine and an oxime (at present obidoxime, pralidoxime, TMB-4 or HI-6) are not effective against all nerve agents. A more aggressive atropinisation has to be considered and more effective oximes (if possible with a broad spectrum or a combination of different oximes) as well as alternative strategies to cope with high acetylcholine levels at synaptic sites should be developed. A further gap exists for the treatment of patients with sustained cholinergic crisis that has to be expected after exposure to persistent nerve agents, e.g. VX. The requirement for long-lasting artificial ventilation can be reduced with an oxime therapy that is optimized by using the cholinesterase status for guidance or by measures (e.g. scavengers) that are able to reduce the poison load substantially in the patients. For sulfur mustard poisoning no specific antidote is available until now. Symptomatic measures as used for treatment of burns are recommended together with surgical or laser debridement. Thus, huge amounts of resources are expected to be consumed as wound healing is impaired. Possible depots of sulfur mustard in tissues may aggravate the situation. More basic knowledge is necessary to improve substantially therapeutic options. The use of stem cells may provide a new and promising option. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Chemical warfare nerve agents. A review of cardiopulmonary pathophysiology and resuscitation. Technical report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Franz, D.R.

1986-12-01

The purpose of this document is to provide the medical research community with a digest of the open and internal literature related to cardiopulmonary pathophysiology, resuscitation, and animal modeling of chemical warfare nerve agent intoxication. Though not comprehensive, this review makes available to the reader a cross section of what research was done in this small but important part of the medical chemical defense research program between World War II and the early 1980's.

Neuroinflammatory Pathobiology in Gulf War Illness: Characterization with an Animal Model

DTIC Science & Technology

2013-08-01

GFAP,IL6,CCL2, TNF, L118, Lif, IL10 Hip, Ctx Ctx Ctx CORT=corticosterone;(200mg/L) for days 7-14 P8= pyridostigmine bromide ;P8(2.5 mg/kg/day, s.c...reversible acetylcholinesterase (AChE) inhibitor pyridostigmine bromide (PB), the insect repellent DEET and, potentially, the nerve agent, sarin. These...acetylcholinesterase (AChE) inhibitor, pyridostigmine bromide (PB), the insect repellent, DEET, and, potentially, acutely to the nerve agent sarin. Previously, we

Stoichiometric and Catalytic Scavengers as Protection Against Nerve Agent Toxicity: A Mini Review

DTIC Science & Technology

2007-01-01

signs of nerve agent toxicity following exposure . Assessments of motor activity , coordination, and acquisition of spatial memory were performed for 2...serious side occur before endogenous AChE is affected (approxi- effects if administered in the absence of cholinesterase mately 2 min after exposure to an...after guinea pigs of cholinesterase in the blood and the level of protec- were administered 60mg/kg of HuBuChE (-󈧎-fold tion against OP poisoning

Enhanced catalytic activity through the tuning of micropore environment and supercritical CO2 processing: Al(porphyrin)-based porous organic polymers for the degradation of a nerve agent simulant.

PubMed

Totten, Ryan K; Kim, Ye-Seong; Weston, Mitchell H; Farha, Omar K; Hupp, Joseph T; Nguyen, SonBinh T

2013-08-14

An Al(porphyrin) functionalized with a large axial ligand was incorporated into a porous organic polymer (POP) using a cobalt-catalyzed acetylene trimerization strategy. Removal of the axial ligand afforded a microporous POP that is catalytically active in the methanolysis of a nerve agent simulant. Supercritical CO2 processing of the POP dramatically increased the pore size and volume, allowing for significantly higher catalytic activities.

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

DTIC Science & Technology

2010-11-01

particular nerve agent and oxime uti- lized in the treatment regimen. Atropine is the universal treatment for organophospho- rus anticholinesterase poisoning...general, to the recovery of AChE activity either through decarbamylation of PB protected enzyme or by use of an effective oxime. The results against...this protected enzyme in the first few minutes after intoxication and treat- ment provides sufficient enzyme activity to sustain survival.̂ ’"* A

Improving the Catalytic Activity of Hyperthermophilic Pyrococcus horikoshii Prolidase for Detoxification of Organophosphorus Nerve Agents over a Broad Range of Temperatures

DTIC Science & Technology

2011-01-01

affinity for metal, and increased thermostability compared to P. furiosus prolidase, Pf prol (PF1343). To obtain a better enzyme for OP nerve agent...decontamination and to investigate the structural factors that may influence protein thermostability and thermoactivity, randomly mutated Ph1prol enzymes ...Introduction Pyrococcus horikoshii and Pyrococcus furiosus are both hyper- thermophilic archaea, growing optimally at 98 –100◦C that were isolated from a

Subacute Low Dose Nerve Agent Exposure Causes DNA Fragmentation in Guinea Pig Leukocytes

DTIC Science & Technology

2005-10-01

1 SUBACUTE LOW DOSE NERVE AGENT EXPOSURE CAUSES DNA FRAGMENTATION IN GUINEA PIG LEUKOCYTES. Jitendra R. Dave1, John R. Moffett1, Sally M...DNA fragmentation in blood leukocytes from guinea pigs by ‘Comet’ assay after exposure to soman at doses ranging from 0.1LD50 to 0.4 LD50, once per...computer. Data obtained for exposure to soman demonstrated significant increases in DNA fragmentation in circulating leukocytes in CWNA treated guinea pigs as

A Nerve Clamp Electrode Design for Indirect Stimulation of Skeletal Muscle

DTIC Science & Technology

2010-10-01

neurons. This device enables stimulation of muscle contraction indirectly as opposed to contraction from direct muscle stimulation. The electrode is able...to stimulate indirect muscle contraction when tested on ex vivo preparations from rodent phrenic nerve-hemidiaphragm muscle in similar fashion to...unsuccessful in stimulating indirect muscle contraction . Therefore, this novel electrode is useful for physiological assessment of nerve agents and

Detoxification of Chemical Warfare Agents Using a Zr6 -Based Metal-Organic Framework/Polymer Mixture.

PubMed

Moon, Su-Young; Proussaloglou, Emmanuel; Peterson, Gregory W; DeCoste, Jared B; Hall, Morgan G; Howarth, Ashlee J; Hupp, Joseph T; Farha, Omar K

2016-10-10

Owing to their high surface area, periodic distribution of metal sites, and water stability, zirconium-based metal-organic frameworks (Zr 6 -MOFs) have shown promising activity for the hydrolysis of nerve agents GD and VX, as well as the simulant, dimethyl 4-nitrophenylphosphate (DMNP), in buffered solutions. A hurdle to using MOFs for this application is the current need for a buffer solution. Here the destruction of the simulant DMNP, as well as the chemical warfare agents (GD and VX) through hydrolysis using a MOF catalyst mixed with a non-volatile, water-insoluble, heterogeneous buffer is reported. The hydrolysis of the simulant and nerve agents in the presence of the heterogeneous buffer was fast and effective. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Effect of anticholinesterase agents on airway epithelial function. Annual report, 15 July 1888-14 August 1989

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marin, M.G.

1989-09-15

Irreversible anticholinesterase compounds have potential serious health effects when employed as chemical warfare agents. Intoxication with these agents will cause an accumulation of acetylcholine at nerve muscle and nerve-gland junctions. Because tracheal glands have rich cholinergic innervation, we hypothesized that exposure to anticholinesterase agents, such as soman, would stimulate glandular secretion. This would cause pathological changes in the important lung defense mechanism of mucociliary clearance. Initial work on this contract revealed a dose-related increase in mucociliary transport in the ferret in response to soman. This effect could be inhibited by atropine but not by pralidoxime. The investigation described in thismore » report relates to the effects of soman and its antidotes on glycoconjugate secretion of ferret trachea in vitro.« less

Detoxification of organophosphate nerve agents by bacterial phosphotriesterase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ghanem, Eman; Raushel, Frank M.

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 utilizedmore » 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.« less

Effects of anesthetic agents on in vivo axonal HCN current in normal mice.

PubMed

Osaki, Yusuke; Nodera, Hiroyuki; Banzrai, Chimeglkham; Endo, Sachiko; Takayasu, Hirokazu; Mori, Atsuko; Shimatani, Yoshimitsu; Kaji, Ryuji

2015-10-01

The objective was to study the in vivo effects of anesthetic agents on peripheral nerve excitability. Normal male mice were anesthetized by either isoflurane inhalation or a combination of medetomidine, midazolam, and butorphanol intraperitoneal injection ("triple agents"). Immediately after induction, the tail sensory nerve action potential was recorded and its excitability was monitored. Under both anesthetic protocols, there was an interval excitability change by long hyperpolarizing currents. There was greater threshold reduction approximately 30min post induction, in comparison to immediately post induction. Other excitability parameters were stable over time. Modeling suggested interval suppression of internodal H conductance or leak current. Anesthetic agents affected responses to long hyperpolarizing currents. Axonal excitability during intraoperative monitoring may be affected by anesthetic agents. Interpretation of interval excitability changes under anesthesia requires caution, especially with long hyperpolarizing currents. Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Epidemiologic evidence of health effects from long-distance transit of chemical weapons fallout from bombing early in the 1991 Persian Gulf War.

PubMed

Haley, Robert W; Tuite, James J

2013-01-01

Military intelligence data published in a companion paper explain how chemical fallout from US and Coalition bombing of Iraqi chemical weapons facilities early in the air campaign transited long distance, triggering nerve agent alarms and exposing US troops. We report the findings of a population-based survey designed to test competing hypotheses on the impact on chronic Gulf War illness of nerve agent from early-war bombing versus post-war demolition. The US Military Health Survey performed computer-assisted telephone interviews of a stratified random sample of Gulf War-era veterans (n = 8,020). Early-war exposure was measured by having heard nerve agent alarms and post-war exposure, by the computer-generated plume from the Khamisiyah demolition. Gulf War illness was measured by two widely published case definitions. The OR (95% CI) for the association of alarms with the Factor case definition was 4.13 (95% CI 2.51-6.80) compared with 1.21 (95% CI 0.86-1.69) for the Khamisiyah plume. There was a dose-related trend for the number of alarms (p(trend) < 0.001) but not for the number of days in the Khamisiyah plume (p(trend) = 0.17). Exposure to low-level sarin nerve agent in fallout from bombing early in the air campaign contributed more to chronic illness than post-war demolition. Copyright © 2012 S. Karger AG, Basel.

Effect of O-methyl-β-cyclodextrin-modified magnetic nanoparticles on the uptake and extracellular level of l-glutamate in brain nerve terminals.

PubMed

Horák, Daniel; Beneš, Milan; Procházková, Zuzana; Trchová, Miroslava; Borysov, Arsenii; Pastukhov, Artem; Paliienko, Konstantin; Borisova, Tatiana

2017-01-01

Changes in cholesterol concentration in the plasma membrane of presynaptic nerve terminals nonspecifically modulate glutamate transport and homeostasis in the central nervous system. Reduction of the cholesterol content in isolated rat brain nerve terminals (synaptosomes) using cholesterol-depleting agents decreases the glutamate uptake and increases the extracellular level of glutamate in nerve terminals. Extraction of cholesterol from the plasma membrane and its further removal from the synaptosomes by external magnetic field can be achieved by means of magnetic nanoparticles with immobilized cholesterol-depleting agent such as O-methyl-β-cyclodextrin (MCD). A simple approach is developed for preparation of maghemite (γ-Fe 2 O 3 ) nanoparticles containing chemically bonded MCD. The method is based on preparation of a silanization agent containing MCD. It is synthesized by the reaction of triethoxy(3-isocyanatopropyl)silane with MCD. Base-catalyzed silanization of superparamagnetic γ-Fe 2 O 3 provides a relatively stable colloid product containing 48μmol of MCDg -1 . MCD-modified γ-Fe 2 O 3 nanoparticles decrease the initial rate of the uptake and accumulation of l-[ 14 C]glutamate and increase the extracellular l-[ 14 C]glutamate level in the preparation of nerve terminals. The effect of MCD-immobilized nanoparticles is the same as that of MCD solution; moreover, magnetic manipulation of the nanoparticles enables removal of bonded cholesterol. Copyright © 2016 Elsevier B.V. All rights reserved.

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). Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.

Catalytic degradation of organophosphorous nerve agent simulants by polymer beads@graphene oxide with organophosphorus hydrolase-like activity based on rational design of functional bimetallic nuclear ligand.

PubMed

Ma, Xuejuan; Zhang, Lin; Xia, Mengfan; Zhang, Xiaohong; Zhang, Yaodong

2018-05-15

The degradation of organophosphorous nerve agents is of primary concern due to the severe toxicity of these agents. Based on the active center of organophosphorus hydrolase (OPH), a bimetallic nuclear ligand, (5-vinyl-1,3-phenylene)bis(di(1H-imidazol-2-yl) methanol) (VPIM), was designed and synthesized, which contains four imidazole groups to mimic the four histidines at OPH active center. By grafting VPIM on graphene oxide (GO) surface via polymerization, the VPIM-polymer beads@GO was produced. The obtained OPH mimics has an impressive activity in dephosphorylation reactions (turnover frequency (TOF) towards paraoxon: 2.3 s -1 ). The synergistic catalytic effect of the bimetallic Zn 2+ nuclear center and carboxyl groups on surface of GO possibly contributes to the high hydrolysis on organophosphate substrate. Thus, a biomimetic catalyst for efficient degradation of some organophosphorous nerve agent simulants, such as paraoxon and chlorpyrifos, was prepared by constructing catalytic active sites. The proposed mechanism and general synthetic strategy open new avenues for the engineering of functional GOs for biomimetic catalysts. Copyright © 2018 Elsevier B.V. All rights reserved.

Parameters for Estimation of Casualties from Ammonia (NH3), Tabun (GA), Soman (GD),Cyclosarin (GF) and Lewisite (L)

DTIC Science & Technology

2015-09-01

2000): 493–497. Anno , George H. Anno , Siegmund J . Baum, H. Rodney Withers, and Robert W. Young. “Symptomatology of Acute Radiation Effects in Humans...Radiological and Nuclear (CBRN) Defense ( J -8/JRO) and the U.S. Army Office of The Surgeon General (OTSG). The views, opinions, and findings should not be...treatment 3 George H. Anno et al., “Symptomatology of Acute Radiation Effects in Humans after

Human Metabolism and Interactions of Deployment-Related Chemicals

DTIC Science & Technology

2008-08-01

metabolic detoxification pathway for permethrin. Other deployment related compounds, an insect repellent (N,N-diethyl-m- toluamide) a nerve gas ...Leo, K. U. 1997. Metabolism of proposed nerve agent pretreatment, pyridostigmine bromine. Walter Reed Army Institute of Research Report No. NTIS/AD...against possible nerve gas attack. It has been reported that chlorpyrifos and DEET are metabo- lized by human P450s (Tang et al., 2001; Usmani et al., 2002

Neural control of renal tubular sodium reabsorption of the dog.

PubMed

DiBona, G F

1978-04-01

The evidence supporting a role for direct neurogenic control of renal tubular sodium reabsorption is reviewed. Electron microscopic and fluorescence histochemical studies demonstrate adrenergic nerve terminals in direct contact with basement membranes of mammalian renal tubular epithelial cells. Low level direct or baroreceptor reflex stimulation of renal sympathetic nerves produces an increase in renal tubular sodium reabsorption without alterations in glomerular filtration rate, renal blood flow, or intrarenal distribution of blood flow. The antinatriuresis is prevented by prior treatment of the kidney with guanethidine or phenoxybenzamine. Possible indirect mediation of the antinatriuresis by other humoral agents known to be released from the kidney upon renal nerve stimulation (angiotensin II, prostaglandin) was excluded by experiments with appropriate blocking agents. Reflex diminutions in renal nerve activity (left atrial distention, stellate ganglion stimulation) produce a decrease in renal tubular sodium reabsorption independent of glomerular filtration rate or renal blood flow. The anatomically described adrenergic innervation of the renal tubules participates in the direct regulation of renal tubular sodium reabsorption.

2010 Department of Defense (DoD) Chemical and Biological Defense Program (CBDP) Portfolio

DTIC Science & Technology

2010-03-01

a new oxime and (2) obtaining approval for use of pyridostigmine bromide , the component of Soman Nerve Agent Pretreatment Pyridostigmine (SNAPP) for...Pralidoxime Chloride Autoinjector N/A 6505-01-125-3248 11704-620-01 N/A DLA 8 Pyridostigmine Bromide Tabs USP 30 mg I.S. (SNAPP) N/A 6505-01-178-7903 N...Soman Nerve Agent Pretreatment Pyridostigmine (SNAPP) N/A 6505-01-483-7162 N/A N/A N/A N/A Vaccines Anthrax Vaccine Adsorbed (AVA) N/A 6505-01-399

Soman Induces Ictogenesis in the Amygdala and Interictal Activity in the Hippocampus That Are Blocked by a GluR5 Kainate Receptor Antagonist In Vitro

DTIC Science & Technology

2009-01-01

to organophosphorus nerve agents in- uces brain seizures, which can cause profound brain dam- ge resulting in death or long-term cognitive deficits...The mygdala and the hippocampus are two of the most seizure- rone brain structures, but their relative contribution to the eneration of seizures after...nerve agent exposure is unclear. ere, we report that application of 1 M soman for 30 min, in at coronal brain slices containing both the hippocampus

Presynaptic facilitatory adenosine A2A receptors mediate fade induced by neuromuscular relaxants that exhibit anticholinesterase activity.

PubMed

Bornia, Elaine Cs; Correia-de-Sá, Paulo; Alves-Do-Prado, Wilson

2011-03-01

1. Pancuronium, cisatracurium and vecuronium are antinicotinic agents that, in contrast with d-tubocurarine and hexamethonium, exhibit anticholinesterase activity. Pancuronium-, cisatracurium- and vecuronium-induced fade results from blockade of facilitatory nicotinic receptors on motor nerves, but fade produced by such agents also depends on the presynaptic activation of inhibitory muscarinic M2 receptors by acetylcholine released from motor nerve terminals and activation of inhibitory adenosine A1 receptors by adenosine released from motor nerves and muscles. The participation of presynaptic facilitatory A2A receptors in fade caused by pancuronium, cisatracurium and vecuronium has not yet been investigated. In the present study, we determined the effects of ZM241385, an antagonist of presynaptic facilitatory A2A receptors, on fade produced by these neuromuscular relaxants in the rat phrenic nerve-diaphragm (PND) preparation. 2. The muscles were stimulated indirectly at 75±3Hz to induce a sustained tetanizing muscular contraction. The lowest concentration at which each antinicotinic agent produced fade without modifying initial tetanic tension (presynaptic action) was determined. 3. d-Tubocurarine-induced fade occurred only at 55 nmol/L, a concentration that also reduced maximal tetanic tension (post-synaptic action). At 10 nmol/L, ZM 241385 alone did not produce fade, but it did attenuate pancuronium (0.32 μmol/L)-, cisatracurium (0.32 μmol/L)- and vecuronium (0.36 μmol/L)-induced fade. 4. The fade induced by the 'pure' antinicotinic agents d-tubocurarine (55 nmol/L) and hexamethonium (413 μmol/L) was not altered by 10 nmol/L ZM 241385, indicating that presynaptic adenosine A2A receptors play a significant role in the fade produced by antinicotinic agents when such agents have anticholinesterase activity. © 2011 The Authors. Clinical and Experimental Pharmacology and Physiology © 2011 Blackwell Publishing Asia Pty Ltd.

Temporary Blindness after Inferior Alveolar Nerve Block.

PubMed

Barodiya, Animesh; Thukral, Rishi; Agrawal, Shaila Mahendra; Rai, Anshul; Singh, Siddharth

2017-03-01

Inferior Alveolar Nerve Block (IANB) anaesthesia is one of the common procedures in dental clinic. This procedure is safe, but complications may still occur. Ocular complications such as diplopia, loss of vision, or ophthalmoplegia are extremely rare. This case report explains an event where due to individual anatomic variation of the sympathetic vasoconstrictor nerve and maxillary and middle meningeal arteries, intravascular administration of anaesthetic agent caused unusual ocular signs and symptoms such as temporary blindness.

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 molecular and biochemical changes and subsequent long term neurological effects induced by nerve agents. PMID:24708580

Functionalized polymer nanofibre membranes for protection from chemical warfare stimulants

NASA Astrophysics Data System (ADS)

Ramaseshan, Ramakrishnan; Sundarrajan, Subramanian; Liu, Yingjun; Barhate, R. S.; Lala, Neeta L.; Ramakrishna, S.

2006-06-01

A catalyst for the detoxification of nerve agents is synthesized from β-cyclodextrin (β-CD) and o-iodosobenzoic acid (IBA). Functionalized polymer nanofibre membranes from PVC polymer are fabricated with β-CD, IBA, a blend of β-CD+IBA, and the synthesized catalyst. These functionalized nanofibres are then tested for the decontamination of paraoxon, a nerve agent stimulant, and it is observed that the stimulant gets hydrolysed. The kinetics of hydrolysis is investigated using UV spectroscopy. The rates of hydrolysis for different organophosphate hydrolyzing agents are compared. The reactivity and amount of adsorption of these catalysts are of higher capacity than the conventionally used activated charcoal. A new design for protective wear is proposed based on the functionalized nanofibre membrane.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Guodong; Lin, Yuehe

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 greatlymore » 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.« less

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.

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.

VX toxicity in the Göttingen minipig.

PubMed

Langston, Jeffrey L; Myers, Todd M

2016-12-15

The present experiments determined the intramuscular LD 50 of VX in male Göttingen minipigs at two stages of development. In pubertal animals (115 days old), the LD 50 of VX was indeterminate, but approximated 33.3μg/kg. However, in sexually mature animals (152 days old), the LD 50 was estimated to be only 17.4μg/kg. Signs of nerve agent toxicity in the Göttingen minipig were similar to those described for other species, with some notable exceptions (such as urticaria and ejaculation). Latencies to the onset of sustained convulsions were inversely related to the administered dose of VX in both ages of minipigs. Additionally, actigraphy was used to quantify the presence of tremor and convulsions and, in some cases, was useful for precisely estimating time of death. The main finding indicates that in minipigs, as in other species, even relatively small differences in age can substantially alter the toxicity of nerve agents. Additionally, actigraphy can serve as a non-invasive method of characterizing the tremors and convulsions that often accompany nerve agent intoxication. Published by Elsevier Ireland Ltd.

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

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.

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

Graphene oxide/MnO2 nanocomposite as destructive adsorbent of nerve-agent simulants in aqueous media

NASA Astrophysics Data System (ADS)

Šťastný, Martin; Tolasz, Jakub; Štengl, Václav; Henych, Jiří; Žižka, David

2017-08-01

Graphene oxide/MnO2 nanocomposite was prepared by thermal hydrolysis of potassium permanganate (KMnO4) and 2-chloroacetamide aqueous solutions with graphene oxide (GO) suspension. The synthesized samples were characterized by specific surface area (BET) and porosity determination (BJH), X-ray Diffraction (XRD) and high-resolution electron microscopes (HRSEM, HRTEM). These nanocomposites were used in an experimental evaluation of their adsorption activity with nerve agent simulants dimethyl methyl phosphonate (DMMP) and triethyl phosphate (TEP) in aqueous media. The nanocomposites exhibited enhanced adsorptive degradation ability compared to pure manganese oxide (MnO2) and GO. The GO amount in the nanocomposites affected their degradation activity substantially. The best adsorption efficiency was observed for samples with moderate GO amount. Three methods were used to observe the mechanism of the nerve-agent simulants deactivation: Gas chromatography with mass spectrometry (GC-MS), High-Performance Liquid Chromatography (HPLC) and in situ Infrared spectroscopy (FTIR). It was shown that the hydrolysis on the surface of prepared nanocomposites yields volatile primary alcohols (methanol and ethanol) as the main hydrolysis products.

Bioengineered nerve regeneration and muscle reinnervation

PubMed Central

Kingham, Paul J; Terenghi, Giorgio

2006-01-01

The peripheral nervous system has the intrinsic capacity to regenerate but the reinnervation of muscles is often suboptimal and results in limited recovery of function. Injuries to nerves that innervate complex organs such as the larynx are particularly difficult to treat. The many functions of the larynx have evolved through the intricate neural regulation of highly specialized laryngeal muscles. In this review, we examine the responses of nerves and muscles to injury, focusing on changes in the expression of neurotrophic factors, and highlight differences between the skeletal limb and laryngeal muscle systems. We also describe how artificial nerve conduits have become a useful tool for delivery of neurotrophic factors as therapeutic agents to promote peripheral nerve repair and might eventually be useful in the treatment of laryngeal nerve injury. PMID:17005023

The role of oxidative stress in organophosphate and nerve agent toxicity

PubMed Central

Pearson, Jennifer N.; Patel, Manisha

2016-01-01

Organophosphate nerve agents exert their toxicity through inhibition of acetylcholinesterase. The excessive stimulation of cholinergic receptors rapidly causes neuronal damage, seizures, death, and long-term neurological impairment in those that survive. Owing to the lethality of organophosphorus agents and the growing risk they pose, medical interventions that prevent organophosphate toxicity and the delayed injury response are much needed. Studies have shown that oxidative stress occurs in models of subacute, acute, and chronic exposure to organophosphate agents. Key findings of these studies include alterations in mitochondrial function and increased free radical–mediated injury, such as lipid peroxidation. This review focuses on the role of reactive oxygen species in organophosphate neurotoxicity and its dependence on seizure activity. Understanding the sources, mechanisms, and pathological consequences of organophosphate-induced oxidative stress can lead to the development of rational therapies for treating toxic exposures. PMID:27371936

A comparison of organophosphate degradation genes and bioremediation applications.

PubMed

Iyer, Rupa; Iken, Brian; Damania, Ashish

2013-12-01

Organophosphates (OPs) form the bulk of pesticides that are currently in use around the world accounting for more than 30% of the world market. They also form the core for many nerve-based warfare agents including sarin and soman. The widespread use and the resultant build-up of OP pesticides and chemical nerve agents has led to the development of major health problems due to their extremely toxic interaction with any biological system that encounters them. Growing concern over the accumulation of OP compounds in our food products, in the soils from which they are harvested and in wastewater run-off has fuelled a growing interest in microbial biotechnology that provides cheap, efficient OP detoxification to supplement expensive chemical methods. In this article, we review the current state of knowledge of OP pesticide and chemical agent degradation and attempt to clarify confusion over identification and nomenclature of two major families of OP-degrading enzymes through a comparison of their structure and function. The isolation, characterization, utilization and manipulation of the major detoxifying enzymes and the molecular basis of degradation of OP pesticides and chemical nerve agents are discussed as well as the achievements and technological advancements made towards the bioremediation of such compounds. © 2013 John Wiley & Sons Ltd and Society for Applied Microbiology.

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.

Immobilization of Enzymes in Nanoporous Host Materials: A Nanobiotechnological Approach to Decontamination and Demilitarization of Chemical and Biological Warfare Agents

DTIC Science & Technology

2002-05-06

Organophosphorus compounds (OPs) are highly toxic and found extensive use as pesticides , insecticides and potential chemical warfare (CW) agents . Recently...commonly used substrate, the serine protease inhibitor diisopropyl fluorophosphates (DFP), and different fluoride-containing G-type nerve agents such as...

Combining SBR systems for chemical and biological treatment: the destruction of the nerve agent VX.

PubMed

Irvine, R L; Haraburda, S S; Galbis-Reig, C

2004-01-01

The US Army is pilot testing the neutralization of VX nerve agent stockpiled at Newport, Indiana using caustic hydrolysis in a Sequencing Batch Reactor (SBR). The resulting hydrolysate was tested at the bench-scale for treatment with activated sludge biodegradation in two distinct studies, one in the SBR and another, in the PACT process. The feed to both biological systems was pretreated to enhance the biodegradability of the hydrolysis products. Both biodegradation studies demonstrated that the hydrolysate could easily meet the Chemical Weapons Convention treaty and US environmental regulations following pretreatment.

Treatment of great auricular neuralgia with real-time ultrasound-guided great auricular nerve block

PubMed Central

Jeon, Younghoon; Kim, Saeyoung

2017-01-01

Abstract Rationale: The great auricular nerve can be damaged by the neck surgery, tumor, and long-time pressure on the neck. But, great auricular neuralgia is very rare condition. It was managed by several medication and landmark-based great auricular nerve block with poor prognosis. Patient concerns: A 25-year-old man presented with a pain in the left lateral neck and auricle. Diagnosis: He was diagnosed with great auricular neuralgia. Interventions: His pain was not reduced by medication. Therefore, the great auricular nerve block with local anesthetics and steroid was performed under ultrasound guidance. Outcomes: Ultrasound guided great auricular nerve block alleviated great auricular neuralgia. Lessons: This medication-resistant great auricular neuralgia was treated by the ultrasound guided great auricular nerve block with local anesthetic agent and steroid. Therefore, great auricular nerve block can be a good treatment option of medication resistant great auricular neuralgia. PMID:28328811

May the Inferior Petrosal Sinus Recanalization During Endovascular Treatment for Carotid-Cavernous Fistulas Increase the Risk of Sixth Nerve Palsy?

PubMed

Robert, Thomas; Valsecchi, Daniele; Sylvestre, Philippe; Blanc, Raphaël; Ciccio, Gabriele; Smajda, Stanislas; Redjem, Hocine; Piotin, Michel

2018-05-03

Sixth nerve palsy is a common complication of endovascular treatment for carotid-cavernous fistulas (CCF). Two hypotheses are evoked: the spontaneous venous congestion into the cavernous sinus and the direct compression of the nerve by the embolic agent into the cavernous sinus. Nevertheless, the evidence is still uncertain. Knowing the vicinity of the sixth nerve with the inferior petrosal sinus (IPS) in the Dorello canal, we hypothesized that the recanalization of the IPS increased the risk of nerve damage. We analyzed a prospective database of patients treated for CCFs from March 2009 to April 2016. We excluded patients who did not need treatment, cases of high-flow CCF, and patients lost to follow-up, obtaining a homogeneous population of 82 patients with indirect CCFs. This population was divided in 2 groups: patients without new-onset/worsening of sixth nerve palsy and patients with this postprocedural complication. Our main endpoints were the potential differences between patients with or without recanalization of IPS and between those who underwent or not an embolization with Onyx-18. We did not find any statistically meaningful difference between the 2 groups concerning the necessity of IPS recanalization (P > 0.999, odds ratio 0.97, 95% confidence interval 0.32-2.96) or with the use of Onyx-18 as an embolic agent (P = 0.56; odds ratio 1.41, 95% confidence interval 0.41-2.45). The recanalization of a thrombosed IPS does not increase the risk of procedural sixth nerve damage. The initial injury seems to relate with development/worsening of a sixth nerve palsy. Copyright © 2018 Elsevier Inc. All rights reserved.

Development of a microinstillation model of inhalation exposure to assess lung injury following exposure to toxic chemicals and nerve agents in Guinea pigs.

PubMed

Nambiar, Madhusoodana P; Wright, Benjamin S; Rezk, Peter E; Smith, Kelvin B; Gordon, Richard K; Moran, Theodore S; Richards, Shannon M; Sciuto, Alfred M

2006-01-01

Respiratory disturbances due to chemical warfare nerve agents (CWNAs) are the starting point of mass casualty and the primary cause of death by these weapons of terror and mass destruction. However, very few studies have been implemented to assess respiratory toxicity and exacerbation induced by CWNAs, especially methylphosphonothioic acid S-(2-(bis(1-methylethyl)amino)ethyl)O-ethyl ester (VX). In this study, we developed a microinstillation technique of inhalation exposure to assess lung injury following exposure to CWNAs and toxic chemicals. Guinea pigs were gently intubated by placing a microcatheter into the trachea 1.5 to 2.0 cm centrally above the bifurcation. This location is crucial to deliver aerosolized agents uniformly to the lung's lobes. The placement of the tube is calculated by measuring the distance from the upper front teeth to the tracheal bifurcation, which is typically 8.5 cm for guinea pigs of equivalent size and a weight range of 250 g to 300 g. The catheter is capable of withstanding 100 psi pressure; the terminus has five peripheral holes to pump air that aerosolizes the nerve agent that is delivered in the central hole. The microcatheter is regulated by a central control system to deliver the aerosolized agent in a volume lower than the tidal volume of the guinea pigs. The average particle size of the nerve agent delivered was 1.48 +/- 0.07 micrometer. The microinstillation technology has been validated by exposing the animals to Coomassie brilliant blue, which showed a uniform distribution of the dye in different lung lobes. In addition, the concentration of the dye in the lungs correlated with the dose/time of exposure. Furthermore, histopathological analysis confirmed the absence of barotraumas following micoinstillation. This novel technique delivers the agent safely, requires less amount of agent, avoids exposure to skin, pelt, and eye, and circumvents the concern of deposition of the particles in the nasal and palette due to the switching of breathing from nasal to oronasal in whole-body dynamic chamber or nose only exposure. Currently, we are using this inhalation exposure technique to investigate lung injuries and respiratory disturbances following direct exposure to VX.

Local anesthetic-induced myotoxicity as a cause of severe trismus after inferior alveolar nerve block.

PubMed

Smolka, Wenko; Knoesel, Thomas; Mueller-Lisse, Ullrich

2018-01-01

A case of a 60-year-old man with severe trismus after inferior alveolar nerve block is presented. MRI scans as well as histologic examination revealed muscle fibrosis and degeneration of the medial part of the left temporal muscle due to myotoxicity of a local anesthetic agent.

Multiphoton Microscopy of Prostate and Periprostatic Neural Tissue: A Promising Imaging Technique for Improving Nerve-Sparing Prostatectomy

PubMed Central

Yadav, Rajiv; Mukherjee, Sushmita; Hermen, Michael; Tan, Gerald; Maxfield, Frederick R.; Webb, Watt W.

2009-01-01

Abstract Background and Purpose Various imaging modalities are under investigation for real-time tissue imaging of periprostatic nerves with the idea of improving the results of nerve-sparing radical prostatectomy. We explored multiphoton microscopy (MPM) for real-time tissue imaging of the prostate and periprostatic neural tissue in a male Sprague-Dawley rat model. The unique advantage of this technique is the acquisition of high-resolution images without necessitating any extrinsic labeling agent and with minimal phototoxic effect on tissue. Materials and Methods The prostate and cavernous nerves were surgically excised from male Sprague-Dawley rats. The imaging was carried out using intrinsic fluorescence and scattering properties of the tissues without any exogenous dye or contrast agent. A custom-built MPM, consisting of an Olympus BX61WI upright frame and a modified MRC 1024 scanhead, was used. A femtosecond pulsed titanium/sapphire laser at 780-nm wavelength was used to excite the tissue; laser power under the objective was modulated via a Pockels cell. Second harmonic generation (SHG) signals were collected at 390 (±35 nm), and broadband autofluorescence was collected at 380 to 530 nm. The images obtained from SHG and from tissue fluorescence were then merged and color coded during postprocessing for better appreciation of details. The corresponding tissues were subjected to hematoxylin and eosin staining for histologic confirmation of the structures. Results High-resolution images of the prostate capsule, underlying acini, and individual cells outlining the glands were obtained at varying magnifications. MPM images of adipose tissue and the neural tissues were also obtained. Histologic confirmation and correlation of the prostate gland, fat, cavernous nerve, and major pelvic ganglion validated the findings of MPM. Conclusion Real-time imaging and microscopic resolution of prostate and periprostatic neural tissue using MPM is feasible without the need for any extrinsic labeling agents. Integration of this imaging modality with operative technique has the potential to improve the precision of nerve-sparing prostatectomy. PMID:19425823

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Guodong; Wang, Jun; Barry, Richard C.

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 electrochemicalmore » 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.« less

A High-Throughput UHPLC-MS/MS Method for the Quantification of Five Aged Butyrylcholinesterase Biomarkers from Human Exposure to Organophosphorus Nerve Agents

PubMed Central

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.

2017-01-01

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 (MeP-BChE), ethyl phosphonate (EtP-BChE), propyl phosphonate (PrP-BChE), ethyl phosphoryl (ExP-BChE), phosphoryl (P-BChE), 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 three minutes making the time to first unknown results, including calibration curve and quality controls, less than one hour. 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. PMID:27572107

Comparison of the efficacy of HI6 and 2-PAM against soman, tabun, sarin, and VX in the rabbit

DOE Office of Scientific and Technical Information (OSTI.GOV)

Koplovitz, I.; Stewart, J.R.

1994-12-31

This study compared the efficacy of H16 and 2-PAM against nerve agent (soman tabun sarin and VX) -induced lethality in the atropinesterase-free rabbits pretreated with vehicle (controls) or pyridostigmine. Treatment was administered at signs or 2 min after agent challenge and consisted ofoxime (l00umol/lkg) + atropine 13 mg(kg) (alone or together with diazepam). Twenty-four-h LD50 values were calculated for soman- and tabun-intoxicated animals, whereas 24-h survival was noted in animals given 10 LD50s of sarin or VX. In pyridostigmine and control rabbits intoxicated with soman and treated with oxime + atropine (alone or together with diazepam), HI6 was 35 timesmore » more effective than 2-PAM. In contrast 1116 was less effective than 2-PAM against tabun poisoning. In pyridostigmine-pretreated animals exposed to tabun, efficacy was increased more than 3-fold when compare to tabun-challenged animals treated with atropine + H16 alone. Both oximes were highly effective against satin and VX. These findings suggest that Hifi could replace 2-PAM as therapy for nerve agent poisoning because it is superior to 2-PAM against soman, and when used in pyridostigmine-pretreated animals it affords excellent protection against all four nerve agents when used in combination with atropine (alone or together with diazepam) therapy.« less

Treating exposure to chemical warfare agents: implications for health care providers and community emergency planning.

PubMed Central

Munro, N B; Watson, A P; Ambrose, K R; Griffin, G D

1990-01-01

Current treatment protocols for exposure to nerve and vesicant agents found in the U.S. stockpile of unitary chemical weapons are summarized, and the toxicities of available antidotes are evaluated. The status of the most promising of the new nerve agent antidotes is reviewed. In the U.S. atropine and pralidoxime compose the only approved antidote regimen for organophosphate nerve agent poisoning. Diazepam may also be used if necessary to control convulsions. To avoid death, administration must occur within minutes of substantial exposure together with immediate decontamination. Continuous observation and repeated administration of antidotes are necessary as symptoms warrant. Available antidotes do not necessarily prevent respiratory failure or incapacitation. The toxicity of the antidotes themselves and the individualized nature of medical care preclude recommending that autoinjectors be distributed to the general public. In addition, precautionary administration of protective drugs to the general population would not be feasible or desirable. No antidote exists for poisoning by the vesicant sulfur mustard (H, HD, HT); effective intervention can only be accomplished by rapid decontamination followed by palliative treatment of symptoms. British anti-Lewisite (BAL) (2,3-dimercapto-1-propanolol) is the antidote of choice for treatment of exposure to Lewisite, another potent vesicant. Experimental water-soluble BAL analogues have been developed that are less toxic than BAL. Treatment protocols for each antidote are summarized in tabular form for use by health care providers. PMID:2088748

Preliminary assessment of the health and environmental impacts of transporting M55 rockets from Lexington-Blue Grass Depot activity, Anniston Army depot, and Umatilla depot activity to alternative disposal facilities

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carnes, S.A.; Breck, J.E.; Copenhaver, E.D.

1986-03-01

This assessment discusses the potential health and environmental impacts of transporting M55 rockets filled with nerve agent GB or VX from various existing Army storage depots to alternative Army depots for disposal. The origin depots include Anniston Army Depot in Alabama, Lexington-Blue Grass Depot Activity in Kentucky, and Umatilla Depot Activity in Oregon. The destination depots include Pine Bluff Arsenal in Arkansas, Tooele Army Depot in Utah, and the facility on Johnston Island in the central Pacific Ocean. This assessment considers the possible impacts of normal transport operations and of two postulated accident scenarios on the air quality, ground andmore » surface water, aquatic ecology, terrestrial ecology, human health, and cultural and socioeconomic resources of the various transport corridors involved. The impacts of these scenarios are assessed for truck, train, and air transport for each orgin-destination pair. The analysis considers three basic scenario during transport: (1) normal operations with no atmospheric release of nerve agent; (2) a minor agent spill (the contents of one rocket being released to the biosphere); and (3) a worst-case accident involving the release of a large, specified quantity of nerve agent to the biosphere. The extremely low probabilities of such accidents, which are reported elsewhere, are noted.« less

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.

Nitrotyrosine localization to dermal nerves in borderline leprosy.

PubMed

Schön, T; Hernández-Pando, R; Baquera-Heredia, J; Negesse, Y; Becerril-Villanueva, L E; Eon-Contreras, J C L; Sundqvist, T; Britton, S

2004-03-01

Nerve damage is a common and disabling feature of leprosy, with unclear aetiology. It has been reported that the peroxidizing agents of myelin lipids-nitric oxide (NO) and peroxynitrite-are produced in leprosy skin lesions. To investigate the localization of nitrotyrosine (NT)-a local end-product of peroxynitrite-in leprosy lesions where dermal nerves are affected by a granulomatous reaction. We investigated by immunohistochemistry and immunoelectron microscopy the localization of the inducible NO synthase (iNOS) and NT in biopsies exhibiting dermal nerves from patients with untreated leprosy. There were abundant NT-positive and iNOS-positive macrophages in the borderline leprosy granulomas infiltrating peripheral nerves identified by light microscopy, S-100 and neurofilament immunostaining. Immunoelectron microscopy showed NT reactivity in neurofilament aggregates and in the cell wall of Mycobacterium leprae. Our results suggest that NO and peroxynitrite could be involved in the nerve damage following borderline leprosy.

Ion mobility spectrometric analysis of vaporous chemical warfare agents by the instrument with corona discharge ionization ammonia dopant ambient temperature operation.

PubMed

Satoh, Takafumi; Kishi, Shintaro; Nagashima, Hisayuki; Tachikawa, Masumi; Kanamori-Kataoka, Mieko; Nakagawa, Takao; Kitagawa, Nobuyoshi; Tokita, Kenichi; Yamamoto, Soichiro; Seto, Yasuo

2015-03-20

The ion mobility behavior of nineteen chemical warfare agents (7 nerve gases, 5 blister agents, 2 lachrymators, 2 blood agents, 3 choking agents) and related compounds including simulants (8 agents) and organic solvents (39) was comparably investigated by the ion mobility spectrometry instrument utilizing weak electric field linear drift tube with corona discharge ionization, ammonia doping, purified inner air drift flow circulation operated at ambient temperature and pressure. Three alkyl methylphosphonofluoridates, tabun, and four organophosphorus simulants gave the intense characteristic positive monomer-derived ion peaks and small dimer-derived ion peaks, and the later ion peaks were increased with the vapor concentrations. VX, RVX and tabun gave both characteristic positive monomer-derived ions and degradation product ions. Nitrogen mustards gave the intense characteristic positive ion peaks, and in addition distinctive negative ion peak appeared from HN3. Mustard gas, lewisite 1, o-chlorobenzylidenemalononitrile and 2-mercaptoethanol gave the characteristic negative ion peaks. Methylphosphonyl difluoride, 2-chloroacetophenone and 1,4-thioxane gave the characteristic ion peaks both in the positive and negative ion mode. 2-Chloroethylethylsulfide and allylisothiocyanate gave weak ion peaks. The marker ion peaks derived from two blood agents and three choking agents were very close to the reactant ion peak in negative ion mode and the respective reduced ion mobility was fluctuated. The reduced ion mobility of the CWA monomer-derived peaks were positively correlated with molecular masses among structurally similar agents such as G-type nerve gases and organophosphorus simulants; V-type nerve gases and nitrogen mustards. The slope values of the calibration plots of the peak heights of the characteristic marker ions versus the vapor concentrations are related to the detection sensitivity, and within chemical warfare agents examined the slope values for sarin, soman, tabun and nitrogen mustards were higher. Some CWA simulants and organic solvents gave the ion peaks eluting at the similar positions of the CWAs, resulting in false positive alarms. Copyright © 2015 Elsevier B.V. All rights reserved.

[Pay attention to the secondary optic neuropathy and the safe appropriate applications of optic neuroprotection].

PubMed

Zhong, Y

2016-12-11

Secondary optic neuropathy of optic nerve abnormalities is the leading cause of persistent visual impairment. Previous ocular neuroprotection studies have proved that the nerve growth factor and other agents are of significant in the preservation of optic nerve axon and retinal ganglion cells. However, finding novel safe and effective approach as well as the appropriate applications of optic neuroprotection should be highly emphasized and would be very helpful in the treatment of optic neuropathy. (Chin J Ophthalmol, 2016, 52: 881 - 884) .

Efficacy of ketamine hydrochloride administered as a basilar sesamoid nerve block in alleviating foot pain in horses caused by natural disease.

PubMed

Schumacher, J; DeGraves, F; Cesar, F; Duran, S

2014-09-01

A local anaesthetic agent capable of temporarily resolving lameness after being administered perineurally would be helpful because rapid return of lameness would allow for other analgesic techniques to be performed within a short period of time. To determine if a 3% solution of ketamine hydrochloride (HCl), administered around the palmar nerves at the level of the base of the proximal sesamoid bones, can improve naturally occurring lameness that can be improved or abolished with a basilar sesamoid nerve block performed using lidocaine HCl and to compare the change in gait produced using lidocaine to the change in gait produced using ketamine by using objective lameness assessment. Experimental trial using research horses with naturally occurring lameness. Seven horses, chronically lame on a thoracic limb, were chosen for the study. A wireless, inertial, sensor-based, motion analysis system was used to evaluate lameness before and after administration of 2% lidocaine and later, before and after administration of 3% ketamine over the palmar digital nerves at the base of the proximal sesamoid bones (a basilar sesamoid nerve block) at 5 min intervals for 30 min. Lameness scores obtained before and after administration of lidocaine and ketamine HCl were compared using repeated measures analysis. Gait significantly improved after basilar sesamoid nerve blocks using 2% lidocaine, but gait did not significantly improve after performing the same nerve block using 3% ketamine HCl. Ketamine (3%) administered perineurally for regional anaesthesia of the digit does not desensitise the digit to the same extent as does lidocaine and thus 3% ketamine appears to have no value as a local anaesthetic agent for diagnostic regional anaesthesia. © 2013 EVJ Ltd.

Estimated Chemical Warfare Agent Surface Clearance Goals for Remediation Pre-Planning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dolislager, Frederick; Bansleben, Dr. Donald; Watson, Annetta Paule

2010-01-01

Health-based surface clearance goals, in units of mg/cm2, have been developed for the persistent chemical warfare agents sulfur mustard (HD) and nerve agent VX as well as their principal degradation products. Selection of model parameters and critical receptor (toddler child) allow calculation of surface residue estimates protective for the toddler child, the general population and adult employees of a facilty that has undergone chemical warfare agent attack.

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.

A Comprehensive Evaluation of the Efficacy of Leading Oxime Therapies in Guinea Pigs Exposed to Organophosphorus Chemical Warfare Agents or Pesticides

PubMed Central

Wilhelm, Christina M.; Snider, Thomas H.; Babin, Michael C.; Jett, David A.; Platoff, Gennady E.; Yeung, David T.

2014-01-01

The currently fielded pre-hospital therapeutic regimen for the treatment of organophosphorus (OP) poisoning in the United States (U.S.) is the administration of atropine in combination with an oxime antidote (2-PAM Cl) to reactivate inhibited acetylcholinesterase (AChE). Depending on clinical symptoms, an anticonvulsant, e.g., diazepam, may also be administered. Unfortunately, 2-PAM Cl does not offer sufficient protection across the range of OP threat agents, and there is some question as to whether it is the most effective oxime compound available. The objective of the present study is to identify an oxime antidote, under standardized and comparable conditions, that offers protection at the FDA approved human equivalent dose (HED) of 2-PAM Cl against tabun (GA), sarin (GB), soman (GD), cyclosarin (GF), and VX, and the pesticides paraoxon, chlorpyrifos oxon, and phorate oxon. Male Hartley guinea pigs were subcutaneously challenged with a lethal level of OP and treated at approximately 1 min post challenge with atropine followed by equimolar oxime therapy (2-PAM Cl, HI-6 DMS, obidoxime Cl2, TMB-4, MMB4-DMS, HLö-7 DMS, MINA, and RS194B) or therapeutic-index (TI) level therapy (HI-6 DMS, MMB4-DMS, MINA, and RS194B). Clinical signs of toxicity were observed for 24 hours post challenge and blood cholinesterase [AChE and butyrylcholinesterase (BChE)] activity was analyzed utilizing a modified Ellman’s method. When the oxime is standardized against the HED of 2-PAM Cl for guinea pigs, the evidence from clinical observations, lethality, quality of life (QOL) scores, and cholinesterase reactivation rates across all OPs indicated that MMB4 DMS and HLö-7 DMS were the two most consistently efficacious oximes. PMID:25448441

[Effects of nootropic agents on visual functions and lacrimal antioxidative activity in patients with primary open-angle glaucoma].

PubMed

Davydova, N G; Kuznetsova, T P; Borisova, S A; Abdulkadyrova, M Zh

2006-01-01

The paper presents the results of an investigation of the effect of the nootropic agents pantogam and nooclerine on visual functions in patients with primary open-angle glaucoma. These agents have been found to have a beneficial effect on the functional activity of the retina and optic nerve, light sensitivity, hemo- and hydrodynamics of the eye.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lin, Yuehe; Wang, Jun; Liu, Guodong

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-basedmore » 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.« less

Heme-Containing Metal-Organic Frameworks for the Oxidative Degradation of Chemical Warfare Agents

DTIC Science & Technology

2016-04-14

stability of the oxo without sacrificing its inherent reactivity, we have synthesized a new framework featuring fluorinated groups in the ortho...especially suitable for the degradation of electrophilic phosphorous center, leading to the cleavage of P-S or P-O bond present in VX nerve agents

Detection of vapor-phase organophosphate threats using wearable conformable integrated epidermal and textile wireless biosensor systems.

PubMed

Mishra, Rupesh K; Martín, Aida; Nakagawa, Tatsuo; Barfidokht, Abbas; Lu, Xialong; Sempionatto, Juliane R; Lyu, Kay Mengjia; Karajic, Aleksandar; Musameh, Mustafa M; Kyratzis, Ilias L; Wang, Joseph

2018-03-15

Flexible epidermal tattoo and textile-based electrochemical biosensors have been developed for vapor-phase detection of organophosphorus (OP) nerve agents. These new wearable sensors, based on stretchable organophosphorus hydrolase (OPH) enzyme electrodes, are coupled with a fully integrated conformal flexible electronic interface that offers rapid and selective square-wave voltammetric detection of OP vapor threats and wireless data transmission to a mobile device. The epidermal tattoo and textile sensors display a good reproducibility (with RSD of 2.5% and 4.2%, respectively), along with good discrimination against potential interferences and linearity over the 90-300mg/L range, with a sensitivity of 10.7µA∙cm 3 ∙mg -1 (R 2 = 0.983) and detection limit of 12mg/L in terms of OP air density. Stress-enduring inks, used for printing the electrode transducers, ensure resilience against mechanical deformations associated with textile and skin-based on-body sensing operations. Theoretical simulations are used to estimate the OP air density over the sensor surface. These fully integrated wearable wireless tattoo and textile-based nerve-agent vapor biosensor systems offer considerable promise for rapid warning regarding personal exposure to OP nerve-agent vapors in variety of decentralized security applications. Copyright © 2017 Elsevier B.V. All rights reserved.

(-)-Phenserine Attenuates Soman-Induced Neuropathology

PubMed Central

Chen, Jun; Pan, Hongna; Chen, Cynthia; Wu, Wei; Iskandar, Kevin; He, Jeffrey; Piermartiri, Tetsade; Jacobowitz, David M.; Yu, Qian-Sheng; McDonough, John H.; Greig, Nigel H.; Marini, Ann M.

2014-01-01

Organophosphorus (OP) nerve agents are deadly chemical weapons that pose an alarming threat to military and civilian populations. The irreversible inhibition of the critical cholinergic degradative enzyme acetylcholinesterase (AChE) by OP nerve agents leads to cholinergic crisis. Resulting excessive synaptic acetylcholine levels leads to status epilepticus that, in turn, results in brain damage. Current countermeasures are only modestly effective in protecting against OP-induced brain damage, supporting interest for evaluation of new ones. (-)-Phenserine is a reversible AChE inhibitor possessing neuroprotective and amyloid precursor protein lowering actions that reached Phase III clinical trials for Alzheimer's Disease where it exhibited a wide safety margin. This compound preferentially enters the CNS and has potential to impede soman binding to the active site of AChE to, thereby, serve in a protective capacity. Herein, we demonstrate that (-)-phenserine protects neurons against soman-induced neuronal cell death in rats when administered either as a pretreatment or post-treatment paradigm, improves motoric movement in soman-exposed animals and reduces mortality when given as a pretreatment. Gene expression analysis, undertaken to elucidate mechanism, showed that (-)-phenserine pretreatment increased select neuroprotective genes and reversed a Homer1expression elevation induced by soman exposure. These studies suggest that (-)-phenserine warrants further evaluation as an OP nerve agent protective strategy. PMID:24955574

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.

Characterization of chemical warfare G-agent hydrolysis products by surface-enhanced Raman spectroscopy

NASA Astrophysics Data System (ADS)

Inscore, Frank E.; Gift, Alan D.; Maksymiuk, Paul; Farquharson, Stuart

2004-12-01

The United States and its allies have been increasingly challenged by terrorism, and since the September 11, 2001 attacks and the war in Afghanistan and Iraq, homeland security has become a national priority. The simplicity in manufacturing chemical warfare agents, the relatively low cost, and previous deployment raises public concern that they may also be used by terrorists or rogue nations. We have been investigating the ability of surface-enhanced Raman spectroscopy (SERS) to detect extremely low concentrations (e.g. part-per-billion) of chemical agents, as might be found in poisoned water. Since trace quantities of nerve agents can be hydrolyzed in the presence of water, we have expanded our studies to include such degradation products. Our SERS-active medium consists of silver or gold nanoparticles incorporated into a sol-gel matrix, which is immobilized in a glass capillary. The choice of sol-gel precursor allows controlling hydrophobicity, while the porous silica network offers a unique environment for stabilizing the SERS-active metals. Here we present the use of these metal-doped sol-gels to selectively enhance the Raman signal of the hydrolyzed products of the G-series nerve agents.

A T-cell-dependent humoral immune response is preserved during the administration of the nerve agent pre-treatment pyridostigmine bromide in a murine model.

PubMed

Griffiths, Gareth D; Telford, Gary; Hooi, Doreen S W; Cook, David L; Wilkinson, Lucy J; Green, Christopher A; Pritchard, David I

2005-03-01

Immune regulation, either via the autonomic nervous system or by a proposed "non-neuronal" cholinergic system, suggests that the immune system may be susceptible to perturbation by compounds affecting cholinergic function. Here, the current UK and US nerve agent pre-treatment, pyridostigmine bromide (PB) and the related anti-acetylcholinesterase (AChE) compounds physostigmine (PHY) and BW284c51 were tested for their ability to affect mouse splenocyte function in vitro. In addition, PB, at a dose equivalent to that received during pre-treatment for nerve agent poisoning, was tested for its effect on a T-cell-dependent humoral response to antigen in vivo in the mouse. None of the anti-AChEs tested affected concanavalin A (Con A)-, anti-CD3- or lipopolysaccharide LPS-driven splenocyte proliferation, in vitro, at concentrations expected to give effective nerve agent pre-treatment. However, higher concentrations (>100 microM) particularly of PHY caused some inhibition of the proliferative responses. In vivo, PB or saline was administered via 28-day mini-osmotic pumps to give a 25-40% inhibition of whole blood AChE in the PB-treated animals. During PB or saline administration, primary and secondary doses (i.p.) of sheep red blood cells (SRBC) were given and the humoral response determined by monitoring anti-SRBC IgM and IgG levels. Splenocytes isolated from the experimental animals were also examined for their proliferative and cytokine responses to stimulation. No remarkable effects of PB were seen during the period of AChE inhibition on the humoral immune response. However, a modest elevation in IL-2 and IFN(gamma) in Con A-stimulated lymphocytes was seen in PB-treated animals following pump removal. Overall these data suggest that, in vivo, the SRBC stimulated T-cell-dependent immune response is unaffected by the administration of PB at pre-treatment doses.

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.

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

Pharmacokinetic profile and quantitation of protection against soman poisoning by the antinicotinic compound MB327 in the guinea-pig.

PubMed

Price, Matthew E; Docx, Cerys J; Rice, Helen; Fairhall, Sarah J; Poole, Sarah J C; Bird, Michael; Whiley, Luke; Flint, Daniel P; Green, A Christopher; Timperley, Christopher M; Tattersall, John E H

2016-02-26

Current organophosphorus nerve agent medical countermeasures do not directly address the nicotinic effects of poisoning. A series of antinicotinic bispyridinium compounds has been synthesized in our laboratory and screened in vitro. Their actions can include open-channel block at the nicotinic receptor which may contribute to their efficacy. The current lead compound from these studies, MB327 1,1'-(propane-1,3-diyl)bis(4-tert-butylpyridinium) as either the diiodide (I2) or dimethanesulfonate (DMS) has been examined in vivo for efficacy against nerve agent poisoning. MB327 I2 (0-113mgkg(-1)) or the oxime HI-6 DMS (0-100mgkg(- 1)), in combination with atropine and avizafone (each at 3mgkg(-1)) was administered to guinea-pigs 1min following soman poisoning. Treatment increased the LD50 of soman in a dose-dependent manner. The increase was statistically significant (p<0.01) at the 33.9mgkg(-1) (MB327) or 30mgkg(-1) (HI-6) dose with a comparable degree of protection obtained for both compounds. Following administration of 10mgkg(-1) (i.m.), MB327 DMS reached plasma Cmax of 22μM at 12min with an elimination t1/2 of 22min. In an adverse effect study, in the absence of nerve agent poisoning, a dose of 100mgkg(-1) or higher of MB327 DMS was lethal to the guinea-pigs. A lower dose of MB327 DMS (30mgkg(-1)) caused flaccid paralysis accompanied by respiratory impairment. Respiration normalised by 30min, although the animals remained incapacitated to 4h. MB327 or related compounds may be of utility in treatment of nerve agent poisoning as a component of therapy with atropine, anticonvulsant and oxime, or alternatively as an infusion under medical supervision. Crown Copyright © 2015. Published by Elsevier Ireland Ltd. All rights reserved.

Curcumin promotes nerve regeneration and functional recovery after sciatic nerve crush injury in diabetic rats.

PubMed

Ma, Junxiong; Yu, Hailong; Liu, Jun; Chen, Yu; Wang, Qi; Xiang, Liangbi

2016-01-01

Curcumin is capable of promoting peripheral nerve regeneration in normal condition. However, it is unclear whether its beneficial effect on nerve regeneration still exists under diabetic mellitus. The present study was designed to investigate such a possibility. Diabetes in rats was developed by a single dose of streptozotocin at 50 mg/kg. Immediately after nerve crush injury, the diabetic rats were intraperitoneally administrated daily for 4 weeks with curcumin (50 mg/kg, 100 mg/kg and 300 mg/kg), or normal saline, respectively. The axonal regeneration was investigated by morphometric analysis and retrograde labeling. The functional recovery was evaluated by electrophysiological studies and behavioral analysis. Axonal regeneration and functional recovery was significantly enhanced by curcumin, which were significantly better than those in vehicle saline group. In addition, high doses of curcumin (100 mg/kg and 300 mg/kg) achieved better axonal regeneration and functional recovery than low dose (50 mg/kg). In conclusion, curcumin is capable of promoting nerve regeneration after sciatic nerve crush injury in diabetes mellitus, highlighting its therapeutic values as a neuroprotective agent for peripheral nerve injury repair in diabetes mellitus. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Structural characterization of chemical warfare agent degradation products in decontamination solutions with proton band-selective (1)H-(31)P NMR spectroscopy.

PubMed

Koskela, Harri; Hakala, Ullastiina; Vanninen, Paula

2010-06-15

Decontamination solutions, which are usually composed of strong alkaline chemicals, are used for efficient detoxification of chemical warfare agents (CWAs). The analysis of CWA degradation products directly in decontamination solutions is challenging due to the nature of the matrix. Furthermore, occasionally an unforeseen degradation pathway can result in degradation products which could be eluded to in standard analyses. Here, we present the results of the application of proton band-selective (1)H-(31)P NMR spectroscopy, i.e., band-selective 1D (1)H-(31)P heteronuclear single quantum coherence (HSQC) and band-selective 2D (1)H-(31)P HSQC-total correlation spectroscopy (TOCSY), for ester side chain characterization of organophosphorus nerve agent degradation products in decontamination solutions. The viability of the approach is demonstrated with a test mixture of typical degradation products of nerve agents sarin, soman, and VX. The proton band-selective (1)H-(31)P NMR spectroscopy is also applied in characterization of unusual degradation products of VX in GDS 2000 solution.

In Situ Probes of Capture and Decomposition of Chemical Warfare Agent Simulants by Zr-Based Metal Organic Frameworks

DOE Office of Scientific and Technical Information (OSTI.GOV)

Plonka, Anna M.; Wang, Qi; Gordon, Wesley O.

Recently, Zr-based metal organic frameworks (MOFs) were shown to be among the fastest catalysts of nerve-agent hydrolysis in solution. Here, we report a detailed study of the adsorption and decomposition of a nerve-agent simulant, dimethyl methylphosphonate (DMMP), on UiO-66, UiO-67, MOF-808, and NU-1000 using synchrotron-based X-ray powder diffraction, X-ray absorption, and infrared spectroscopy, which reveals key aspects of the reaction mechanism. The diffraction measurements indicate that all four MOFs adsorb DMMP (introduced at atmospheric pressures through a flow of helium or air) within the pore space. In addition, the combination of X-ray absorption and infrared spectra suggests direct coordination ofmore » DMMP to the Zr6 cores of all MOFs, which ultimately leads to decomposition to phosphonate products. Our experimental probes into the mechanism of adsorption and decomposition of chemical warfare agent simulants on Zr-based MOFs open new opportunities in rational design of new and superior decontamination materials.« less

In Situ Probes of Capture and Decomposition of Chemical Warfare Agent Simulants by Zr-Based Metal Organic Frameworks

DOE Office of Scientific and Technical Information (OSTI.GOV)

Plonka, Anna M.; Wang, Qi; Gordon, Wesley O.

Zr-based metal organic frameworks (MOFs) have been recently shown to be among the fastest catalysts of nerve-agent hydrolysis in solution. We report a detailed study of the adsorption and decomposition of a nerve-agent simulant, dimethyl methylphosphonate (DMMP), on UiO-66, UiO-67, MOF-808, and NU-1000 using synchrotron-based X-ray powder diffraction, X-ray absorption, and infrared spectroscopy, which reveals key aspects of the reaction mechanism. The diffraction measurements indicate that all four MOFs adsorb DMMP (introduced at atmospheric pressures through a flow of helium or air) within the pore space. In addition, the combination of X-ray absorption and infrared spectra suggests direct coordination ofmore » DMMP to the Zr6 cores of all MOFs, which ultimately leads to decomposition to phosphonate products. These experimental probes into the mechanism of adsorption and decomposition of chemical warfare agent simulants on Zr-based MOFs open new opportunities in rational design of new and superior decontamination materials.« less

In Situ Probes of Capture and Decomposition of Chemical Warfare Agent Simulants by Zr-Based Metal Organic Frameworks

DOE PAGES

Plonka, Anna M.; Wang, Qi; Gordon, Wesley O.; ...

2016-12-30

Recently, Zr-based metal organic frameworks (MOFs) were shown to be among the fastest catalysts of nerve-agent hydrolysis in solution. Here, we report a detailed study of the adsorption and decomposition of a nerve-agent simulant, dimethyl methylphosphonate (DMMP), on UiO-66, UiO-67, MOF-808, and NU-1000 using synchrotron-based X-ray powder diffraction, X-ray absorption, and infrared spectroscopy, which reveals key aspects of the reaction mechanism. The diffraction measurements indicate that all four MOFs adsorb DMMP (introduced at atmospheric pressures through a flow of helium or air) within the pore space. In addition, the combination of X-ray absorption and infrared spectra suggests direct coordination ofmore » DMMP to the Zr6 cores of all MOFs, which ultimately leads to decomposition to phosphonate products. Our experimental probes into the mechanism of adsorption and decomposition of chemical warfare agent simulants on Zr-based MOFs open new opportunities in rational design of new and superior decontamination materials.« less

Designing a Successful Acupuncture Treatment Program for Gulf War Illness

DTIC Science & Technology

2017-10-01

altered white matter microstructural integrity in organophosphate (OP) pesticide, sarin nerve agent and pyridogstigmine bromide (PB) anti-nerve gas... Integration for chronic low back pain" PI: Jacobson (3/4/ 2011-6/21/2013) N = 46. Study Site: Spaulding Rehabilitation Hospital (SRH). In this cohort... integration (SI) plus outpatient rehabili- tation (OR) versus OR alone. The details of the study are described in a recent publication (Jacobson et al

Effects of nicergoline on the cardiovascular system of dogs and rats.

PubMed

Huchet, A M; Mouillé, P; Chelly, J; Lucet, B; Doursout, M F; Lechat, P; Schmitt, H

1981-01-01

In pentobarbitalized closed-chest dogs, nicergoline (10--100 microgram/kg, i.v.) reduced blood pressure, heart rate, and splanchnic nerve activity. Intracisternal administration of nicergoline (3 microgram/kg) only reduced splanchnic nerve activity. In open-chest dogs, nicergoline reduced blood pressure, cardiac output, and total peripheral resistance but did not change heart rate. In pithed rats treated with a beta-adrenoceptor-blocking agent, nicergoline reduced the pressor responses to noradrenaline and adrenaline. Nicergoline slightly attenuated the pressor responses of dogs to noradrenaline and tyramine and, in addition, reversed the hypertension induced by adrenaline and dimethylphenylpiperazinium. Nicergoline (100 microgram/kg) increased the tachycardia induced in dogs by stimulation of the right cardiovascular nerve and prevented the inhibitory effect of clonidine on this response. However, nicergoline only partially antagonized the effect of clonidine once it was fully established. Nicergoline did not antagonize the hypotensive and bradycardic effects of clonidine when they were established. Nicergoline did not affect the vagally mediated bradycardia evoked by carotid nerve stimulation in beta-adrenoceptor-blocked dogs. The compound did not change blood pressure in Cl spinal cord transected dogs. In conclusion, nicergoline appears to decrease blood pressure by blocking alpha-adrenoceptors and, at least at some doses, by a central inhibition of the sympathetic tone. Nicergoline appears to be a preferential alpha 1-adrenoceptor-blocking agent.

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.

Acute and Long-Term Impact of Chemical Weapons: Lessons from the Iran-Iraq War.

PubMed

Haines, D D; Fox, S C

2014-07-01

Chemical weapons have given the human experience of warfare a uniquely terrifying quality that has inspired a general repugnance and led to periodic attempts to ban their use. Nevertheless, since ancient times, toxic agents have been consistently employed to kill and terrorize target populations. The evolution of these weapons is examined here in ways that may allow military, law enforcement, and scientific professionals to gain a perspective on conditions that, in the past, have motivated their use - both criminally and as a matter of national policy during military campaigns. Special emphasis is placed on the genocidal use of chemical weapons by the regime of Saddam Hussein, both against Iranians and on Kurdish citizens of his own country, during the Iran-Iraq War of 1980-88. The historical development of chemical weapons use is summarized to show how progressively better insight into biochemistry and physiology was adapted to this form of warfare. Major attributes of the most frequently used chemical agents and a description of how they affected military campaigns are explained. Portions of this review describing chemical-casualty care devote particular focus to Iranian management of neurotoxic (nerve) agent casualties due to the unique nature of this experience. Both nerve and blistering "mustard" agents were used extensively against Iranian forces. However, Iran is the only nation in history to have sustained large-scale attacks with neurotoxic weapons. For this reason, an understanding of the successes and failures of countermeasures to nerve-agent use developed by the Iranian military are particularly valuable for future civil defense and military planning. A detailed consideration of these strategies is therefore considered. Finally, the outcomes of clinical research into severe chronic disease triggered by mustard-agent exposure are examined in the context of the potential of these outcomes to determine the etiology of illness among US and Allied veterans of the 1991 Persian Gulf War. Copyright © 2014 Central Police University.

Acute toxicity of some nerve agents and pesticides in rats.

PubMed

Misik, Jan; Pavlikova, Ruzena; Cabal, Jiri; Kuca, Kamil

2015-01-01

Highly toxic organophosphorus compounds (V- and G-nerve agents) were originally synthesized for warfare or as agricultural pesticides. Data on their acute toxicity are rare and patchy. Therefore, there is a need for integrated summary comparing acute toxicity of organophosphates using different administration routes in the same animal model with the same methodology. Based on original data, a summary of in vivo acute toxicity of selected V- and G-nerve agents (tabun, sarin, soman, VX, Russian VX) and organophosphates paraoxon (POX) and diisopropyl fluorophosphate (DFP) in rats has been investigated. Male Wistar rats were exposed to organophosphates in several administration routes (i.m., i.p., p.o, s.c., p.c.). The acute toxicity was evaluated by the assessment of median lethal dose (LD50, mg kg(-1)) 2, 4, and 24 hours post exposure. V-agents were the most toxic presented with LD50 ranged from 0.0082 mg kg(-1) (VX, i.m.) to 1.402 mg kg(-1) (Russian VX, p.o.), followed by G-agents (LD50 = 0.069 mg kg(-1)/soman, i.m./ - 117.9 mg kg(-1)/sarin, p.c./), organophosphate POX and DFP (LD50 = 0.321 mg kg(-1)/POX, i.m./ - 420 mg kg(-1)/DFP, p.c./). Generally, i.m. administration was the most toxic throughout all tested agents and ways of administration (LD50 = 0.0082 mg kg(-1)/VX/ - 1.399 mg kg(-1)/DFP/) whereas p.c. way was responsible for lowest acute toxicity (LD50 = 0.085 mg kg(-1)/VX/ - 420 mg kg(-1)/DFP/). The acute toxicity of selected organophosphorus compounds is summarized throughout this study. Although the data assessed in rats are rather illustrative prediction for human, it presents a valuable contribution, indicating the toxic potential and harmfulness of organophosphates.

Air Remedial Investigation. Version 3.1. Volume 1

DTIC Science & Technology

1988-08-01

1987. Construction of facilities for the production of Sarin (CB) nerve agent began in 1950 and was completed in 1953. Manufacture of CB was continued...and chemical warfare agents . Although production has ceased at the South Plants’ facilities, contaminants have been observed in ground water near the... agents , were introduced to Basin A since 1943. Inorganic metals as well as inorganic non-metals are also present. The near-surface soil contamination is

Cardiovascular Regulation in Obstructive Sleep Apnea

PubMed Central

Ziegler, Michael G.; Milic, Milos; Elayan, Hamzeh

2011-01-01

The majority of patients with obstructive sleep apnea (OSA) suffer from hypertension as a complication of both the metabolic syndrome and OSA. In animal studies, intermittent hypoxia that simulates changes seen in OSA leads to chemoreceptor and chromaffin cell stimulation of sympathetic nerve activity, endothelial damage and impaired blood pressure modulation. Human studies reveal activation of sympathetic nerves, endothelial damage and exaggerated pressor responses to sympathetic neurotransmitters and endothelin. Although treatment of the OSA normalizes sympathetic nerve responses, it only lowers blood pressure modestly. Agents that block the consequences of sympathetic over activity, such as β1 blockers and angiotensin antagonists have effectively lowered blood pressure. Diuretics have been less successful. Treatment of hypertensive patients with OSA usually requires consideration of both increased sympathetic nerve activity and the metabolic syndrome. PMID:22125570

Chemical Stockpile Disposal Program Final Programmatic Environmental Impact Statement Volume 3: Appendices A-S

DTIC Science & Technology

1988-01-01

nerve and blister agents evaluated in this appendix have been especially formulated to cause -major injuries or death to enemy forces in wartime...days. Hallucinations, particularly of visual type. Patients may exhibit selfdestructive acts l Seizures may occur, but true convulsions arc rare l Rare...lesions produced in experimental animals by GB and interprets the damage as caused by convulsions or seizure activity that kill neurons (nerve cells

A Structure-Activity Analysis of the Variation in Oxime Efficacy Against Nerve Agents

DTIC Science & Technology

2008-01-01

Literature 3. DATES COVERED (From - To) 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER A structure- activity analysis of the variation in oxime...structure– activity analysis of the variation in oxime efficacy against nerve agents☆ Donald M. Maxwell a,⁎, Irwin Koplovitz a, Franz Worek b, Richard E...structure– activity analysi Received 22 February 2008 Revised 8 April 2008 Accepted 13 April 2008 Available online 22 April 2008 Keywords: Organophosphorus

Neurogenic regulation of renal tubular sodium reabsorption.

PubMed

DiBona, G F

1977-08-01

The evidence supporting a role for direct neurogenic control of renal tubular sodium reabsorption is reviewed. Electron microscopic and fluorescence histochemical studies have demonstrated adrenergic nerve terminals in direct contact with basement membranes of mammalian (rat, dog, and monkey) renal tubular epithelial cells. Low-level direct or baroreceptor reflex stimulation of renal sympathetic nerves produces an increase in renal tubular sodium reabsorption without alterations in glomerular filtration rate, renal blood flow, or intrarenal distribution of blood flow. Antinatriuresis was prevented by prior treatment of the kidney with guanethidine or phenoxybenzamine. Rat kidney micropuncture studies have localized a site of enhanced tubular sodium reabsorption to the proximal tubule. Possible indirect mediation of the antinatriuresis by other humoral agents known to be released from the kidney on renal nerve stimulation (angiotensin II, prostaglandin) was excluded by experiments with appropriate blocking agents. The possible effects of anesthesia and uncertainties about the completeness of surgical renal denervation and other tubular segmental sites of action are critically analyzed. The clinical implications of this mechanism in pathologic conditions of sodium and water retention are discussed and and a prospectus for future work is presented.

Technological advancements for the detection of and protection against biological and chemical warfare agents.

PubMed

Eubanks, Lisa M; Dickerson, Tobin J; Janda, Kim D

2007-03-01

There is a growing need for technological advancements to combat agents of chemical and biological warfare, particularly in the context of the deliberate use of a chemical and/or biological warfare agent by a terrorist organization. In this tutorial review, we describe methods that have been developed both for the specific detection of biological and chemical warfare agents in a field setting, as well as potential therapeutic approaches for treating exposure to these toxic species. In particular, nerve agents are described as a typical chemical warfare agent, and the two potent biothreat agents, anthrax and botulinum neurotoxin, are used as illustrative examples of potent weapons for which countermeasures are urgently needed.

Meteorological and intelligence evidence of long-distance transit of chemical weapons fallout from bombing early in the 1991 Persian Gulf War.

PubMed

Tuite, James J; Haley, Robert W

2013-01-01

Coalition bombings on the night of 18-19 January 1991, early in the Gulf War, targeted the Iraqi chemical weapons infrastructure. On 19 January 1991, nerve agent alarms sounded within Coalition positions hundreds of kilometers to the south, and the trace presence of sarin vapor was identified by multiple technologies. Considering only surface dispersion of plumes from explosions, officials concluded that the absence of casualties around bombed sites precluded long-distance transit of debris to US troop positions to explain the alarms and detections. Consequently, they were discounted as false positives, and low-level nerve agent exposure early in the air war was disregarded in epidemiologic investigations of chronic illnesses. Newly assembled evidence indicates that plumes from those nighttime bombings of Iraqi chemical facilities would have traversed the stable nocturnal boundary layer and penetrated the residual layer where they would be susceptible to rapid transit by supergeostrophic winds. This explanation is supported by plume height predictions, available weather charts, weather satellite images showing transit of a hot air mass, effects of solar mixing of atmospheric layers, and observations of a stationary weather front and thermal inversion in the region. Current evidence supports long-distance transit. Epidemiologic studies of chronic postwar illness should be reassessed using veterans' reports of hearing nerve agent alarms as the measure of exposure. Copyright © 2012 S. Karger AG, Basel.

Midazolam as an anticonvulsant antidote for organophosphate intoxication− A pharmacotherapeutic appraisal

PubMed Central

Reddy, Sandesh D.; Reddy, Doodipala Samba

2015-01-01

SUMMARY Objective This review summarizes the therapeutic potential of midazolam as an anticonvulsant antidote for organophosphate (OP) intoxication. Methods Benzodiazepines are widely used for acute seizures and status epilepticus (SE), a neurological emergency of persistent seizures that can lead to severe neuronal damage or death. Midazolam is a benzodiazepine hypnotic with a rapid onset and short duration of action. Results Midazolam is considered the new drug of choice for persistent acute seizures and SE, including those caused by neurotoxic OPs and nerve agents. Midazolam is a positive allosteric modulator of synaptic GABA-A receptors in the brain. It potentiates GABAergic inhibition and thereby controls hyperexcitability and seizures. Midazolam is administered intravenously or intramuscularly to control acute seizures and SE. Due to its favorable pharmacokinetic features, midazolam is being considered as a replacement anticonvulsant for diazepam in the antidote kit for nerve agents. Clinical studies such as the recent RAMPART trial have confirmed the anticonvulsant efficacy of midazolam in SE in prehospital settings. Significance In experimental models, midazolam is effective when given at the onset of seizures caused by nerve agents. However, benzodiazepines are less effective at terminating seizures when given 30 min or later after OP exposure or seizure onset likely because of internalization or down-regulation of synaptic, but not extrasynaptic, GABA-A receptors, which can lead to diminished potency and seizure recurrence. PMID:26032507

Military Role in Countering Terrorist Use of Weapons of Mass Destruction

DTIC Science & Technology

1999-04-01

chemical and biological mobile point detection. “The M21 Remote Sensing Chemical Agent Alarm (RSCAAL) is an automatic scanning, passive infrared sensor...The M21 detects nerve and blister agent clouds based on changes in the background infrared spectra caused by the presence of the agent vapor.”15...required if greater than 3 years since last vaccine. VEE Yes Multiple vaccines required. VHF No Botulism Yes SEB No Ricin No Mycotoxin s No Source

Relative potency estimates of acceptable residues and reentry intervals after nerve agent release

DOE Office of Scientific and Technical Information (OSTI.GOV)

Watson, A.P.; Jones, T.D.; Adams, J.D.

1992-06-01

In the event of an unplanned release of a chemical warfare agent during any stage of the Chemical Stockpile Disposal Program, the potential exists for off-post contamination of drinking water, forage crops, grains, garden produce, and livestock. The more persistent agents, such as the organophosphate nerve agent VX, pose the greatest human health concern for reentry. A relative potency approach comparing the toxicity of VX to organophosphate insecticide analogues is developed and used to estimate allowable residues for VX in agricultural products and reentry intervals for public access to contaminated areas. Analysis of mammalian LD50 data by all exposure routesmore » indicates that VX is 10(3) to 10(4) times more toxic than most commercially available organophosphate insecticides. Thus, allowable residues of VX could be considered at concentration levels 10(3) to 10(4) lower than those established for certain insecticides by the U.S. EPA. Evaluation of reentry intervals developed for these organophosphate analogues indicate that, if environmental monitoring cannot reliably demonstrate acceptable levels of VX, restricted access to suspect or contaminated areas may be on the order of weeks to months following agent release. Planning for relocation, mass care centers, and quarantine should take this time period into account.« less

Clinical aspects of percutaneous poisoning by the chemical warfare agent VX: effects of application site and decontamination.

PubMed

Hamilton, Murray G; Hill, Ira; Conley, John; Sawyer, Thomas W; Caneva, Duane C; Lundy, Paul M

2004-11-01

O-ethyl S-(2-diisopropylaminoethyl) methylphosphonothioate (VX) is an extremely toxic organophosphate nerve agent that has been weaponized and stockpiled in a number of different countries, and it has been used in recent terrorist events. It differs from other well-known organophosphate nerve agents in that its primary use is as a contact poison rather than as an inhalation hazard. For this reason, we examined the effects of application site and skin decontamination on VX toxicity in anesthetized domestic swine after topical application. VX applied to the surface of the ear rapidly resulted in signs of toxicity consistent with the development of cholinergic crisis, including apnea and death. VX on the epigastrium resulted in a marked delayed development of toxic signs, reduced toxicity, and reduction in the rate of cholinesterase depression compared with animals exposed on the ear. Skin decontamination (15 minutes post-VX on the ear) arrested the development of clinical signs and prevented further cholinesterase inhibition and death. These results confirm earlier work that demonstrates the importance of exposure site on the resultant toxicity of this agent and they also show that decontamination postexposure has the potential to be an integral and extremely important component of medical countermeasures against this agent.

The sympathetic hazards of airborne ultrasound on ultrasound sensitive mice.

PubMed

Ohmori, M; Ogawa, K

1982-01-01

A commercially available ultrasonic equipment (55-50 kHz/sec, 425 W) operated at a distance of 4 m air space caused death in some mice. The physical energy propagated was quite small, being calculated at less than 0.21 W/cm2. Among many strains of mice, the RIII strain was especially sensitive to ultrasound, and the peak of sensitivity was at 3 to 4 weeks of age at which the mortality rate was 95/149 (64%). No death occurred when mice were pretreated by (a) removing all body hair, (b) by administration of morphine hydrochloridum with a tail reaction, and (c) administration of a sympathetic blocking agent. From these results it is assumed that the ultrasound energy absorbed by the body fur reaches the hypothalamus through the sensory nerves of the hair roots. After the hypothalamus where central sympathetic nerve functions are localized, the stimulus passes down the descending tract of the sympathetic nerve, reaching the cardiac nerves via the autonomic nerve ganglion. Thus, death could occur by shock of the sympathetic nerve reflex.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

von Bredow, J.; Corcoran, K.; Maitland, G.

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 frommore » incapacitation. Physostigmine, nerve agent pretreatment, cynomolgus monkeys soman (GD).« less

[Chronic Inflammatory Demyelinating Polyneuropathy].

PubMed

Balke, M; Wunderlich, G; Brunn, A; Fink, G R; Lehmann, H C

2016-12-01

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a chronic progressive or relapsing autoimmune neuropathy with heterogeneous clinical presentation. Symptoms typically include symmetrical, proximal and/or distal paresis and sensory loss. Atypical CIDP variants are increasingly recognized, including subtypes with rapid onset as well as variants with pure sensory, focal or marked asymmetrical deficits. Diagnosis is established by compatible symptoms, characteristic electrophysiological features and cerebrospinal fluid analysis. In unequivocal cases, inflammatory infiltrates in sural nerve biopsy support the diagnosis. Recent studies suggest that diagnostic imaging techniques such as MRI and nerve ultrasound may become useful tools for establishing the diagnosis. First-line therapies include immunoglobulines, steroids, and plasmapheresis. Immunosuppressant agents and monoclonal antibodies are used in therapy-refractory cases or as cortison-saving agents. © Georg Thieme Verlag KG Stuttgart · New York.

Synthesis and characterization of hydrogen-bond acidic functionalized graphene

NASA Astrophysics Data System (ADS)

Yang, Liu; Han, Qiang; Pan, Yong; Cao, Shuya; Ding, Mingyu

2014-05-01

Hexafluoroisopropanol phenyl group functionalized materials have great potential in the application of gas-sensitive materials for nerve agent detection, due to the formation of strong hydrogen-bonding interactions between the group and the analytes. In this paper, take full advantage of ultra-large specific surface area and plenty of carbon-carbon double bonds and hexafluoroisopropanol phenyl functionalized graphene was synthesized through in situ diazonium reaction between -C=C- and p-hexafluoroisopropanol aniline. The identity of the as-synthesis material was confirmed by transmission electron microscopy, Raman spectroscopy, ultraviolet visible spectroscopy, X-ray photoelectron spectroscopy and thermo gravimetric analysis. The synthesis method is simply which retained the excellent physical properties of original graphene. In addition, the novel material can be assigned as an potential candidate for gas sensitive materials towards organophosphorus nerve agent detection.

Compact fluorescence and white-light imaging system for intraoperative visualization of nerves

NASA Astrophysics Data System (ADS)

Gray, Dan; Kim, Evgenia; Cotero, Victoria; Staudinger, Paul; Yazdanfar, Siavash; tan Hehir, Cristina

2012-02-01

Fluorescence image guided surgery (FIGS) allows intraoperative visualization of critical structures, with applications spanning neurology, cardiology and oncology. An unmet clinical need is prevention of iatrogenic nerve damage, a major cause of post-surgical morbidity. Here we describe the advancement of FIGS imaging hardware, coupled with a custom nerve-labeling fluorophore (GE3082), to bring FIGS nerve imaging closer to clinical translation. The instrument is comprised of a 405nm laser and a white light LED source for excitation and illumination. A single 90 gram color CCD camera is coupled to a 10mm surgical laparoscope for image acquisition. Synchronization of the light source and camera allows for simultaneous visualization of reflected white light and fluorescence using only a single camera. The imaging hardware and contrast agent were evaluated in rats during in situ surgical procedures.

A compact fluorescence and white light imaging system for intraoperative visualization of nerves

NASA Astrophysics Data System (ADS)

Gray, Dan; Kim, Evgenia; Cotero, Victoria; Staudinger, Paul; Yazdanfar, Siavash; Tan Hehir, Cristina

2012-03-01

Fluorescence image guided surgery (FIGS) allows intraoperative visualization of critical structures, with applications spanning neurology, cardiology and oncology. An unmet clinical need is prevention of iatrogenic nerve damage, a major cause of post-surgical morbidity. Here we describe the advancement of FIGS imaging hardware, coupled with a custom nerve-labeling fluorophore (GE3082), to bring FIGS nerve imaging closer to clinical translation. The instrument is comprised of a 405nm laser and a white light LED source for excitation and illumination. A single 90 gram color CCD camera is coupled to a 10mm surgical laparoscope for image acquisition. Synchronization of the light source and camera allows for simultaneous visualization of reflected white light and fluorescence using only a single camera. The imaging hardware and contrast agent were evaluated in rats during in situ surgical procedures.

Prophylaxis against Organophosphorous Nerve Agents - State of the Art (profylaxe tegen organofosfaat zenuwgassen - stand van zaken)

DTIC Science & Technology

2005-12-01

consists of those that catalytically hydrolyze (in some cases stereoselectively) OP’s into non-toxic alkyl methyl phosphonic acids. These enzymes are so...8217fluorosphatase’, nowadays known as OPH, capable of hydrolyzing organophosphates. For therapy and/or profylaxis, a hydrolytic enzyme could be...HuPON hydrolyzes OP insecticides and nerve gases and a relationship was found between the amount of enzyme in different species and the toxic response

Molecular Design of Sulfonated Triblock Copolymer Permselective Membranes

DTIC Science & Technology

2008-07-03

factors governing sorption and permeability ofphosphoorganic agents in PEM made of sulfonated triblock copolymers of styrene and lower olefins by means...membrane morphology at environmental conditions, and the membrane sorption and transport properties with respect to water and nerve gas simulant...and chemical factors governing sorption and permeability of phosphoorganic agents in PEM made of sulfonated triblock copolymers of styrene and lower

Spectroscopic investigation of the noncovalent association of the nerve agent simulant diisopropyl methylphosphonate (DIMP) with zinc(II) porphyrins.

PubMed

Maza, William A; Vetromile, Carissa M; Kim, Chungsik; Xu, Xue; Zhang, X Peter; Larsen, Randy W

2013-11-07

Organophosphonates pose a significant threat as chemical warfare agents, as well as environmental toxins in the form of pesticides. Thus, methodologies to sense and decontaminate these agents are of significant interest. Porphyrins and metalloporphyrins offer an excellent platform to develop chemical threat sensors and photochemical degradation systems. These highly conjugated planar molecules exhibit relatively long-lived singlet and triplet states with high quantum yields and also form self-associated complexes with a wide variety of molecules. A significant aspect of porphyrins is the ability to functionalize the peripheral ring system either directly to the pyrrole rings or to the bridging methine carbons. In this report, steady-state absorption and fluorescence are utilized to probe binding affinities of a series of symmetric and asymmetric zinc(II) metalloporphyrins for the nerve agent simulant diisopropyl methylphosphonate (DIMP) in hexane. The red shifts in the absorption and emission spectra observed for all of the metalloporphyrins probed are discussed in the frame of Gouterman's four orbital model and a common binding motif involving coordination between the metalloporphyrin and DIMP via interaction between the zinc metal center of the porphyrin and phosphoryl oxygen of DIMP (Zn-O═P) is proposed.

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 also influenced the degradation rate since the degradation of VX was significantly faster when the NMR analysis was performed in the organic solvent acetonitrile compared to water. In conclusion, we have applied the in vitro flow-through diffusion cell for evaluation of skin decontamination procedures of human epidermis exposed to OPCs. It was demonstrated that early decontamination is crucial for efficient mitigation of epidermal penetration of VX and that almost complete removal of the nerve agent from the skin surface is possible. Our data also indicate that the pH of RSDL together with the solubility of OPC in RSDL are of primary importance for the decontamination efficacy. Copyright © 2017 Elsevier B.V. All rights reserved.

Workshop on Problems in Chemical Toxicology

DTIC Science & Technology

1980-06-20

that is mustard gas , however, there is no proof of that. In Laos and Cambodia there seems to be three agents that they are using, tear- gas or CS...which Is non-lethal for most normal and healthy individuals. Then they are using a nerve agent of unknown origin probably an. organphosphate, but that...use some persistent agent such as "thickened" Soman or you could use mustard gas just as well. Tou would probably figure that they would move about

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.

Enzymatic Neutralization of the Chemical Warfare Agent VX: Evolution of Phosphotriesterase for Phosphorothiolate Hydrolysis

PubMed Central

Bigley, Andrew N.; Xu, Chengfu; Henderson, Terry J.; Harvey, Steven P.; Raushel, Frank M.

2013-01-01

The V-type nerve agents (VX and VR) are among the most toxic substances known. The high toxicity and environmental persistence of VX makes the development of novel decontamination methods particularly important. The enzyme phosphotriesterase (PTE) is capable of hydrolyzing VX but with an enzymatic efficiency more than 5-orders of magnitude lower than with its best substrate, paraoxon. PTE has previously proven amenable to directed evolution for the improvement of catalytic activity against selected compounds through the manipulation of active site residues. Here, a series of sequential two-site mutational libraries encompassing twelve active site residues of PTE was created. The libraries were screened for catalytic activity against a new VX analogue (DEVX), which contains the same thiolate leaving group of VX coupled to a di-ethoxy phosphate core rather than the ethoxy, methylphosphonate core of VX. The evolved catalytic activity with DEVX was enhanced 26-fold relative to wildtype PTE. Further improvements were facilitated by targeted error-prone PCR mutagenesis of Loop-7 and additional PTE variants were identified with up to a 78-fold increase in the rate of DEVX hydrolysis. The best mutant hydrolyzed the racemic nerve agent VX with a value of kcat/Km of 7×104 M−1 s−1; a 230-fold improvement relative to the wild-type PTE. The highest turnover number achieved by the mutants created for this investigation was 137 s−1; an enhancement of 152-fold relative to wild-type PTE. The stereoselectivity for the hydrolysis of the two enantiomers of VX was relatively low. These engineered mutants of PTE are the best catalysts ever reported for the hydrolysis of nerve agent VX. PMID:23789980

Enzymatic neutralization of the chemical warfare agent VX: evolution of phosphotriesterase for phosphorothiolate hydrolysis.

PubMed

Bigley, Andrew N; Xu, Chengfu; Henderson, Terry J; Harvey, Steven P; Raushel, Frank M

2013-07-17

The V-type nerve agents (VX and VR) are among the most toxic substances known. The high toxicity and environmental persistence of VX make the development of novel decontamination methods particularly important. The enzyme phosphotriesterase (PTE) is capable of hydrolyzing VX but with an enzymatic efficiency more than 5 orders of magnitude lower than with its best substrate, paraoxon. PTE has previously proven amenable to directed evolution for the improvement of catalytic activity against selected compounds through the manipulation of active-site residues. Here, a series of sequential two-site mutational libraries encompassing 12 active-site residues of PTE was created. The libraries were screened for catalytic activity against a new VX analogue, DEVX, which contains the same thiolate leaving group of VX coupled to a diethoxyphosphate core rather than the ethoxymethylphosphonate core of VX. The evolved catalytic activity with DEVX was enhanced 26-fold relative to wild-type PTE. Further improvements were facilitated by targeted error-prone PCR mutagenesis of loop-7, and additional PTE variants were identified with up to a 78-fold increase in the rate of DEVX hydrolysis. The best mutant hydrolyzed the racemic nerve agent VX with a value of kcat/Km = 7 × 10(4) M(-1) s(-1), a 230-fold improvement relative to wild-type PTE. The highest turnover number achieved by the mutants created for this investigation was 137 s(-1), an enhancement of 152-fold relative to wild-type PTE. The stereoselectivity for the hydrolysis of the two enantiomers of VX was relatively low. These engineered mutants of PTE are the best catalysts ever reported for the hydrolysis of nerve agent VX.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Halbrook, R.S.; Shugart, L.R.; Watson, A.P.

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. Amore » 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.« less

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.

The Blood Volume of the Guinea Pig: Effects of Epinephrine and Isoproterenol upon the Red Cell and Plasma Volumes, Heart Rate, and Mean Arterial Pressure,

DTIC Science & Technology

1987-09-01

capillaries (4), blood volumes calculated from plasma volume measures must correct for label that has left the system between the time of the injected dose...Splenic sequestration and contraction are mediated by the autonomic nervous system and blood-borne agents (10). Sympathetic nerve fibers from the truncus...sympathlcus and parasympathetic neurons of the nervus vagus (cranial nerve X) innervate the celiac plexus (8, 11). A subdivision of the celiac plexus

Synthesis and biodegradation of the VX nerve agent derivative 2-DIISO-propylaminoethylsulfonic acid

DOE Office of Scientific and Technical Information (OSTI.GOV)

Warner, C.H.; Labare, M.P.; Wessel, T.E.

1996-10-01

The United States is currently examining biodegradation methods to demilitarize chemical weapons. The nerve agent, O-ethyl-S-(2-diisopropylamino-ethyl)methylphosphonothiolate (VX) is first chemically inactivated with water at 90% yielding two fragments. One fragment is 2-diisopropylaminoethanethiol which quickly reacts with another thiol fragment forming the disulfide, bis(2-diisopropylaminoethyl)disulfide. The presence of the disulfide bond in this compound renders it resistant to biodegradation. Methods for converting the disulfide to the sulfonic acid are currently being pursued by treatment with performic acid. However, the sulfonic: acid has been synthesized by an independent method. Preliminary experiments indicate that the sulfonic acid at 1.0 and 0.5 mM is degradedmore » by Rhodococcus dp. strain IGTS8 as evidenced by an increase in the optical density at 600 nm.« less

Cluster headache: present and future therapy.

PubMed

Leone, Massimo; Giustiniani, Alessandro; Cecchini, Alberto Proietti

2017-05-01

Cluster headache is characterized by severe, unilateral headache attacks of orbital, supraorbital or temporal pain lasting 15-180 min accompanied by ipsilateral lacrimation, rhinorrhea and other cranial autonomic manifestations. Cluster headache attacks need fast-acting abortive agents because the pain peaks very quickly; sumatriptan injection is the gold standard acute treatment. First-line preventative drugs include verapamil and carbolithium. Other drugs demonstrated effective in open trials include topiramate, valproic acid, gabapentin and others. Steroids are very effective; local injection in the occipital area is also effective but its prolonged use needs caution. Monoclonal antibodies against calcitonin gene-related peptide are under investigation as prophylactic agents in both episodic and chronic cluster headache. A number of neurostimulation procedures including occipital nerve stimulation, vagus nerve stimulation, sphenopalatine ganglion stimulation and the more invasive hypothalamic stimulation are employed in chronic intractable cluster headache.

Hydrolysis of DFP and the Nerve Agent (S)-Sarin by DFPase Proceeds Along Two Different Reaction Pathways: Implica-tions for Engineering Bioscavengers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wymore, Troy W; Langan, Paul; Smith, Jeremy C

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 pentavalentmore » 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.« less

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

Facilitatory effects of piracetam on excitability of motor nerve terminals and neuromuscular transmission.

PubMed

Hall, E D; Von Voigtlander, P F

1987-11-01

The possible in vivo facilitatory effects of the pyrrolidine acetamide no-otropic agent piracetam on neuromuscular transmission, were studied based upon reports of enhancement of central cholinergic function. Piracetam was shown to antagonize the lethal effects of the neuromuscular blocking agent hemicholinium-3 (HC-3), in female CF-1 mice when administered in a dose of 100 mg/kg (i.p.) simultaneously with HC-3. A 30 mg/kg (i.p.) dose of piracetam was ineffective by itself, although it potentiated the protective effects of choline (25 mg/kg i.p.). The analogs of piracetam, aniracetam, oxiracetam, pramiracetam and dupracetam also significantly antagonized the lethality of HC-3 at doses over a 30-300 mg/kg range. The acute facilitatory properties of piracetam on neuromuscular transmission were examined in more detail in vivo in the soleus nerve muscle preparation of the cat. A 100 mg/kg (i.v.) dose of piracetam, while having no effect on its own, significantly enhanced the ability of a 200 micrograms/kg (i.v.) dose of edrophonium to produce a potentiation of muscle contraction dependent on repetitive discharges in the soleus motor nerve terminals. In preparations in which the motor nerve terminals of the soleus were in a partially degenerated state as a result of section of the motor axons 48 hr earlier, piracetam acted to restore their sensitivity to edrophonium. Furthermore, in both normal and partially degenerated preparations, piracetam significantly decreased the neuromuscular blocking effects of a 150 micrograms/kg (i.v.) dose of d-tubocurarine. The mechanism of the neuromuscular facilitatory effects of piracetam on neuromuscular transmission is discussed in terms of an enhanced excitability of motor nerve terminals together with an action to increase the synthesis and/or release of acetylcholine.

Facial nerve conduction after sclerotherapy in children with facial lymphatic malformations: report of two cases.

PubMed

Lin, Pei-Jung; Guo, Yuh-Cherng; Lin, Jan-You; Chang, Yu-Tang

2007-04-01

Surgical excision is thought to be the standard treatment of choice for lymphatic malformations. However, when the lesions are limited to the face only, surgical scar and facial nerve injury may impair cosmetics and facial expression. Sclerotherapy, an injection of a sclerosing agent directly through the skin into a lesion, is an alternative method. By evaluating facial nerve conduction, we observed the long-term effect of facial lymphatic malformations after intralesional injection of OK-432 and correlated the findings with anatomic outcomes. One 12-year-old boy with a lesion over the right-side preauricular area adjacent to the main trunk of facial nerve and the other 5-year-old boy with a lesion in the left-sided cheek involving the buccinator muscle were enrolled. The follow-up data of more than one year, including clinical appearance, computed tomography (CT) scan and facial nerve evaluation were collected. The facial nerve conduction study was normal in both cases. Blink reflex in both children revealed normal results as well. Complete resolution was noted on outward appearance and CT scan. The neurophysiologic data were compatible with good anatomic and functional outcomes. Our report suggests that the inflammatory reaction of OK-432 did not interfere with adjacent facial nerve conduction.

Quadriplegic areflexic ICU illness: selective thick filament loss and normal nerve histology.

PubMed

Sander, Howard W; Golden, Marianna; Danon, Moris J

2002-10-01

Areflexic quadriplegia that occurs in the intensive care unit (ICU) is commonly ascribed to critical illness polyneuropathy based upon electrophysiology or muscle light microscopy. However, electron microscopy often documents a selective thick filament loss myopathy. Eight ICU patients who developed areflexic quadriplegia underwent biopsy. Seven patients had received steroids, and 2 had also received paralytic agents. Electrodiagnostic studies revealed absent or low-amplitude motor responses in 7. Sensory responses were normal in 5 of 6 and absent in 1. Initial electromyography revealed absent (n = 3), small (n = 3), or polyphasic (n = 1) motor unit potentials, and diffuse fibrillation potentials (n = 5). In all 8, light microscopy of muscle revealed numerous atrophic-angulated fibers and corelike lesions, and electron microscopy revealed extensive thick filament loss. Morphology of sural and intramuscular nerves, and, in one autopsied case, of the obturator nerve and multiple nerve roots, was normal. Although clinical, electrodiagnostic, and light microscopic features mimicked denervating disease, muscle electron microscopy revealed thick filament loss, and nerve histology was normal. This suggests that areflexic ICU quadriplegia is a primary myopathy and not an axonal polyneuropathy. Copyright 2002 Wiley Periodicals, Inc. Muscle Nerve 26: 499-505, 2002

DOE Office of Scientific and Technical Information (OSTI.GOV)

Capacio, B.R.; Harris, L.W.; Anderson, D.R.

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,more » 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.« less

Description of a new approach for great auricular and auriculotemporal nerve blocks: A cadaveric study in foxes and dogs.

PubMed

Stathopoulou, Thaleia-Rengina; Pinelas, Rui; Haar, Gert Ter; Cornelis, Ine; Viscasillas, Jaime

2018-05-01

Otitis externa is a painful condition that may require surgical intervention in dogs. A balanced analgesia protocol should combine systemic analgesic agents and local anaesthesia techniques. The aim of the study was to find anatomical landmarks for the great auricular and the auriculotemporal nerves that transmit nociceptive information from the ear pinna and to develop the optimal technique for a nerve block. The study consisted of two phases. In phase I, one fox cadaver was used for dissection and anatomical localization of the auricular nerves to derive landmarks for needle insertion. Eight fox cadavers were subsequently used to evaluate the accuracy of the technique by injecting methylene blue bilaterally. In phase II findings from phase I were applied in four Beagle canine cadavers. A block was deemed successful if more than 0.6 cm of the nerve's length was stained. Successful great auricular nerve block was achieved by inserting the needle superficially along the wing of the atlas with the needle pointing towards the jugular groove. For the auriculotemporal nerve block the needle was inserted perpendicular to the skin at the caudal lateral border of the zygomatic arch, close to the temporal process. The overall success rate was 24 out of 24 (100%) and 22 out of 24 (91%) for the great auricular and the auriculotemporal nerves, respectively, while the facial nerve was stained on three occasions. Our results suggest that it is feasible to achieve a block of the auricular nerves, based on anatomical landmarks, without concurrently affecting the facial nerve. © 2018 The Authors. Veterinary Medicine and Science Published by John Wiley & Sons Ltd.

Real-time, label-free, intraoperative visualization of peripheral nerves and micro-vasculatures using multimodal optical imaging techniques

PubMed Central

Cha, Jaepyeong; Broch, Aline; Mudge, Scott; Kim, Kihoon; Namgoong, Jung-Man; Oh, Eugene; Kim, Peter

2018-01-01

Accurate, real-time identification and display of critical anatomic structures, such as the nerve and vasculature structures, are critical for reducing complications and improving surgical outcomes. Human vision is frequently limited in clearly distinguishing and contrasting these structures. We present a novel imaging system, which enables noninvasive visualization of critical anatomic structures during surgical dissection. Peripheral nerves are visualized by a snapshot polarimetry that calculates the anisotropic optical properties. Vascular structures, both venous and arterial, are identified and monitored in real-time using a near-infrared laser-speckle-contrast imaging. We evaluate the system by performing in vivo animal studies with qualitative comparison by contrast-agent-aided fluorescence imaging. PMID:29541506

Proceedings of the Army Numerical Analysis Conference (11th) Held at Frankford Arsenal, Philadelphia, Pa., on 13-14 February 1974

DTIC Science & Technology

1974-12-01

incineration of chemical agent mustard and pesticides are presented. 1. EDGEWOOD ARSENAL INCINERATION PROGRAM The name of the program which we...only 5 elements to a compound read. -This was fine for mustard, but had to be altered when we wished to simulate the incineration of a nerve agent VX...input data to this program. A process flow sheet of the scrubber system is shown in Figure 1. The incinerator burns Mustard Agent . The off gas from

Transcriptional Inducers of Acetylcholinesterase Expression as Novel Antidotes for Protection Against Chemical Warfare Agents

DTIC Science & Technology

2005-10-01

neuroblastoma cell line , P19 and a human neuroblastoma cell line SH - SY5Y (data not shown). Effect of trichostatin A on...mouse neuroblastoma P19 cell line and a human neuroblastoma cell line SH - SY5Y . More experiments are needed to prove the potential of AChE expression in...treatment of nerve agent exposure. MATERIALS AND METHODS Neuronal cell lines and

Technical and Associated R&D Laboratory/Project Support to AFRL/RXQL Airbase Sciences Branch

DTIC Science & Technology

2011-10-01

the organophosphorus nerve agents . The coupons were allowed to sit overnight at room temperature to allow the phosphoric acid to adsorb into the...of chlorine and of ammonia across samples of several soil types; measurements of adsorption of two chemical agent surrogates (dimethyl...methylphosphonate and diisopropyl fluorophosphate) on cellulose and silica gel surfaces by inverse gas chromatography, to infer enthalpies of adsorption. Reactive

Mass Spectrometry to Identify New Biomarkers of Nerve Agent Exposure

DTIC Science & Technology

2010-04-01

target for oganophosphorus agent (OP) binding to enzymes is the active site serine in the consensus sequence GlyXSerXGly of acetylcholinesterase. By...human plasma. Task 6. Use a second method, for example enzyme activity assays or immunoprecipitation, to confirm the identity of soman-labeled proteins...spectrometry identifies covalent binding of soman, sarin, chlorpyrifos oxon, diisopropyl fluorophosphate, and FP-biotin to tyrosines on tubulin: a potential

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.

Genipin-Cross-Linked Chitosan Nerve Conduits Containing TNF-α Inhibitors for Peripheral Nerve Repair.

PubMed

Zhang, Li; Zhao, Weijia; Niu, Changmei; Zhou, Yujie; Shi, Haiyan; Wang, Yalin; Yang, Yumin; Tang, Xin

2018-07-01

Tissue engineered nerve grafts (TENGs) are considered a promising alternative to autologous nerve grafting, which is considered the "gold standard" clinical strategy for peripheral nerve repair. Here, we immobilized tumor necrosis factor-α (TNF-α) inhibitors onto a nerve conduit, which was introduced into a chitosan (CS) matrix scaffold utilizing genipin (GP) as the crosslinking agent, to fabricate CS-GP-TNF-α inhibitor nerve conduits. The in vitro release kinetics of TNF-α inhibitors from the CS-GP-TNF-α inhibitor nerve conduits were investigated using high-performance liquid chromatography. The in vivo continuous release profile of the TNF-α inhibitors released from the CS-GP-TNF-α inhibitor nerve conduits was measured using an enzyme-linked immunosorbent assay over 14 days. We found that the amount of TNF-α inhibitors released decreased with time after the bridging of the sciatic nerve defects in rats. Moreover, 4 and 12 weeks after surgery, histological analyses and functional evaluations were carried out to assess the influence of the TENG on regeneration. Immunochemistry performed 4 weeks after grafting to assess early regeneration outcomes revealed that the TENG strikingly promoted axonal outgrowth. Twelve weeks after grafting, the TENG accelerated myelin sheath formation, as well as functional restoration. In general, the regenerative outcomes following TENG more closely paralleled findings observed with autologous grafting than the use of the CS matrix scaffold. Collectively, our data indicate that the CS-GP-TNF-α inhibitor nerve conduits comprised an elaborate system for sustained release of TNF-α inhibitors in vitro, while studies in vivo demonstrated that the TENG could accelerate regenerating axonal outgrowth and functional restoration. The introduction of CS-GP-TNF-α-inhibitor nerve conduits into a scaffold may contribute to an efficient and adaptive immune microenvironment that can be used to facilitate peripheral nerve repair.

Sex and Violence in Neuroscience.

ERIC Educational Resources Information Center

Barnes, Deborah M.

1988-01-01

Describes advances made in the understanding of how sex hormones may modify various cognitive skills, how normal brain signaling mechanisms may cause nerve cell death, and how many cells appear to hold genetic agents which determine their own destruction. (RT)

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

PubMed Central

Colman, E

2017-01-01

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. PMID:28238224

Neuroprotective Drug for Nerve Trauma Revealed Using Artificial Intelligence.

PubMed

Romeo-Guitart, David; Forés, Joaquim; Herrando-Grabulosa, Mireia; Valls, Raquel; Leiva-Rodríguez, Tatiana; Galea, Elena; González-Pérez, Francisco; Navarro, Xavier; Petegnief, Valerie; Bosch, Assumpció; Coma, Mireia; Mas, José Manuel; Casas, Caty

2018-01-30

Here we used a systems biology approach and artificial intelligence to identify a neuroprotective agent for the treatment of peripheral nerve root avulsion. Based on accumulated knowledge of the neurodegenerative and neuroprotective processes that occur in motoneurons after root avulsion, we built up protein networks and converted them into mathematical models. Unbiased proteomic data from our preclinical models were used for machine learning algorithms and for restrictions to be imposed on mathematical solutions. Solutions allowed us to identify combinations of repurposed drugs as potential neuroprotective agents and we validated them in our preclinical models. The best one, NeuroHeal, neuroprotected motoneurons, exerted anti-inflammatory properties and promoted functional locomotor recovery. NeuroHeal endorsed the activation of Sirtuin 1, which was essential for its neuroprotective effect. These results support the value of network-centric approaches for drug discovery and demonstrate the efficacy of NeuroHeal as adjuvant treatment with surgical repair for nervous system trauma.

Additives to local anesthetics for peripheral nerve blocks: Evidence, limitations, and recommendations.

PubMed

Bailard, Neil S; Ortiz, Jaime; Flores, Roland A

2014-03-01

The therapeutic rationale, clinical effectiveness, and potential adverse effects of medications used in combination with local anesthetics for peripheral nerve block therapy are reviewed. A wide range of agents have been tested as adjuncts to peripheral nerve blocks, which are commonly performed for regional anesthesia during or after hand or arm surgery, neck or spine surgery, and other procedures. Studies to determine the comparative merits of nerve block adjuncts are complicated by the wide variety of coadministered local anesthetics and sites of administration and by the heterogeneity of primary endpoints. Sodium bicarbonate has been shown to speed the onset of mepivacaine nerve blocks but delay the onset of others. Epinephrine has been shown to prolong sensory nerve blockade and delay systemic uptake of local anesthetics, thus reducing the risk of anesthetic toxicity. Tramadol, buprenorphine, dexamethasone, and clonidine appear to be effective additives in some situations. Midazolam, magnesium, dexmedetomidine, and ketamine cannot be routinely recommended as nerve block additives due to a dearth of supportive data, modest efficacy, and (in the case of ketamine) significant adverse effects. Recent studies suggest that administering additives intravenously or intramuscularly can provide many of the benefits of perineural administration while reducing the potential for neurotoxicity, contamination, and other hazards. Some additives to local anesthetics can hasten the onset of nerve block, prolong block duration, or reduce toxicity. On the other hand, poorly selected or unnecessary additives may not have the desired effect and may even expose patients to unnecessary risks.

High-Resolution Nerve Ultrasound and Electrophysiological Findings in Restless Legs Syndrome.

PubMed

Pitarokoili, K; Fels, M; Kerasnoudis, A; Toenges, L; Gold, R; Yoon, M-S

2018-05-11

Restless legs syndrome (RLS) is a multifactorial network disorder of a sensorimotor system extending from dopaminergic and glutamatergic cerebral structures to the spinal neurons and peripheral nerves. The role of peripheral nerve damage in the causality and severity progression for RLS patients remains unclear. We performed a clinical and epidemiological study on a cohort of 34 RLS patients focusing on RLS risk factors and disease severity. We investigated the peripheral nerves with nerve conduction studies and with high-resolution nerve ultrasound (HRUS). In 18 of the 34 patients (mean age 67.4 ± 15 years old), a sensorimotor axonal neuropathy was diagnosed. These patients presented with late-onset RLS were treated with membrane stabilizing agents, whereas no neuropathy predisposing comorbidity could be identified for the majority of them. We could show an inverse correlation between the amplitudes of the tibial nerve for the patients with polyneuropathy and the RLS severity index. Neuropathy patients were characterized by an increase of the cross-sectional area (CSA) of the tibial nerve in the popliteal fossa and by increased intranerve and internerve variability values showing an asymmetry of CSA distribution. This pattern resembles previous studies on diabetic neuropathy. Early diagnosis, characterization, and treatment of neuropathy are increasingly relevant for RLS patients as it correlates with disease severity. HRUS revealed a pattern resembling diabetic neuropathy, which implies a similar pathophysiology with metabolic and ischemic origin of RLS-related axonal neuropathy. Copyright © 2018 by the American Society of Neuroimaging.

Recent Advances in the Treatment of Organophosphorous Poisonings

PubMed Central

Balali-Mood, Mahdi; Saber, Hamidreza

2012-01-01

Organophosphorous compounds have been employed as pesticides and chemical warfare nerve agents. Toxicity of organophosphorous compounds is a result of excessive cholinergic stimulation through inhibition of acetyl cholinesterase. Clinical manifestations include cholinergic syndromes, central nervous system and cardiovascular disorders. Organophosphorous pesticide poisonings are common in developing worlds including Iran and Sri Lanka. Nerve agents were used during the Iraq-Iran war in 1983-1988 and in a terrorist attack in Japan in 1994-1995. Following decontamination, depending on the severity of intoxication the administration of atropine to counteract muscarinic over-stimulation, and an oxime to reactivate acetyl cholinesterase are indicated. Supportive and intensive care therapy including diazepam to control convulsions and mechanical respiration may be required. Recent investigations have revealed that intravenous infusion of sodium bicarbonate to produce mild to moderate alkalinization is effective. Gacyclidine; an antiglutamatergic compound, was also proved to be beneficial in conjunction with atropine, pralidoxime, and diazepam in nerve agent poisoning. Intravenous magnesium sulfate decreased hospitalization duration and improved outcomes in patients with organophosphorous poisoning. Bio-scavengers including fresh frozen plasma or albumin have recently been suggested as a useful therapy through clearing of free organophosphates. Hemofiltration and antioxidants are also suggested for organophosphorous poisoning. Recombinant bacterial phosphotriesterases and hydrolases that are able to transfer organophosphorous-degrading enzymes are very promising in delayed treatment of organophosphorous poisoning. Recently, encapsulation of drugs or enzymes in nanocarriers has also been proposed. Given the signs and symptoms of organophosphorous poisoning, health professionals should remain updated about the recent advances in treatment of organophosphorous poisoning poisonings. PMID:23115436

Esterase metabolism of cholinesterase inhibitors using rat liver in vitro

EPA Science Inventory

A variety of chemicals, such as organophosphate (OP) and carbamate pesticides, nerve agents, and industrial chemicals, inhibit acetylcholinesterase (AChE) leading to overstimulation of the cholinergic nervous system. The resultant neurotoxicity is similar across mammalian species...

40 CFR 272.2251 - Utah State-Administered program: Final authorization.

Code of Federal Regulations, 2014 CFR

2014-07-01

...: nerve, military, and chemical agents) as more stringent than the Federal rule. To the extent that unused... Wastewaters, Carbamate Wastes, and Spent Potliners (Revision Checklist 151) 61 FR 15566;61 FR 15660; 4/8/96;4...

40 CFR 272.2251 - Utah State-Administered program: Final authorization.

Code of Federal Regulations, 2011 CFR

2011-07-01

...: nerve, military, and chemical agents) as more stringent than the Federal rule. To the extent that unused... Wastewaters, Carbamate Wastes, and Spent Potliners (Revision Checklist 151) 61 FR 15566;61 FR 15660; 4/8/96;4...

40 CFR 272.2251 - Utah State-Administered program: Final authorization.

Code of Federal Regulations, 2012 CFR

2012-07-01

...: nerve, military, and chemical agents) as more stringent than the Federal rule. To the extent that unused... Wastewaters, Carbamate Wastes, and Spent Potliners (Revision Checklist 151) 61 FR 15566;61 FR 15660; 4/8/96;4...

40 CFR 272.2251 - Utah State-Administered program: Final authorization.

Code of Federal Regulations, 2013 CFR

2013-07-01

...: nerve, military, and chemical agents) as more stringent than the Federal rule. To the extent that unused... Wastewaters, Carbamate Wastes, and Spent Potliners (Revision Checklist 151) 61 FR 15566;61 FR 15660; 4/8/96;4...

Wearable Flexible and Stretchable Glove Biosensor for On-Site Detection of Organophosphorus Chemical Threats

DTIC Science & Technology

2017-03-03

finger enables rapid on-site detection of organophosphate (OP) nerve-agent compounds on suspicious surfaces and agricultural products following their...used as pesticides in agricultural and domestic settings.21,22 These OP neurotoxins severely affect the nervous system and lead to rapid death. Due to...The “on-hand” detection of different OP chemical agents on a variety of surfaces and agricultural foodstuffs demonstrate that the new wireless glove

Experimental Therapeutics Against the Toxic and Lethal Effects Resulting from Acute Exposure to Nerve Agents Without Carbamate Pretreatment in Guinea Pigs

DTIC Science & Technology

2010-09-01

or VX. Guinea pigs chronically instrumented for concurrent recordings of EEG, cardiorespiratory activities , diaphragm and skeletal muscle EMG were... activities , or any debilitating effects. The animals were asymptomatic within 30 min following therapy and survived the agent challenge 24 hr later. In...For a thorough efficacy evaluation, the animals were chronically instrumented to permit concurrent recordings of central nervous system activity

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

DTIC Science & Technology

2012-04-26

in the following categories: PaperReceived TOTAL: (b) Papers published in non-peer-reviewed journals (N/A for none) Number of ... biodegradable , yet they are extremely toxic to mammals because they bind to acetyl cholinesterase and render it inactive leading to a buildup of the ...respiratory complications, respiratory failure, coma and death. OP compounds exist mainly in the form of pesticides and chemical warfare agents

Immunohistopathology in the Guinea Pig Following Chronic Low-Level Exposure to Chemical Warfare Agents

DTIC Science & Technology

2005-11-01

U.S. Army Medical Research Institute of Chemical Defense USAMRICD-TR-05-09 Immunohistopathology in the Guinea Pig Following Chronic Low...2005 2. REPORT TYPE Technical Report 3. DATES COVERED (From - To) May 2003 to April 2005 4. TITLE AND SUBTITLE Immunohistopathology in the Guinea Pig Following...release; distribution unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Guinea pigs exposed repeatedly to low levels of chemical warfare nerve agents

Mapping auditory nerve firing density using high-level compound action potentials and high-pass noise masking a

PubMed Central

Earl, Brian R.; Chertoff, Mark E.

2012-01-01

Future implementation of regenerative treatments for sensorineural hearing loss may be hindered by the lack of diagnostic tools that specify the target(s) within the cochlea and auditory nerve for delivery of therapeutic agents. Recent research has indicated that the amplitude of high-level compound action potentials (CAPs) is a good predictor of overall auditory nerve survival, but does not pinpoint the location of neural damage. A location-specific estimate of nerve pathology may be possible by using a masking paradigm and high-level CAPs to map auditory nerve firing density throughout the cochlea. This initial study in gerbil utilized a high-pass masking paradigm to determine normative ranges for CAP-derived neural firing density functions using broadband chirp stimuli and low-frequency tonebursts, and to determine if cochlear outer hair cell (OHC) pathology alters the distribution of neural firing in the cochlea. Neural firing distributions for moderate-intensity (60 dB pSPL) chirps were affected by OHC pathology whereas those derived with high-level (90 dB pSPL) chirps were not. These results suggest that CAP-derived neural firing distributions for high-level chirps may provide an estimate of auditory nerve survival that is independent of OHC pathology. PMID:22280596

Pathogenesis of Borna disease in rats: evidence that intra-axonal spread is the major route for virus dissemination and the determinant for disease incubation.

PubMed

Carbone, K M; Duchala, C S; Griffin, J W; Kincaid, A L; Narayan, O

1987-11-01

Borna disease virus is an uncharacterized agent that causes sporadic but fatal neurological disease in horses and sheep in Europe. Studies of the infection in rats have shown that the agent has a strict tropism for neural tissues, in which it persists indefinitely. Inoculated rats developed encephalitis after an incubation period of 17 to 90 days. This report shows that the incubation period is the time required for transport of the agent in dendritic-axonal processes from the site of inoculation to the hippocampus. The immune responses to the agent had no effect on replication or transport of the virus. The neural conduit to the brain was proven by intranasal inoculation of virus that resulted in rapid transport of the agent via olfactory nerves to the hippocampus and in development of disease in 20 days. Virus inoculation into the feet resulted in spread along nerve fibers from neuron to neuron. There was sequential replication in neurons of the dorsal root ganglia adjacent to the lumbar spinal cord, the gracilis nucleus in the medulla, and pyramidal cells in the cerebral cortex, followed by infection of the hippocampal neurons and onset of disease. This progression required 50 to 60 days. The exclusiveness of the neural conduit was proven by failure to cause infection after injection of the virus intravenously or into the feet of neurectomized rats.

Neuroprotection trek--the next generation: neuromodulation II. Applications--epilepsy, nerve regeneration, neurotrophins

NASA Technical Reports Server (NTRS)

Andrews, Russell J.

2003-01-01

Three examples of neuroprotective applications of electrical stimulation-neuromodulation-are considered: (1) the diagnosis and treatment of epilepsy, (2) the augmentation of peripheral nerve regeneration after transection, and (3) the interaction between electrical stimulation and neurotrophins (notably brain derived neurotrophic factor [BDNF]) in various neuroprotective situations. The research cited demonstrates clear benefit from appropriate electrical stimulation in the treatment of (1) certain patients with medication-refractory epilepsy, and (2) the functional regeneration of peripheral nerves after transection and surgical repair. Furthermore, neuromodulation of peripheral nerve regeneration has been associated with an increase in the neurotrophin BDNF. The roles of BDNF and other neurotrophins in several disorders of the nervous system are discussed in the context of neuromodulation and its augmentation of neurotrophins. Neuromodulation-at least in part through its effect on BDNF and other neurotrophins-will likely play a major role in the treatment (and possibly prevention) of disorders of the nervous system for which neuroproteive pharmacologic agents have traditionally been sought.

Neuroprotection trek--the next generation: neuromodulation II. Applications--epilepsy, nerve regeneration, neurotrophins.

PubMed

Andrews, Russell J

2003-05-01

Three examples of neuroprotective applications of electrical stimulation-neuromodulation-are considered: (1) the diagnosis and treatment of epilepsy, (2) the augmentation of peripheral nerve regeneration after transection, and (3) the interaction between electrical stimulation and neurotrophins (notably brain derived neurotrophic factor [BDNF]) in various neuroprotective situations. The research cited demonstrates clear benefit from appropriate electrical stimulation in the treatment of (1) certain patients with medication-refractory epilepsy, and (2) the functional regeneration of peripheral nerves after transection and surgical repair. Furthermore, neuromodulation of peripheral nerve regeneration has been associated with an increase in the neurotrophin BDNF. The roles of BDNF and other neurotrophins in several disorders of the nervous system are discussed in the context of neuromodulation and its augmentation of neurotrophins. Neuromodulation-at least in part through its effect on BDNF and other neurotrophins-will likely play a major role in the treatment (and possibly prevention) of disorders of the nervous system for which neuroproteive pharmacologic agents have traditionally been sought.

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 Paraoxon pair, the following results were achieved (using the three SVM kernels: (1) ROC Az indices from approximately 93% to greater than 99%, (2) partial Az values from ~79% to 93%, (3) specificities from 76% to ~84% at 100 and 98% sensitivity, and (4) PPVs from 73% to ~84% at 100% and 98% sensitivities. These are excellent results, considering only one atom differentiates these nerve agents.

Comparison of the efficacy of articaine and prilocaine local anaesthesia for pulpotomy of maxillary and mandibular primary molars.

PubMed

Yilmaz, Y; Eyuboglu, O; Keles, S

2011-06-01

The aim of this study was to compare the local anaesthetic efficacy of articaine HCl and prilocaine HCl during an operative procedure after their administration by either mandibular nerve block or maxillary infiltration. The study was a double-blind clinical study which comprised 162 children (81 boys and 81 girls), who required a pulpotomy on their primary molars. Pain-related behaviours were used to assess the severity of pain during the injection of either prilocaine HCl or articaine HCl and the operative procedures following either a maxillary infiltration or mandibular nerve block of the two local anaesthetic agents. The frequencies of post-procedural adverse events in the prilocaine and articaine anaesthetised groups were also determined. Significantly more discomfort (p<0.05) was observed following maxillary infiltration compared to mandibular nerve block. There were no significant differences in the pain-related behaviours scores between the two local anaesthetic agents administered during the dental operative procedures, except for the removal of the coronal pulp. For this latter procedure, the pain-related behaviour score was 1.5- times higher in the prilocain-anaesthetised children than in the articaine-anaesthetised children. The frequencies of post- procedural adverse events in the prilocaine-treated children were similar to those found in the articaine-treated children. We concluded that local anaesthesia following mandibular nerve block is more effective than that following maxillary infiltration in 6-8-year-old children. However, the intensity of pain that was experienced by the children during administration of either prilocaine or articaine and some of the dental procedures after their administration were similar.

Just-in-time learning is effective in helping first responders manage weapons of mass destruction events.

PubMed

Motola, Ivette; Burns, William A; Brotons, Angel A; Withum, Kelly F; Rodriguez, Richard D; Hernandez, Salma; Rivera, Hector F; Issenberg, Saul Barry; Schulman, Carl I

2015-10-01

Chemical, biologic, radiologic, nuclear, and explosive (CBRNE) incidents require specialized training. The low frequency of these events leads to significant skill decay among first responders. To address skill decay and lack of experience with these high-impact events, educational modules were developed for mobile devices to provide just-in-time training to first responders en route to a CBRNE event. This study assessed the efficacy and usability of the mobile training. Ninety first responders were randomized to a control or an intervention group. All participants completed a pretest to measure knowledge of CBRNE topics. The intervention group then viewed personal protective equipment and weapons of mass destruction field management videos as an overview. Both groups were briefed on a disaster scenario (chemical nerve agent, radiologic, or explosives) requiring them to triage, assess, and manage a patient. Intervention group participants watched a mobile training video corresponding to the scenario. The control group did not receive prescenario video training. Observers rated participant performance in each scenario. After completing the scenarios, all participants answered a cognitive posttest. Those in the intervention group also answered a questionnaire on their impressions of the training. The intervention group outperformed the control group in the explosives and chemical nerve agent scenarios; the differences were statistically significant (explosives, mean of 26.32 for intervention and 22.85 for control, p < 0.01; nerve agent, mean of 23.14 for intervention and 16.61 for control, p < 0.01). There was no statistically significant difference between the groups in the radiologic scenario (mean, 12.7 for intervention and 11.8 for control; p = 0.51). The change in pretest to posttest cognitive scores was significantly higher in the intervention group than in the control group (t = 3.28, p < 0.05). Mobile just-in-time training improved first-responder knowledge of CBRNE events and is an effective tool in helping first responders manage simulated explosive and chemical agent scenarios. Therapeutic/care management study, level II.

Somatosensory Neurotoxicity: Agents and Assessment Methodology.

EPA Science Inventory

The somatosensory system is comprised of a variety of sensory receptors located in the skin, muscle tendons, and visceral organs that are innervated by myelinated and nonmyelinated axons of the peripheral nervous system. These peripheral sensory nerve fibers in tum communicate so...

Somatosensory Neurotoxicity: Agents and Assessment Methodology

EPA Science Inventory

The somatosensory system is comprised of a variety of sensory receptors located in the skin, muscle tendons, and visceral organs that are innervated by myelinated and nonmyelinated axons of the peripheral nervous system. These peripheral sensory nerve fibers in turn communicate s...

Micromotor-based on-off fluorescence detection of sarin and soman simulants.

PubMed

Singh, Virendra V; Kaufmann, Kevin; Orozco, Jahir; Li, Jinxing; Galarnyk, Michael; Arya, Gaurav; Wang, Joseph

2015-06-30

Self-propelled micromotor-based fluorescent "On-Off" detection of nerve agents is described. The motion-based assay utilizes Si/Pt Janus micromotors coated with fluoresceinamine toward real-time "on-the-fly" field detection of sarin and soman simulants.

Acetylcholinesterases of Blood-feeding Flies and Ticks

USDA-ARS?s Scientific Manuscript database

Acetylcholinesterase (AChE) is the biochemical target of organophosphate (OP) and carbamate pesticides for invertebrates, vertebrate nerve agents, and AChE inhibitors used to reduce effects of Alzheimer’s disease. Organophosphate pesticides (OPs) are widely used to control blood-feeding arthropods, ...

Complexity of acetylcholinesterases in biting flies and ticks

USDA-ARS?s Scientific Manuscript database

Acetylcholinesterase (AChE) inhibitors function as pesticides for invertebrates, vertebrate nerve agents, and medicine to reduce cognitive effects of Alzheimer’s disease. Organophosphate (OP) pesticides have been widely used to control biting flies and ticks, however, OP-resistance has compromised c...

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.

Study of the n-methyl-d-aspartate antagonistic properties of anticholinergic drugs

DOE Office of Scientific and Technical Information (OSTI.GOV)

McDonough, J.H.; Shih, T.M.

1995-12-31

A study of the N-methyl-D-aspartate antagonistic properties of anticholinergic drugs. PHARMACOL BIOCHEM BEHAV. 51(2/3) 249-253, 1995. Drugs that act at the N-methyl-D-aspartate (NMDA) receptor complex have the ability to terminate nerve agent-induced seizures and modulate the neuropathologic consequences of agent exposure. Drugs with mixed anticholinergic and anti-NMDA properties potentially provide an ideal class of compounds for development as anticonvulsant treatments for nerve agent casualties. The present experiment evaluated the potential NMDA antagonist activity of 11 anticholinergic drugs by determining whether pretreatment with the compound was capable of protecting mice from the lethal effects of NMDA. The following anticholinergic drugs antagonizedmore » NMDA lethality and are ranked according to their potency: mecamylamine > procyclidine = benactyzine > biperiden > tribexyphenidyl. The anticholinergics atropine, aprophen, azaprophen, benztropine, 3-quinudidinyl benzilate (QNB), and scopolamine failed to show NMDA antagonist properties. In addition, and unexpectedly, diazepam, ethanol, and pentobarbital were also shown to be capable of antagonizing NMDA lethality over a certain range of doses. The advantages and limitations of using antagonism of NMDA lethality in mice as a bioassay for determining the NMDA antagonist properties of drugs are also discussed.« less

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.

Deficit, recovery and the vis nervosa.

PubMed

McDonald, Ian

2006-01-01

Physicians have long sought to explain neurological deficit and recovery on the basis of alterations in the agent of nervous action. The ancient Greeks knew that the brain influences muscles and they showed experimentally that the effects were mediated by nerves. Galen believed that the agent of action was the animal spirits. Ideas began to change with a new approach to knowledge and the revival of experimentation that followed the arrival in Venice of ancient Greek manuscripts after the fall of Constantinople in 1453. In the mid-18th century the notion of animal spirits was replaced by that of the vis nervosa and speculation began that the agent might be electrical. This was established by the mid-19th century. The nature of conduction in nerve was clearly different from that in a wire but how it took place remained uncertain until Hodgkin and Huxley proved the ionic hypothesis in the mid-20th century. In the following decades the membrane mechanisms of conduction failure and restoration were elucidated, with practical consequences in the form of improved diagnostic methods and the potential for more rational approaches to treatment. The demonstration that adaptive cortical plasticity contributes to recovery raises the possibility of new strategies for neurological rehabilitation.

Thoracoscopic patch insulation to correct phrenic nerve stimulation secondary to cardiac resynchronization therapy.

PubMed

Mediratta, Neeraj; Barker, Diane; McKevith, James; Davies, Peter; Belchambers, Sandra; Rao, Archana

2012-07-01

Cardiac resynchronization therapy is an established therapy for heart failure, improving quality of life and prognosis. Despite advances in technique, available leads and delivery systems, trans-venous left ventricular (LV) lead positioning remains dependent on the patient's underlying venous anatomy. The left phrenic nerve courses over the surface of the pericardium laterally and may be stimulated by the LV pacing lead, causing uncomfortable diaphragmatic twitch. This paper describes a video-assisted thoracoscopic (VATS) procedure to correct phrenic nerve stimulation secondary to cardiac resynchronization therapy. Most current ways of avoiding phrenic stimulation involve either electronic reprogramming to distance the phrenic nerve from the stimulation circuit or repositioning the lead. We describe a case where the phrenic nerve was surgically insulated from the stimulating current by insinuating a patch of bovine pericardium between the epicardium and native pericardium of the heart thus completely resolving previously intolerable and incessant diaphragmatic twitch. The procedure was performed under general anaesthesia with single-lung ventilation and minimal use of neuromuscular blocking agents. Surgical patch insulation of the phrenic nerve was performed using minimally invasive VATS surgery, as a short-stay procedure, with no complications. No diaphragmatic twitch occurred post-surgery and the patient continued to gain symptomatic benefit from cardiac synchronization therapy (New York Heart Association Class III to II), enabling return to work. In cases where the trans-venous position of a LV lead is limited by troublesome phrenic nerve stimulation, thoracoscopic surgical patch insulation of the phrenic nerve could be considered to allow beneficial cardiac resynchronization therapy.

Comparative Kinetics and Distribution to Target Tissues of Organophosphates Using Physiologically - Based Pharmacokinetic Modeling

DTIC Science & Technology

2008-03-01

throughout history where nerve agents have been used on human populations, such as the subway bombing in Tokyo and Matsumoto, Japan. Data can be...kidney, fat, diaphragm, arterial blood, venous blood, bronchial passages, and the skin. The remaining tissues will be lumped together as either slowly...were then further developed as a weapon, whose primary effect is on the central nervous system. These agents are tabun, sarin, soman, and VX. They

Spectroscopic and Computational Investigation of Room-Temperature Decomposition of a Chemical Warfare Agent Simulant on Polycrystalline Cupric Oxide

DOE PAGES

Trotochaud, Lena; Tsyshevsky, Roman; Holdren, Scott; ...

2017-08-21

Certain organophosphorus molecules are infamous due to their use as highly toxic nerve agents. The filtration materials currently in common use for protection against chemical warfare agents were designed before organophosphorus compounds were used as chemical weapons. A better understanding of the surface chemistry between simulant molecules and the individual filtration-material components is a critical precursor to the development of more effective materials for filtration, destruction, decontamination, and/or sensing of nerve agents. Here, we report on the surface adsorption and reactions of a sarin simulant molecule, dimethyl methylphosphonate (DMMP), with cupric oxide surfaces. In situ ambient pressure X-ray photoelectron andmore » infrared spectroscopies are coupled with density functional calculations to propose mechanisms for DMMP decomposition on CuO. We find extensive room temperature decomposition of DMMP on CuO, with the majority of decomposition fragments bound to the CuO surface. We observe breaking of PO-CH3, P-OCH3, and P-CH3bonds at room temperature. On the basis of these results, we identify specific DMMP decomposition mechanisms not seen on other metal oxides. Participation of lattice oxygen in the decomposition mechanism leads to significant changes in chemical and electronic surface environment, which are manifest in the spectroscopic and computational data. This study establishes a computational baseline for the study of highly toxic organophosphorous compounds on metal oxide surfaces.« less

Using Metal Complex Ion-Molecule Reactions in a Miniature Rectilinear Ion Trap Mass Spectrometer to Detect Chemical Warfare Agents

NASA Astrophysics Data System (ADS)

Graichen, Adam M.; Vachet, Richard W.

2013-06-01

The gas-phase reactions of a series of coordinatively unsaturated [Ni(L)n]y+ complexes, where L is a nitrogen-containing ligand, with chemical warfare agent (CWA) simulants in a miniature rectilinear ion trap mass spectrometer were investigated as part of a new approach to detect CWAs. Results show that upon entering the vacuum system via a poly(dimethylsiloxane) (PDMS) membrane introduction, low concentrations of several CWA simulants, including dipropyl sulfide (simulant for mustard gas), acetonitrile (simulant for the nerve agent tabun), and diethyl phosphite (simulant for nerve agents sarin, soman, tabun, and VX), can react with metal complex ions generated by electrospray ionization (ESI), thereby providing a sensitive means of detecting these compounds. The [Ni(L)n]2+ complexes are found to be particularly reactive with the simulants of mustard gas and tabun, allowing their detection at low parts-per-billion (ppb) levels. These detection limits are well below reported exposure limits for these CWAs, which indicates the applicability of this new approach, and are about two orders of magnitude lower than electron ionization detection limits on the same mass spectrometer. The use of coordinatively unsaturated metal complexes as reagent ions offers the possibility of further tuning the ion-molecule chemistry so that desired compounds can be detected selectively or at even lower concentrations.

Spectroscopic and Computational Investigation of Room-Temperature Decomposition of a Chemical Warfare Agent Simulant on Polycrystalline Cupric Oxide

DOE Office of Scientific and Technical Information (OSTI.GOV)

Trotochaud, Lena; Tsyshevsky, Roman; Holdren, Scott

Certain organophosphorus molecules are infamous due to their use as highly toxic nerve agents. The filtration materials currently in common use for protection against chemical warfare agents were designed before organophosphorus compounds were used as chemical weapons. A better understanding of the surface chemistry between simulant molecules and the individual filtration-material components is a critical precursor to the development of more effective materials for filtration, destruction, decontamination, and/or sensing of nerve agents. Here, we report on the surface adsorption and reactions of a sarin simulant molecule, dimethyl methylphosphonate (DMMP), with cupric oxide surfaces. In situ ambient pressure X-ray photoelectron andmore » infrared spectroscopies are coupled with density functional calculations to propose mechanisms for DMMP decomposition on CuO. We find extensive room temperature decomposition of DMMP on CuO, with the majority of decomposition fragments bound to the CuO surface. We observe breaking of PO-CH3, P-OCH3, and P-CH3bonds at room temperature. On the basis of these results, we identify specific DMMP decomposition mechanisms not seen on other metal oxides. Participation of lattice oxygen in the decomposition mechanism leads to significant changes in chemical and electronic surface environment, which are manifest in the spectroscopic and computational data. This study establishes a computational baseline for the study of highly toxic organophosphorous compounds on metal oxide surfaces.« less

[Chemical weapons and chemical terrorism].

PubMed

Nakamura, Katsumi

2005-10-01

Chemical Weapons are kind of Weapons of Mass Destruction (WMD). They were used large quantities in WWI. Historically, large quantities usage like WWI was not recorded, but small usage has appeared now and then. Chemical weapons are so called "Nuclear weapon for poor countrys" because it's very easy to produce/possession being possible. They are categorized (1) Nerve Agents, (2) Blister Agents, (3) Cyanide (blood) Agents, (4) Pulmonary Agents, (5) Incapacitating Agents (6) Tear Agents from the viewpoint of human body interaction. In 1997 the Chemical Weapons Convention has taken effect. It prohibits chemical weapons development/production, and Organization for the Prohibition of Chemical Weapons (OPCW) verification regime contributes to the chemical weapons disposal. But possibility of possession/use of weapons of mass destruction by terrorist group represented in one by Matsumoto and Tokyo Subway Sarin Attack, So new chemical terrorism countermeasures are necessary.

Neuroinflammatory Pathobiology in Gulf War Illness: Characterization with an Animal Model

DTIC Science & Technology

2011-08-01

evaluated alone and in combination (i.e. pyridostigmine bromide (PB), diethyl-m-toluamide (DEET), 5 lipopolysaccharide (LPS), corticosterone (CORT) and...acetylcholinesterase (AChE) inhibitor pyridostigmine bromide (PB), the insect repellent DEET and, potentially, the nerve agent, sarin. These combined

Nerve-gas destruction with metal organic frameworks

EPA Science Inventory

Chemical warfare agents (CWAs) such as saran, soman, and tabun have been developed since World War I. Their mode of action involves the rapid formation of phosphate ester bonds with acetylcholinesterase to attenuate activity. The cumulative result of this activity loss leads to a...

[Orbital apex syndrome of the aspergillus etiology--a case report].

PubMed

Fric, E; Rehák, M; Vlcková, I; Burval, S; Chrapek, O; Rehák, J

2007-04-01

The authors present a case report of a patient, in whom after a head injury the monolateral blindness occurred. Because of autoimmune thrombocytopeny the patient was treated with long-term corticosteroids. The clinical findings corresponded with the orbital apex syndrome. According to the results of the CT and MRI examinations, the sphenoidotomy was indicated, and the histological findings verified fragments of paranasal sinuses' aspergiloma. During the next course of the disease, despite antimycotic therapy, the progression of the aspergiloma in to the anterior cranial fossa occurred. Invasive sino-orbital aspergilosis, after the penetration of the infectious agent across the wall of the sinus, may cause the orbital apex syndrome with paralysis of all three cranial nerves innervating the extraocular muscles, sensoric defect in the area of the ophthalmic nerve and the involvement of the optic nerve.

Agent Orange exposure and prevalence of self-reported diseases in Korean Vietnam veterans.

PubMed

Yi, Sang-Wook; Ohrr, Heechoul; Hong, Jae-Seok; Yi, Jee-Jeon

2013-09-01

The aim of this study was to evaluate the association between Agent Orange exposure and self-reported diseases in Korean Vietnam veterans. A postal survey of 114 562 Vietnam veterans was conducted. The perceived exposure to Agent Orange was assessed by a 6-item questionnaire. Two proximity-based Agent Orange exposure indices were constructed using division/brigade-level and battalion/company-level unit information. Adjusted odds ratios (ORs) for age and other confounders were calculated using a logistic regression model. The prevalence of all self-reported diseases showed monotonically increasing trends as the levels of perceived self-reported exposure increased. The ORs for colon cancer (OR, 1.13), leukemia (OR, 1.56), hypertension (OR, 1.03), peripheral vasculopathy (OR, 1.07), enterocolitis (OR, 1.07), peripheral neuropathy (OR, 1.07), multiple nerve palsy (OR, 1.14), multiple sclerosis (OR, 1.24), skin diseases (OR, 1.05), psychotic diseases (OR, 1.07) and lipidemia (OR, 1.05) were significantly elevated for the high exposure group in the division/brigade-level proximity-based exposure analysis, compared to the low exposure group. The ORs for cerebral infarction (OR, 1.08), chronic bronchitis (OR, 1.05), multiple nerve palsy (OR, 1.07), multiple sclerosis (OR, 1.16), skin diseases (OR, 1.05), and lipidemia (OR, 1.05) were significantly elevated for the high exposure group in the battalion/company-level analysis. Korean Vietnam veterans with high exposure to Agent Orange experienced a higher prevalence of several self-reported chronic diseases compared to those with low exposure by proximity-based exposure assessment. The strong positive associations between perceived self-reported exposure and all self-reported diseases should be evaluated with discretion because the likelihood of reporting diseases was directly related to the perceived intensity of Agent Orange exposure.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nambiar, Madhusoodana P.; Gordon, Richard K.; Rezk, Peter E.

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 didmore » 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.« less

A rat model of nerve agent exposure applicable to the pediatric population: The anticonvulsant efficacies of atropine and GluK1 antagonists

PubMed Central

Miller, Steven L.; Aroniadou-Anderjaska, Vassiliki; Figueiredo, Taiza H.; Prager, Eric M.; Almeida-Suhett, Camila P.; Apland, James P.; Braga, Maria F.M.

2015-01-01

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 LD50 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 (1.2XLD50), 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. PMID:25689173

Gasserian Ganglion and Retrobulbar Nerve Block in the Treatment of Ophthalmic Postherpetic Neuralgia: A Case Report.

PubMed

Huang, Jie; Ni, Zhongge; Finch, Philip

2017-09-01

Varicella zoster virus reactivation can cause permanent histological changes in the central and peripheral nervous system. Neural inflammatory changes or damage to the dorsal root ganglia sensory nerve fibers during reactivation can lead to postherpetic neuralgia (PHN). For PHN of the first division of the fifth cranial nerve (ophthalmic division of the trigeminal ganglion), there is evidence of inflammatory change in the ganglion and adjacent ocular neural structures. First division trigeminal nerve PHN can prove to be difficult and sometimes even impossible to manage despite the use of a wide range of conservative measures, including anticonvulsant and antidepressant medication. Steroids have been shown to play an important role by suppressing neural inflammatory processes. We therefore chose the trigeminal ganglion as an interventional target for an 88-year-old woman with severe ophthalmic division PHN after she failed to respond to conservative treatment. Under fluoroscopic guidance, a trigeminal ganglion nerve block was performed with lidocaine combined with dexamethasone. A retrobulbar block with lidocaine and triamcinolone settled residual oculodynia. At 1-year follow-up, the patient remained pain free and did not require analgesic medication. To our knowledge, this is the first reported case of ophthalmic division PHN successfully treated with a combination of trigeminal ganglion and retrobulbar nerve block using a local anesthetic agent and steroid for central and peripheral neural inflammatory processes. © 2016 World Institute of Pain.

Pharmacokinetics of IM,IV and IO Atropine in Normovolemic and Hypovolemic Swine

DTIC Science & Technology

2016-06-12

nursing care is provided”.1 On and off the battlefield, highly specialized, well-educated nurses are managing complex injuries as integral member of...Rapid and complete bioavailability of antidotes for organophosphorus nerve agent and cyanide poisoning in minipigs after intraosseous

DETOXIFICATION OF ORGANOPHOSPHATE PESTICIDES BY IMMOBILIZED ESCHERICHIA COLI EXPRESSING ORGANOPHOSPHORUS HYDROLASE ON CELL SURFACE. (R823663)

EPA Science Inventory

An improved whole-cell technology for detoxifying organophosphate nerve agents was recently developed based on genetically engineered Escherichia coli with organophosphorus hydrolase anchored on the surface. This article reports the immobilization of these novel biocatalys...

CAPILLARY ELECTROPHORESIS MICROCHIPS FOR RAPID SEPARATION AND DETECTION OF ORGANOPHOSPHATE NERVE AGENTS. (R828160)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

Furthering the Enzymatic Destruction of Nerve Agents

DTIC Science & Technology

2002-01-01

properties of an organophosphorus acid anhydrase from a halophilic bacterial isolate. J. Bacteriol. 173, 1938-1943. DeFrank, J.J.; Beaudry, W.T...Cheng, T.-c.; Harvey, S.P.; Stroup, A.N. and Szafraniec, L.L. (1993) Screening of halophilic bacteria and Alteromonas species for organophosphorus

Optimization of Glial Fibrillary Acidic Protein Immunoreactivity in Formalin-fixed, Paraffin-Embedded Guinea Pig Brain Sections

DTIC Science & Technology

2003-09-01

fixed, paraffin-embedded guinea pig brain sections using a variety of commercially available GFAP antibody clones. Of the 7 clones tested for cross...determining neuropathological consequences in the guinea pig following exposure to chemical warfare nerve agent.

Female rats are less susceptible during puberty to the lethal effects of percutaneous exposure to VX.

PubMed

Wright, Linnzi K M; Lee, Robyn B; Clarkson, Edward D; Lumley, Lucille A

2016-01-01

Nerve agents with low volatility such as VX are primarily absorbed through the skin when released during combat or a terrorist attack. The barrier function of the stratum corneum may be compromised during certain stages of development, allowing VX to more easily penetrate through the skin. However, age-related differences in the lethal potency of VX have yet to be evaluated using the percutaneous (pc) route of exposure. Thus, we estimated the 24 and 48 h median lethal dose for pc exposure to VX in male and female rats during puberty and early adulthood. Pubescent, female rats were less susceptible than both their male and adult counterparts to the lethal effects associated with pc exposure to VX possibly because of hormonal changes during that stage of development. This study emphasizes the need to control for both age and sex when evaluating the toxicological effects associated with nerve agent exposure in the rat model.

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. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

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

PubMed

Reddy, D S; Colman, E

2017-05-01

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. © 2017 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

State-wide hospital clinical laboratory plan for measuring cholinesterase activity for individuals suspected of exposure to nerve agent chemical weapons.

PubMed

Wu, Alan H B; Smith, Andrew; McComb, Robert; Bowers, George N; Makowski, Gregory S; McKay, Charles A; Vena, Jason; McDonagh, John; Hopfer, Sidney; Sena, Salvatore F; Malkus, Herbert; Forte, Elaine; Kelly, Katherine

2008-02-01

Hospital laboratories currently lack the capacity to provide emergency determination of cholinesterase activity. We have developed a hospital-based 3-tiered system to test plasma for butyrylcholinesterase (BChE) activity and whole blood for red cell acetylcholinesterase (AChE) activity using available technology and personnel. Interagency communications, toxidrome definition, and patient triage will be coordinated by the Connecticut Department of Public Health and the Poison Control Center. Initial BChE data documents good precision between institutions (coefficient of variation < 8%). Laboratory testing of plasma or blood for cholinesterase activity is important in the management of nerve agent exposure and in ruling out disease in those with non-specific symptoms in the setting of a terrorist attack or accidental exposure. Rapid availability of strong hospital-based analytic support in a smoothly functioning network of clinical, public health, and laboratory services will facilitate overall regional response to chemical terrorism or large scale HazMat events.

Structural elucidation of direct analysis in real time ionized nerve agent simulants with infrared multiple photon dissociation spectroscopy.

PubMed

Rummel, Julia L; Steill, Jeffrey D; Oomens, Jos; Contreras, Cesar S; Pearson, Wright L; Szczepanski, Jan; Powell, David H; Eyler, John R

2011-06-01

Infrared multiple photon dissociation (IRMPD) was used to generate vibrational spectra of ions produced with a direct analysis in real time (DART) ionization source coupled to a 4.7 T Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer. The location of protonation on the nerve agent simulants diisopropyl methylphosphonate (DIMP) and dimethyl methylphosphonate (DMMP) was studied while solutions of the compounds were introduced for extended periods of time with a syringe pump. Theoretical vibrational spectra were generated with density functional theory calculations. Visual comparison of experimental mid-IR IRMPD spectra and theoretical spectra could not establish definitively if a single structure or a mixture of conformations was present for the protonated parent of each compound. However, theoretical calculations, near-ir IRMPD spectra, and frequency-to-frequency and statistical comparisons indicated that the protonation site for both DIMP and DMMP was predominantly, if not exclusively, the phosphonyl oxygen instead of one of the oxygen atoms with only single bonds.

Is rivastigmine safe as pretreatment against nerve agents poisoning? A pharmacological, physiological and cognitive assessment in healthy young adult volunteers.

PubMed

Lavon, Ophir; Eisenkraft, Arik; Blanca, Merav; Raveh, Lily; Ramaty, Erez; Krivoy, Amir; Atsmon, Jacob; Grauer, Ettie; Brandeis, Rachel

2015-07-01

Rivastigmine, a reversible cholinesterase inhibitor, approved as a remedy in Alzheimer's disease, was suggested as pretreatment against nerve agents poisoning. We evaluated the pharmacokinetic, pharmacodynamic, physiologic, cognitive and emotional effects of repeated rivastigmine in young healthy male adults, in a double blind, placebo controlled crossover trial. Three groups completed 3 treatment periods: 0, 1.5 and 3mg twice a day, for a total of 5 intakes. Parameters monitored were: vital signs, ECG, laboratory tests, sialometry, visual accommodation, inspiratory peak flow, and cognitive function tests. Adverse reactions were mild. Peak blood levels and peak cholinesterase inhibition increased with repeated intakes, and high variability and non-linear pharmacokinetics were demonstrated. In addition, two cognitive functions were affected (perceptual speed and dynamic tracking). The complicated pharmacological profile and the high inter-personal variability limit the potential use of rivastigmine as pretreatment for war fighters and first responders. Copyright © 2015 Elsevier Inc. All rights reserved.

Protective Effect of a Mitochondria-Targeted Peptide against the Development of Chemotherapy-Induced Peripheral Neuropathy in Mice.

PubMed

Toyama, Satoshi; Shimoyama, Naohito; Szeto, Hazel H; Schiller, Peter W; Shimoyama, Megumi

2018-04-18

Several chemotherapeutic agents used for cancer treatment induce dose-limiting peripheral neuropathy that compromises patients' quality of life and limits cancer treatment. Recently, mitochondrial dysfunction has been shown to be involved in the mechanism of chemotherapy-induced peripheral neuropathy. SS-20 is a mitochondria-targeted peptide that promotes mitochondrial respiration and restores mitochondrial bioenergetics. In the present study, we examined the protective effect of SS-20 against the development of chemotherapy-induced peripheral neuropathy utilizing a murine model of peripheral neuropathy induced by oxaliplatin, a first-line chemotherapy agent for colon cancer. Weekly administrations of oxaliplatin induced peripheral neuropathy as demonstrated by the development of neuropathic pain and loss of intraepidermal nerve fibers in the hind paw. Continuous administration of SS-20 protected against the development of oxaliplatin-induced neuropathic pain and mitigated the loss of intraepidermal nerve fibers to normal levels. Our findings suggest that SS-20 may be a drug candidate for the prevention of chemotherapy-induced peripheral neuropathy.

Fatal motor vehicle crashes among veterans of the 1991 Gulf War and exposure to munitions demolitions at Khamisiyah: a nested case-control study.

PubMed

Gackstetter, Gary D; Hooper, Tomoko I; DeBakey, Samar F; Johnson, Amy; Nagaraj, Barbara E; Heller, Jack M; Kang, Han K

2006-04-01

A proposed explanation for the observed higher risk of fatal motor vehicle crashes (MVC) among 1991 Gulf War-deployed veterans is neurocognitive deficits resulting from nerve agent exposure at Khamisiyah, Iraq. Our objective was to assess any association between postwar fatal MVC and possible nerve agent exposure based on 2000 modeled plume data. Cases were defined as MVC deaths with a record in the Department of Transportation Fatality Analysis Reporting System through 1995. Cases (n = 282) and controls (n = 3,131) were derived from a larger nested case-control study of Gulf War-era veterans and limited to Army, male, deployed personnel. Exposure and cumulative dose by case-control status were analyzed using multivariate techniques. Exposure status was not associated with fatal MVC (OR 0.96, 95% CI 0.72-1.26), nor were tertiles of cumulative dose. Findings do not support an association between possible exposures at Khamisiyah and postwar fatal MVC among Gulf War veterans.

Autoregulation of Neuromuscular Transmission by Nerve Terminals

DTIC Science & Technology

1985-12-01

converted to choline by AChE (EC 3.1.1.7); second, choline 24 is converted to betaine and H2 02 by choline oxidase (ChOx) (EC 1.1.3.17); and finally, H2...obtained that choline avail- ability can influence ACh release. Low levels of choline decrease release. However, this modulatory mechanism appears to...fects of various toxic agents on the axonal transport of these binding sites. The effects of organophosphate agents in vitro and in vivo on choline efflux

2005 USSOCOM Chemical, Biological, Radiological Conference and Exhibition

DTIC Science & Technology

2005-12-08

Cree, Inc. 22 Signal respose to releases 12:42 12:48 12:54 13:0 13:6 13:12 13:18 -2 0 2 4 6 8 10 12 x 10-3 Processed Data for AS-B2-009-09-03-05...acrid smell and onset of nerve agent symptoms Confidential USSOCOM Scenario 3: Chemical Agent Attack • First responders don their Self -Contained...Nuclear (CBRN) detectors Smart Threads is a dynamic, easily expandable, self - configuring platform Smart Threads Integrated Radiation Sensors (STIRS

A System Dynamics Approach to the Efficacy of Oxime Therapy in Sub Lethal Exposure to Sarin Gas

DTIC Science & Technology

2015-06-18

effective treatments , including antidotes, is considered to contribute to this high mortality rate (Buckley et al., 2004:1231). The efficacy of current...officials to reduce the risk associated with high -consequence threats”. Nerve agents, such as Sarin gas, are considered high consequence threats...The threat of use of agents such as Sarin is as much a threat today as any other time in our history. However, the suggested treatment protocol is

Neuroprotective effect of lurasidone via antagonist activities on histamine in a rat model of cranial nerve involvement.

PubMed

He, Baoming; Yu, Liang; Li, Suping; Xu, Fei; Yang, Lili; Ma, Shuai; Guo, Yi

2018-04-01

Cranial nerve involvement frequently involves neuron damage and often leads to psychiatric disorder caused by multiple inducements. Lurasidone is a novel antipsychotic agent approved for the treatment of cranial nerve involvement and a number of mental health conditions in several countries. In the present study, the neuroprotective effect of lurasidone by antagonist activities on histamine was investigated in a rat model of cranial nerve involvement. The antagonist activities of lurasidone on serotonin 5‑HT7, serotonin 5‑HT2A, serotonin 5‑HT1A and serotonin 5‑HT6 were analyzed, and the preclinical therapeutic effects of lurasidone were examined in a rat model of cranial nerve involvement. The safety, maximum tolerated dose (MTD) and preliminary antitumor activity of lurasidone were also assessed in the cranial nerve involvement model. The therapeutic dose of lurasidone was 0.32 mg once daily, administered continuously in 14‑day cycles. The results of the present study found that the preclinical prescriptions induced positive behavioral responses following treatment with lurasidone. The MTD was identified as a once daily administration of 0.32 mg lurasidone. Long‑term treatment with lurasidone for cranial nerve involvement was shown to improve the therapeutic effects and reduce anxiety in the experimental rats. In addition, treatment with lurasidone did not affect body weight. The expression of the language competence protein, Forkhead‑BOX P2, was increased, and the levels of neuroprotective SxIP motif and microtubule end‑binding protein were increased in the hippocampal cells of rats with cranial nerve involvement treated with lurasidone. Lurasidone therapy reinforced memory capability and decreased anxiety. Taken together, lurasidone treatment appeared to protect against language disturbances associated with negative and cognitive impairment in the rat model of cranial nerve involvement, providing a basis for its use in the clinical treatment of patients with cranial nerve involvement.

Surface-enhanced Raman as a water monitor for warfare agents

NASA Astrophysics Data System (ADS)

Spencer, Kevin M.; Sylvia, James M.; Clauson, Susan L.; Janni, James A.

2002-02-01

The threat of chemical warfare agents being released upon civilian and military personnel continues to escalate. One aspect of chemical preparedness is to analyze and protect the portable water supply for the military. Chemical nerve, blister, and choking agents, as well as biological threats must all be analyzed and low limits of detection must be verified. For chemical agents, this generally means detection down to the low ppb levels. Surface-Enhanced Raman Spectroscopy (SERS) is a spectroscopic technique that can detect trace levels of contaminants directly in the aqueous environment. In this paper, results are presented on the use of SERS to detect chemical and biological agent simulants with an end goal of creating a Joint Service Agent Water Monitor. Detection of cyanide, 2-chloroethyl ethyl sulfide, phosphonates, Gram-positive and Gram-negative bacteria using SERS has been performed and is discussed herein. Aspects of transferring laboratory results to an unattended field instrument are also discussed.

Military chemical warfare agent human subjects testing: part 2--long-term health effects among participants of U.S. military chemical warfare agent testing.

PubMed

Brown, Mark

2009-10-01

Military chemical warfare agent testing from World War I to 1975 produced thousands of veterans with concerns about how their participation affected their health. A companion article describes the history of these experiments, and how the lack of clinical data hampers evaluation of long-term health consequences. Conversely, much information is available about specific agents tested and their long-term health effects in other populations, which may be invaluable for helping clinicians respond effectively to the health care and other needs of affected veterans. The following review describes tested agents and their known long-term health consequences. Although hundreds of chemicals were tested, they fall into only about a half-dozen pharmaceutical classes, including common pharmaceuticals; anticholinesterase agents including military nerve agents and pesticides; anticholinergic glycolic acid esters such as atropine; acetylcholine reactivators such as 2-PAM; psychoactive compounds including cannabinoids, phencyclidine, and LSD; and irritants including tear gas and riot control agents.

Clinical Practice Guidelines for Sustained Neuromuscular Blockade in the Adult Critically Ill Patient.

PubMed

Murray, Michael J; DeBlock, Heidi; Erstad, Brian; Gray, Anthony; Jacobi, Judi; Jordan, Che; McGee, William; McManus, Claire; Meade, Maureen; Nix, Sean; Patterson, Andrew; Sands, M Karen; Pino, Richard; Tescher, Ann; Arbour, Richard; Rochwerg, Bram; Murray, Catherine Friederich; Mehta, Sangeeta

2016-11-01

To update the 2002 version of "Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient." A Task Force comprising 17 members of the Society of Critical Medicine with particular expertise in the use of neuromuscular-blocking agents; a Grading of Recommendations Assessment, Development, and Evaluation expert; and a medical writer met via teleconference and three face-to-face meetings and communicated via e-mail to examine the evidence and develop these practice guidelines. Annually, all members completed conflict of interest statements; no conflicts were identified. This activity was funded by the Society for Critical Care Medicine, and no industry support was provided. Using the Grading of Recommendations Assessment, Development, and Evaluation system, the Grading of Recommendations Assessment, Development, and Evaluation expert on the Task Force created profiles for the evidence related to six of the 21 questions and assigned quality-of-evidence scores to these and the additional 15 questions for which insufficient evidence was available to create a profile. Task Force members reviewed this material and all available evidence and provided recommendations, suggestions, or good practice statements for these 21 questions. The Task Force developed a single strong recommendation: we recommend scheduled eye care that includes lubricating drops or gel and eyelid closure for patients receiving continuous infusions of neuromuscular-blocking agents. The Task Force developed 10 weak recommendations. 1) We suggest that a neuromuscular-blocking agent be administered by continuous intravenous infusion early in the course of acute respiratory distress syndrome for patients with a PaO2/FIO2 less than 150. 2) We suggest against the routine administration of an neuromuscular-blocking agents to mechanically ventilated patients with status asthmaticus. 3) We suggest a trial of a neuromuscular-blocking agents in life-threatening situations associated with profound hypoxemia, respiratory acidosis, or hemodynamic compromise. 4) We suggest that neuromuscular-blocking agents may be used to manage overt shivering in therapeutic hypothermia. 5) We suggest that peripheral nerve stimulation with train-of-four monitoring may be a useful tool for monitoring the depth of neuromuscular blockade but only if it is incorporated into a more inclusive assessment of the patient that includes clinical assessment. 6) We suggest against the use of peripheral nerve stimulation with train of four alone for monitoring the depth of neuromuscular blockade in patients receiving continuous infusion of neuromuscular-blocking agents. 7) We suggest that patients receiving a continuous infusion of neuromuscular-blocking agent receive a structured physiotherapy regimen. 8) We suggest that clinicians target a blood glucose level of less than 180 mg/dL in patients receiving neuromuscular-blocking agents. 9) We suggest that clinicians not use actual body weight and instead use a consistent weight (ideal body weight or adjusted body weight) when calculating neuromuscular-blocking agents doses for obese patients. 10) We suggest that neuromuscular-blocking agents be discontinued at the end of life or when life support is withdrawn. In situations in which evidence was lacking or insufficient and the study results were equivocal or optimal clinical practice varies, the Task Force made no recommendations for nine of the topics. 1) We make no recommendation as to whether neuromuscular blockade is beneficial or harmful when used in patients with acute brain injury and raised intracranial pressure. 2) We make no recommendation on the routine use of neuromuscular-blocking agents for patients undergoing therapeutic hypothermia following cardiac arrest. 3) We make no recommendation on the use of peripheral nerve stimulation to monitor degree of block in patients undergoing therapeutic hypothermia. 4) We make no recommendation on the use of neuromuscular blockade to improve the accuracy of intravascular-volume assessment in mechanically ventilated patients. 5) We make no recommendation concerning the use of electroencephalogram-derived parameters as a measure of sedation during continuous administration of neuromuscular-blocking agents. 6) We make no recommendation regarding nutritional requirements specific to patients receiving infusions of neuromuscular-blocking agents. 7) We make no recommendation concerning the use of one measure of consistent weight over another when calculating neuromuscular-blocking agent doses in obese patients. 8) We make no recommendation on the use of neuromuscular-blocking agents in pregnant patients. 9) We make no recommendation on which muscle group should be monitored in patients with myasthenia gravis receiving neuromuscular-blocking agents. Finally, in situations in which evidence was lacking or insufficient but expert consensus was unanimous, the Task Force developed six good practice statements. 1) If peripheral nerve stimulation is used, optimal clinical practice suggests that it should be done in conjunction with assessment of other clinical findings (e.g., triggering of the ventilator and degree of shivering) to assess the degree of neuromuscular blockade in patients undergoing therapeutic hypothermia. 2) Optimal clinical practice suggests that a protocol should include guidance on neuromuscular-blocking agent administration in patients undergoing therapeutic hypothermia. 3) Optimal clinical practice suggests that analgesic and sedative drugs should be used prior to and during neuromuscular blockade, with the goal of achieving deep sedation. 4) Optimal clinical practice suggests that clinicians at the bedside implement measure to attenuate the risk of unintended extubation in patients receiving neuromuscular-blocking agents. 5) Optimal clinical practice suggests that a reduced dose of an neuromuscular-blocking agent be used for patients with myasthenia gravis and that the dose should be based on peripheral nerve stimulation with train-of-four monitoring. 6) Optimal clinical practice suggests that neuromuscular-blocking agents be discontinued prior to the clinical determination of brain death.

Essential oil of Croton zehntneri and its main constituent anethole block excitability of rat peripheral nerve.

PubMed

da Silva-Alves, Kerly Shamyra; Ferreira-da-Silva, Francisco Walber; Coelho-de-Souza, Andrelina Noronha; Albuquerque, Aline Alice Cavalcante; do Vale, Otoni Cardoso; Leal-Cardoso, José Henrique

2015-03-01

Croton zehntneri is an aromatic plant native to Northeast Brazil and employed by local people to treat various diseases. The leaves of this plant have a rich content of essential oil. The essential oil of C. zehntneri samples, with anethole as the major constituent and anethole itself, have been reported to have several pharmacological activities such as antispasmodic, cardiovascular, and gastroprotective effects and inducing the blockade of neuromuscular transmission and antinociception. Since several works have demonstrated that essential oils and their constituents block cell excitability and in view of the multiple effects of C. zehntneri essential oil and anethole on biological tissues, we undertook this investigation aiming to characterize and compare the effects of this essential oil and its major constituent on nerve excitability. Sciatic nerves of Wistar rats were used. They were mounted in a moist chamber, and evoked compound action potentials were recorded. Nerves were exposed in vitro to the essential oil of C. zehntneri and anethole (0.1-1 mg/mL) up to 180 min, and alterations in excitability (rheobase and chronaxie) and conductibility (peak-to-peak amplitude and conduction velocity) parameters of the compound action potentials were evaluated. The essential oil of C. zehntneri and anethole blocked, in a concentration-dependent manner with similar pharmacological potencies (IC50: 0.32 ± 0.07 and 0.22 ± 0.11 mg/mL, respectively), rat sciatic nerve compound action potentials. Strength-duration curves for both agents were shifted upward and to the right compared to the control curve, and the rheobase and chronaxie were increased following essential oil and anethole exposure. The time courses of the essential oil of C. zehntneri and anethole effects on peak-to-peak amplitude of compound action potentials followed an exponential decay and reached a steady state. The essential oil of C. zehntneri and anethole caused a similar reduction in conduction velocities of the compound action potential waves investigated. In conclusion, we demonstrated here that the essential oil of C. zehntneri blocks neuronal excitability and that this effect, which can be predominantly attributable to its major constituent, anethole, is important since these agents have several pharmacological effects likely related to the alteration of excitability. This finding is relevant due to the use of essential oils in aromatherapy and the low acute toxicity of this agent, which exhibits other effects of potential therapeutic usefulness. Georg Thieme Verlag KG Stuttgart · New York.

Human Serum Butyrylcholinesterase: A Bioscavenger for the Protection of Humans from Organophosphorus Exposure

DTIC Science & Technology

2009-10-01

Current medical countermeasures against OP nerve agent poisoning include a combination of pretreatment with a carbamate, pyridostigmine bromide , to...The protection of primates against soman poisoning by pretreatment with pyridostigmine , J. Pharm. Pharmacol. 31 (1979) 295-299. [2] C.G. McLeod

The effect of triamcinolone hexacetonide on the spontaneous and mechanically-induced ectopic discharge following lingual nerve injury in the ferret.

PubMed

Yates, Julian M; Smith, Keith G; Robinson, Peter P

2004-10-01

Investigations into the aetiology of nerve injury-induced dysaesthesia have revealed the development of spontaneous and mechanically-induced activity from damaged axons. Pharmacological manipulation of this activity could provide a method of treatment for this intractable condition. This study has investigated the effect of a corticosteroid applied to the injury site, as these agents are known to reduce inflammation and scarring. In 24 anaesthetised adult ferrets the left lingual nerve was sectioned and the animals allowed to recover. In eight of these animals the nerve was re-exposed under anaesthesia after 1 month and 100 microl of corticosteroid (triamcinolone hexacetonide, 20 mg/ml) was injected into and around the injury site. In eight others, 100 microl of the steroid carrier was injected, and the eight remaining animals were used as controls. In terminal experiments under general anaesthesia, 3 months after the initial injury, electrophysiological recordings were made from axons in fine filaments dissected from the nerve central to both the injury site and junction with the chorda tympani nerve. Spontaneous activity (SA) was found in approximately 13% of units in control animals, 12% following the application of steroid, and 14% in the carrier group. Mechanically-induced activity at the injury site was found in approximately 13% of units in controls, significantly fewer after the application of steroid 4% (P<0.001) and 12% in the carrier group. These data suggest that local application of the corticosteroid triamcinolone hexacetonide could reduce the level of mechanically-induced, but not spontaneous, dysaesthesia following lingual nerve injury.

Evaluation of Buccal Infiltration with Articaine and Inferior Alveolar Nerve Block with Lignocaine for Pulp Therapy in Mandibular Primary Molars.

PubMed

Chopra, Radhika; Marwaha, Mohita; Bansal, Kalpana; Mittal, Meenu

2016-01-01

Failure of inferior alveolar nerve block in achieving profound anesthesia of the pulp due to various reasons has led to the introduction of more potent local anesthetic agents like articaine. This study was conducted to compare the efficacy of buccal infiltration with articaine in achieving pulpal anesthesia of primary molars as compared to inferior alveolar nerve block with lignocaine. 30 patients (4-8 years) with indication of pulp therapy in at least two mandibular primary molars were selected. Patients were randomly assigned to receive nerve block with lignocaine or infiltration with articaine on first appointment and the other solution on second appointment. All the pulpotomies and pulpectomies were performed by a pediatric dentist. Two researchers standing at a distance of 1.5 m recorded the Pain Scores and Sound, Eye, Motor (SEM) scores. After the completion of procedure, the patient was asked to record the Facial Image score and Heft-Parker Visual Analogue Score (HP-VAS). Pain Score recorded at the time of injection showed significantly more movements with block as compared to infiltration (p<0.001). SEM scores at time of pulp extirpation were also higher for block than infiltration (p<0.001). Articaine infiltration has the potential to replace inferior alveolar nerve block for primary mandibular molars.

[Successful treatment of HIV-associated chronic inflammatory demyelinating polyneuropathy by early initiation of highly active anti-retroviral therapy].

PubMed

Kume, Kodai; Ikeda, Kazuyo; Kamada, Masaki; Touge, Tetsuo; Deguchi, Kazushi; Masaki, Tsutomu

2013-01-01

A 47-year-old man with HIV infection presented with lower leg dominant dysesthesia, muscle weakness and sensory ataxia of 3 month's duration. Nerve conduction studies (NCS) showed demyelination change in the median and tibial nerves and sensory nerve action potential (SNAP) in the sural nerve was not evoked. Somatosensory evoked potential (SEP) showed the delayed N9 latency. Diagnose of HIV-associated chronic inflammatory demyelinating polyneuropathy (CIDP) was made. Although the CD4 lymphocyte counts were relatively preserved (466/μl), highly active anti-retroviral therapy (HAART) was started according to a new guideline for the use of antiretroviral agents in HIV-1-infected adults and adolescents recommending early initiation of treatment. After six months, HIV1-RNA was not detected and the CD4 lymphocyte counts showed a recovering trend (585/μl). His symptoms had disappeared, except for dysesthesia in the tip of a toe. Repeated NCS demonstrated full recovery from the demyelination and appearance of SNAP in the sural nerve. The improvement of his symptoms and NCS findings has been maintained for two years. Although effectiveness of immunotherapies such as oral prednisone, high-dose immunoglobulins and plasmapheresis have been reported in HIV-associated CIDP, early initiation of HAART may be also important for favorable prognosis in HIV-associated CIDP.

The Effect of Memantine on Functional Recovery of the Sciatic Nerve Crush Injury in Rats.

PubMed

Ghayour, Mohammad-Bagher; Abdolmaleki, Arash; Behnam-Rassouli, Morteza

2017-01-01

Following severe peripheral nerve injury (PNI), regeneration is often insufficient and functional recovery is incomplete. In this regard, glutamate N-methyl-D-aspartate (NMDA) receptor antagonist such as Memantine have been shown to have neuroprotective effects. We evaluated the effects of Memantine against sciatic nerve crush injury in male Wistar Rats. Memantine or vehicle was given parenteraly to rats for 7 days postoperative. In Memantine treatment groups, a single dose of agent (5 and 10 mg/kg) was administered daily. The control group was given vehicle in the same manner. The rats were subjected to crush injury in the left sciatic nerve with non-serrated clamp for 30 seconds. Behavioural, electrophysiological and morphological alterations were evaluated during the experimental period. Results showed that Memantine has no significant effect on regeneration process rate and functional recovery quality. In the sciatic functional index (SFI) test no significant difference was observed between Memantine treatment groups (5 and 10 mg/ kg) at any week. Since the major neuroprotective effect of Memantine is due to its protective activity against NMDA receptormediated excitotoxicity, it seems that glutamate excitotoxicity is less important in motor impairment due to sciatic nerve crush injury. It is clear that more research is needed to confirm these findings.

Indoor sorption of surrogates for sarin and related nerve agents.

PubMed

Singer, Brett C; Hodgson, Alfred T; Destaillats, Hugo; Hotchi, Toshifumi; Revzan, Kenneth L; Sextro, Richard G

2005-05-01

Sorption rate parameters were determined for three organophosphorus (OP) compounds [dimethyl methylphosphonate (DMMP), diethyl ethylphosphonate (DEEP), and triethyl phosphate (TEP)] as surrogates for the G-type nerve agents sarin (GB), soman (GD), and tabun (GA). OP surrogates were injected and vaporized with additional volatile organic compounds into a 50 m3 chamber finished with painted wallboard. Experiments were conducted at two furnishing levels: (i) chamber containing only hard surfaces including a desk, a bookcase, tables, and chairs and (ii) with the addition of plush materials including carpet with cushion, draperies, and upholstered furniture. Each furnishing level was studied with aged and new painted wallboard. Gas-phase concentrations were measured during sealed chamber adsorb and desorb phases and then fit to three mathematical variations of a previously proposed sorption model having a surface sink and allowing for an embedded sink. A four-parameter model allowing unequal transport rates between surface and embedded sinks provided excellent fits for all conditions. To evaluate the potential effect of sorption, this model was incorporated into an indoor air quality simulation model to predict indoor concentrations of a G-type agent and a nonsorbing agent for hypothetical outdoor releases with shelter-in-place (SIP) response. Sorption was simulated using a range of parameters obtained experimentally. Simulations considered outdoor Gaussian plumes of 1- and 5-h duration and infiltration rates of 0.1, 0.3, and 0.9 h(-1). Indoor toxic loads (TL) for a 10-h SIP were calculated as integral C2 dt for a G-type agent. For the 5-h plume, sheltering reduced TLs for the nonsorbing agent to approximately 10-65% of outdoor levels. Analogous TLs for a G-type agent were 2-31% or 0.3-12% of outdoor levels assuming slow or moderate sorption. The relative effect of sorption was more pronounced for the longer plume and higher infiltration rates.

Natural Detoxification Capacity to Inactivate Nerve Agents Sarin and VX in the Rat Blood.

PubMed

Bajgar, Jiří; Cabal, Jiří; Kassa, Jiří; Pavlík, Michal

2015-01-01

The method of continual determination of the rat blood cholinesterase activity was developed to study the changes of the blood cholinesterases following different intervetions. The aim of this study is registration of cholinesterase activity in the rat blood and its changes to demonstrate detoxification capacity of rats to inactivate sarin or VX in vivo. The groups of female rats were premedicated (ketamine and xylazine) and cannulated to a. femoralis. Continual blood sampling (0.02 ml/min) and monitoring of the circulating blood cholinesterase activity were performed. Normal activity was monitored 1-2 min and then the nerve agent was administered i.m. (2×LD50). Using different time intervals of the leg compression and relaxation following the agent injection, cholinesterase activity was monitored and according to the inhibition obtained, detoxification capacity was assessed. Administration of sarin to the leg, then 1 and 5 min compression and 20 min later relaxation showed that further inhibition in the blood was not observed. On the other hand, VX was able to inhibit blood cholinesterases after this intervention. The results demonstrated that sarin can be naturally detoxified on the contrary to VX. Described method can be used as model for other studies dealing with changes of cholinesterases in the blood following different factors.

Adaptation of the Conditions of US EPA Method 538 for the ...

EPA Pesticide Factsheets

Report The objective of this study was to evaluate U.S. EPA’s Method 538 for the assessment of drinking water exposure to the nerve agent degradation product, EA2192, the most toxic degradation product of nerve agent VX. As a result of the similarities in sample preparation and analysis that Method 538 uses for nonvolatile chemicals, this method is applicable to the nonvolatile Chemical Warfare Agent (CWA) degradation product, EA2192, in drinking water. The method may be applicable to other nonvolatile CWAs and their respective degradation products as well, but the method will need extensive testing to verify compatibility. Gaps associated with the need for analysis methods capable of analyzing such analytes were addressed by adapting the EPA 538 method for this CWA degradation product. Many laboratories have the experience and capability to run the already rigorous method for nonvolatile compounds in drinking water. Increasing the number of laboratories capable of carrying out these methods serves to significantly increase the surge laboratory capacity to address sample throughput during a large exposure event. The approach desired for this study was to start with a proven high performance liquid chromatography tandem mass spectrometry (HPLC/MS/MS) method for nonvolatile chemicals in drinking water and assess the inclusion of a similar nonvolatile chemical, EA2192.

Decontamination of chemical and biological warfare agents with a single multi-functional material.

PubMed

Amitai, Gabi; Murata, Hironobu; Andersen, Jill D; Koepsel, Richard R; Russell, Alan J

2010-05-01

We report the synthesis of new polymers based on a dimethylacrylamide-methacrylate (DMAA-MA) co-polymer backbone that support both chemical and biological agent decontamination. Polyurethanes containing the redox enzymes glucose oxidase and horseradish peroxidase can convert halide ions into active halogens and exert striking bactericidal activity against gram positive and gram negative bacteria. New materials combining those biopolymers with a family of N-alkyl 4-pyridinium aldoxime (4-PAM) halide-acrylate co-polymers offer both nucleophilic activity for the detoxification of organophosphorus nerve agents and internal sources of halide ions for generation of biocidal activity. Generation of free bromine and iodine was observed in the combined material resulting in bactericidal activity of the enzymatically formed free halogens that caused complete kill of E. coli (>6 log units reduction) within 1 h at 37 degrees C. Detoxification of diisopropylfluorophosphate (DFP) by the polyDMAA MA-4-PAM iodide component was dose-dependent reaching 85% within 30 min. A subset of 4-PAM-halide co-polymers was designed to serve as a controlled release reservoir for N-hydroxyethyl 4-PAM (HE 4-PAM) molecules that reactivate nerve agent-inhibited acetylcholinesterase (AChE). Release rates for HE 4-PAM were consistent with hydrolysis of the HE 4-PAM from the polymer backbone. The HE 4-PAM that was released from the polymer reactivated DFP-inhibited AChE at a similar rate to the oxime antidote 4-PAM. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

MELANOPHORE BANDS AND AREAS DUE TO NERVE CUTTING, IN RELATION TO THE PROTRACTED ACTIVITY OF NERVES

PubMed Central

Parker, G. H.

1941-01-01

1. When appropriate chromatic nerves are cut caudal bands, cephalic areas, and the pelvic fins of the catfish Ameiurus darken. In pale fishes all these areas will sooner or later blanch. By recutting their nerves all such blanched areas will darken again. 2. These observations show that the darkening of caudal bands, areas, and fins on cutting their nerves is not due to paralysis (Brücke), to the obstruction of central influences such as inhibition (Zoond and Eyre), nor to vasomotor disturbances (Hogben), but to activities emanating from the cut itself. 3. The chief agents concerned with the color changes in Ameiurus are three: intermedin from the pituitary gland, acetylcholine from the dispersing nerves (cholinergic fibers), and adrenalin from the concentrating nerves (adrenergic fibers). The first two darken the fish; the third blanches it. In darkening the dispersing nerves appear to initiate the process and to be followed and substantially supplemented by intermedin. 4. Caudal bands blanch by lateral invasion, cephalic areas by lateral invasion and internal disintegration, and pelvic fins by a uniform process of general loss of tint equivalent to internal disintegration. 5. Adrenalin may be carried in such an oil as olive oil and may therefore act as a lipohumor; it is soluble in water and hence may act as a hydrohumor. In lateral invasion (caudal bands, cephalic areas) it probably acts as a lipohumor and in internal disintegration (cephalic areas, pelvic fins) it probably plays the part of a hydrohumor. 6. The duration of the activity of dispersing nerves after they had been cut was tested by means of the oscillograph, by anesthetizing blocks, and by cold-blocks. The nerves of Ameiurus proved to be unsatisfactory for oscillograph tests. An anesthetizing block, magnesium sulfate, is only partly satisfactory. A cold-block, 0°C., is successful to a limited degree. 7. By means of a cold-block it can be shown that dispersing autonomic nerve fibers in Ameiurus can continue in activity for at least 6½ hours. It is not known how much longer they may remain active. So far as the duration of their activity is concerned dispersing nerve fibers in this fish are unlike other types of nerve fibers usually studied. PMID:19873231

FLOW INJECTION AMPEROMETRIC DETECTION OF OP NERVE AGENTS BASED ON AN ORGANOPHOSPHORUS-HYDROLASE BIOSENSOR DETECTOR. (R828160)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

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

DTIC Science & Technology

2016-09-01

Status epilepticus may be caused by loss of adenosine anticonvulsant mechanisms. Neuroscience. 58: 245-261. 37. Bueters, T. J., et al. 2002...Pharmacology. 113: 1386-1390. 57. Niquet, J., et al. 2015. Neuroprotective effects of deep hypothermia in refractory status epilepticus . Annals of

Nerve Agent Hydrolysis Activity Designed into a Human Drug Metabolism Enzyme

DTIC Science & Technology

2011-03-18

11]. To facilitate measurement of additional kinetic constants, secreted forms of wt and V146H/L363E hCE1 were expressed in Spodoptera frugiperda Sf21...Comparison of Escherichia coli, Saccharomyces cerevisiae, Pichia pastoris, Spodoptera frugiperda , and COS7 cells for recombinant gene expression

Reactivation of model cholinesterases by oximes and intermediate phosphyloximes: A computational study

PubMed Central

Vyas, Shubham; Hadad, Christopher M.

2008-01-01

Phosphyloximes (POX) are generated upon the reactivation of organophosphorus (OP) inhibited cholinesterases (ChEs) by pyridinium oximes. These POXs are known to be potent inhibitors of the ChEs following reactivation. However, they can also decompose to give an OP derivative and a cyano derivative of the oxime when a base abstracts the benzylic proton. Using density functional theory, thermodynamic properties were calculated for the reactivation and decomposition pathways of three different oximes (2-PAM, 3-PAM and 4-PAM) with six different OPs (cyclosarin, paraoxon, sarin, tabun, VR and VX). For reactivation purposes, 2-PAM is predicted to be more efficient than 3- and 4-PAM. Based on atomic charges and relative energies, 2-POXs were found to be more inclined towards the decomposition process. PMID:18582852

A comprehensive evaluation of the efficacy of leading oxime therapies in guinea pigs exposed to organophosphorus chemical warfare agents or pesticides

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wilhelm, Christina M., E-mail: wilhelmc@battelle.org; Snider, Thomas H., E-mail: snidert@battelle.org; Babin, Michael C., E-mail: babinm@battelle.org

The currently fielded pre-hospital therapeutic regimen for the treatment of organophosphorus (OP) poisoning in the United States (U.S.) is the administration of atropine in combination with an oxime antidote (2-PAM Cl) to reactivate inhibited acetylcholinesterase (AChE). Depending on clinical symptoms, an anticonvulsant, e.g., diazepam, may also be administered. Unfortunately, 2-PAM Cl does not offer sufficient protection across the range of OP threat agents, and there is some question as to whether it is the most effective oxime compound available. The objective of the present study is to identify an oxime antidote, under standardized and comparable conditions, that offers protection atmore » the FDA approved human equivalent dose (HED) of 2-PAM Cl against tabun (GA), sarin (GB), soman (GD), cyclosarin (GF), and VX, and the pesticides paraoxon, chlorpyrifos oxon, and phorate oxon. Male Hartley guinea pigs were subcutaneously challenged with a lethal level of OP and treated at approximately 1 min post challenge with atropine followed by equimolar oxime therapy (2-PAM Cl, HI-6 DMS, obidoxime Cl{sub 2}, TMB-4, MMB4-DMS, HLö-7 DMS, MINA, and RS194B) or therapeutic-index (TI) level therapy (HI-6 DMS, MMB4-DMS, MINA, and RS194B). Clinical signs of toxicity were observed for 24 h post challenge and blood cholinesterase [AChE and butyrylcholinesterase (BChE)] activity was analyzed utilizing a modified Ellman's method. When the oxime is standardized against the HED of 2-PAM Cl for guinea pigs, the evidence from clinical observations, lethality, quality of life (QOL) scores, and cholinesterase reactivation rates across all OPs indicated that MMB4 DMS and HLö-7 DMS were the two most consistently efficacious oximes. - Highlights: • First comprehensive evaluation of leading AChE oxime reactivators • All oximes are compared against current U.S. therapy 2-PAM Cl. • Relative therapeutic oxime efficacies against OP CWNA and pesticides • Contribution to more effective antidotes for civilian and military populations.« less

Dual-Function Metal-Organic Framework as a Versatile Catalyst for Detoxifying Chemical Warfare Agent Simulants.

PubMed

Liu, Yangyang; Moon, Su-Young; Hupp, Joseph T; Farha, Omar K

2015-12-22

The nanocrystals of a porphyrin-based zirconium(IV) metal-organic framework (MOF) are used as a dual-function catalyst for the simultaneous detoxification of two chemical warfare agent simulants at room temperature. Simulants of nerve agent (such as GD, VX) and mustard gas, dimethyl 4-nitrophenyl phosphate and 2-chloroethyl ethyl sulfide, have been hydrolyzed and oxidized, respectively, to nontoxic products via a pair of pathways catalyzed by the same MOF. Phosphotriesterase-like activity of the Zr6-containing node combined with photoactivity of the porphyrin linker gives rise to a versatile MOF catalyst. In addition, bringing the MOF crystals down to the nanoregime leads to acceleration of the catalysis.

Electrophysiologic changes following treatment with organophosphorus-induced delayed neuropathy-producing agents in the adult hen.

PubMed

Robertson, D G; Schwab, B W; Sills, R D; Richardson, R J; Anderson, R J

1987-03-15

Although clinical, pathological, and biochemical effects of organophosphorus-induced delayed neuropathy (OPIDN) have been intensively investigated in the adult hen, detailed electrophysiological studies are lacking. Adult white leghorn hens were treated with a single oral dose of either 30 mg/kg tri-2-cresyl phosphate (TOCP), 750 mg/kg TOCP, 4 mg/kg di-n-butyl-2,2-dichlorovinyl phosphate (DBCV), or 30 mg/kg di-n-butyl-2,2-dichlorovinyl phosphinate (DBCV-P). The 750 mg/kg TOCP and DBCV, but not the 30 mg/kg TOCP and DBCV-P, treatments resulted in clinical signs of OPIDN and mild to marked damage of the tibial nerve 21 days after dose. Twenty-four hr lymphocyte neurotoxic esterase (NTE) inhibition was used as an index of brain NTE inhibition for the various organophosphorus compound (OP) treatment. Twenty-four hr lymphocyte NTE inhibition for 30 mg/kg TOCP, 750 mg/kg TOCP, DBCV, and DBCV-P was 54.1, 87.1, 84.8, and 68.3%, respectively. Twenty-one days after dose, the TOCP-treated hens exhibited some abnormalities in conduction velocity and action potential duration in the tibial or sciatic nerves. No abnormalities were observed in action potential parameters of either the DBCV or DBCV-P treatments. Neurotoxic OP (TOCP and DBCV) treatment resulted in decreased refractoriness in the tibial nerve, increased refractoriness in the sciatic nerve, and elevated strength duration threshold for both nerves. These changes were not present in nerves from DBCV-P (a non-neurotoxic NTE inhibitor)-treated hens. These results suggest that refractory period and strength duration abnormalities in peripheral nerve correlate well with the production of OPIDN and are evident without coincident clinical signs or histopathology.

New method for comprehensive detection of chemical warfare agents using an electron-cyclotron-resonance ion-source mass spectrometer

NASA Astrophysics Data System (ADS)

Kidera, Masanori; Seto, Yasuo; Takahashi, Kazuya; Enomoto, Shuichi; Kishi, Shintaro; Makita, Mika; Nagamatsu, Tsuyoshi; Tanaka, Tatsuhiko; Toda, Masayoshi

2011-03-01

We developed a detection technology for vapor forms of chemical warfare agents (CWAs) with an element analysis system using an electron cyclotron resonance ion source. After the vapor sample was introduced directly into the ion source, the molecular material was decomposed into elements using electron cyclotron resonance plasma and ionized. The following CWAs and stimulants were examined: diisopropyl fluorophosphonate (DFP), 2-chloroethylethylsulfide (2CEES), cyanogen chloride (CNCl), and hydrogen cyanide (HCN). The type of chemical warfare agents, specifically, whether it was a nerve agent, blister agent, blood agent, or choking agent, could be determined by measuring the quantities of the monatomic ions or CN + using mass spectrometry. It was possible to detect gaseous CWAs that could not be detected by a conventional mass spectrometer. The distribution of electron temperature in the plasma could be closely controlled by adjusting the input power of the microwaves used to generate the electron cyclotron resonance plasma, and the target compounds could be detected as molecular ions or fragment ions, enabling identification of the target agents.

Effects of low-level sarin and cyclosarin exposure on white matter integrity in Gulf War Veterans.

PubMed

Chao, Linda L; Zhang, Yu; Buckley, Shannon

2015-05-01

We previously found evidence of reduced gray and white matter volume in Gulf War (GW) veterans with predicted low-level exposure to sarin (GB) and cyclosarin (GF). Because loss of white matter tissue integrity has been linked to both gray and white matter atrophy, the current study sought to test the hypothesis that GW veterans with predicted GB/GF exposure have evidence of disrupted white matter microstructural integrity. Measures of fractional anisotropy and directional (i.e., axial and radial) diffusivity were assessed from the 4T diffusion tensor images (DTI) of 59 GW veterans with predicted GB/GF exposure and 59 "matched" unexposed GW veterans (mean age: 48 ± 7 years). The DTI data were analyzed using regions of interest (ROI) analyses that accounted for age, sex, total brain gray and white matter volume, trauma exposure, posttraumatic stress disorder, current major depression, and chronic multisymptom illness status. There were no significant group differences in fractional anisotropy or radial diffusivity. However, there was increased axial diffusivity in GW veterans with predicted GB/GF exposure compared to matched, unexposed veterans throughout the brain, including the temporal stem, corona radiata, superior and inferior (hippocampal) cingulum, inferior and superior fronto-occipital fasciculus, internal and external capsule, and superficial cortical white matter blades. Post hoc analysis revealed significant correlations between higher fractional anisotropy and lower radial diffusivity with better neurobehavioral performance in unexposed GW veterans. In contrast, only increased axial diffusivity in posterior limb of the internal capsule was associated with better psychomotor function in GW veterans with predicted GB/GF exposure. The finding that increased axial diffusivity in a region of the brain that contains descending corticospinal fibers was associated with better psychomotor function and the lack of significant neurobehavioral deficits in veterans with predicted GB/GF exposure hint at the possibility that the widespread increases in axial diffusivity that we observed in GW veterans with predicted GB/GF exposure relative to unexposed controls may reflect white matter reorganization after brain injury (i.e., exposure to GB/GF). Published by Elsevier B.V.

BIOSENSOR FOR DIRECT DETERMINATION OF ORGANOPHOSPHATE NERVE AGENTS USING RECOMBINANT ESCHERICHIA COLI WITH SURFACE-EXPRESSED ORGANOPHOSPHORUS HYDROLASE. 1. POTENTIOMETRIC MICROBIAL ELECTRODE. (R823663)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

AMPEROMETRIC MICROBIAL BIOSENSOR FOR DIRECT DETERMINATION OF ORGANOPHOSPHATE NERVE AGENTS USING RECOMBINANT MORAXELLA SP. WITH SURFACE EXPRESSED ORGANOPHOSPHORUS HYDROLASE. (R828160)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

SIMILARITIES BETWEEN PROTEIN IIIA AND PROTEIN IIIB, TWO PROMINENT SYNAPTIC VESICLE-ASSOCIATED PHOSPHOPROTEINS (JOURNAL VERSION)

EPA Science Inventory

Protein IIIa (Mr 74,000) and protein IIIb (Mr 55,000) are two major phosphoproteins found in mammalian brain. It was previously shown in intact nerve cells that the phosphorylation state of these two proteins could be increased by electrical stimulation, by depolarizing agents in...

Hyperspectral Imagery for Large Area Survey of Organophosphate Pesticides

DTIC Science & Technology

2015-03-26

possible (Simonian et al., 2004). Nanotechnology has the potential for the development of handheld, real-time, and accurate OP detectors ( Goltz et...dx.doi.org.wrs.idm.oclc.org/10.1016/j.talanta.2012.10.016 Goltz , Mark, N.Dong Shik, Kim, Racz, LeeAnn. (2011). Using nanotechnology to detect nerve agents. Air & Space

Huperzine a as a pretreatment candidate drug against nerve agent toxicity. (Reannouncement with new availability information)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grunwald, J.; Raveh, L.; Doctor, B.P.

1994-12-31

Huperzine A (HUP) is a naturally-occurring, potent, reversible inhibitor of acetylcholinesterase (AChE) that crosses the blood-brain barrier. To examine its ability to protect against nerve agent poisoning, HUP was administered i.p. to mice, and the s.c. LD50 of soman was determined at various time intervals after pretreatment. Results were compared to those obtained for animals treated with physostigmine. A protective ratio of approximately 2 was maintained for at least 6 hr after a single injection of HUP, without the need for any post-challenge drug therapy. By contrast, pretreatment with physostigmine increased the LD50 of soman by 1.4- to 1.5-fold formore » only up to 90 min. The long-lasting antidotal efficacy displayed by HUP correlated with the time course of the blood-AChE inhibition. The results suggest that the protection of animals by HUP from soman poisoning was achieved by temporarily sequestering the active site region of the physiologically important AChE.« less

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.

Nanometric MIL-125-NH2 Metal–Organic Framework as a Potential Nerve Agent Antidote Carrier

PubMed Central

Vilela, Sérgio M. F.; Salcedo-Abraira, Pablo; Colinet, Isabelle; Salles, Fabrice; Serre, Christian; Horcajada, Patricia

2017-01-01

The three-dimensional (3D) microporous titanium aminoterephthalate MIL-125-NH2 (MIL: Material of Institut Lavoisier) was successfully isolated as monodispersed nanoparticles, which are compatible with intravenous administration, by using a simple, safe and low-cost synthetic approach (100 °C/32 h under atmospheric pressure) so that for the first time it could be considered for encapsulation and the release of drugs. The nerve agent antidote 2-[(hydroxyimino)methyl]-1-methyl-pyridinium chloride (2-PAM or pralidoxime) was effectively encapsulated into the pores of MIL-125-NH2 as a result of the interactions between 2-PAM and the pore walls being mediated by π-stacking and hydrogen bonds, as deduced from infrared spectroscopy and Monte Carlo simulation studies. Finally, colloidal solutions of MIL-125-NH2 nanoparticles exhibited remarkable stability in different organic media, aqueous solutions at different pH and under relevant physiological conditions over time (24 h). 2-PAM was rapidly released from the pores of MIL-125-NH2 in vitro. PMID:29023426

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

A novel organophosphorus hydrolase-based biosensor using mesoporous carbons and carbon black for the detection of organophosphate nerve agents.

PubMed

Lee, Joon Hwan; Park, Jae Yeon; Min, Kyoungseon; Cha, Hyung Joon; Choi, Suk Soon; Yoo, Young Je

2010-03-15

To detect organophosphate chemicals, which are used both as pesticides and as nerve agents, a novel biosensor based on organophosphorus hydrolase was developed. By using mesoporous carbon (MC) and carbon black (CB) as an anodic layer, the sensitivity of the sensor to p-nitrophenol (PNP), which is the product of the organophosphorus hydrolase reaction, was greatly improved. The MC/CB/glass carbon (GC) layer exhibited an enhanced amperometric response relative to a carbon nanotube (CNT)-modified electrode because it promoted electron transfer of enzymatically generated phenolic compounds (p-nitrophenol). The well-ordered nanopores, many edge-plane-like defective sites (EDSs), and high surface area of the MC resulted in increased sensitivity, and allowed for nanomolar-range detection of the analyte paraoxon. Thus, MCs are suitable for use in real-time biosensors. Under the optimized experimental conditions, the biosensor had a detection limit of 0.12 microM (36 ppb) and a sensitivity of 198 nA/microM for paraoxon. (c) 2009 Elsevier B.V. All rights reserved.

Demonstration of in vitro Resurrection of Aged Acetylcholinesterase after Exposure to Organophosphorus Chemical Nerve Agents.

PubMed

Zhuang, Qinggeng; Franjesevic, Andrew J; Corrigan, Thomas S; Coldren, William H; Dicken, Rachel; Sillart, Sydney; DeYong, Ashley; Yoshino, Nathan; Smith, Justin; Fabry, Stephanie; Fitzpatrick, Keegan; Blanton, Travis G; Joseph, Jojo; Yoder, Ryan J; McElroy, Craig A; Dogan Ekici, Ozlem; Callam, Christopher S; Hadad, Christopher M

2018-06-05

After inhibition of acetylcholinesterase (AChE) by organophosphorus (OP) nerve agents, a dealkylation reaction, referred to as aging, of the phosphylated serine can occur. When aged, known reactivators of OP-inhibited AChE are no longer effective. Realkylation of aged AChE may provide a route to reverse aging. We designed and synthesized a library of quinone methide precursors (QMPs) as proposed realkylators of aged AChE. Our lead compound (C8) from an in vitro screening, successfully resurrected 32.7% and 20.4% of the activity of methylphosphonate-aged and isopropyl phosphate-aged electric eel AChE, respectively, after 4 days. C8 displays properties of both resurrection (recovery from the aged to the native state) and reactivation (recovery from the inhibited to the native state). Resurrection of methylphosphonate-aged AChE by C8 was significantly pH-dependent, recovering 21% of activity at 4 mM and pH 9 after only 1 day. C8 is also effective against isopropyl phosphate-aged human AChE.

Rapidly photo-cross-linkable chitosan hydrogel for peripheral neurosurgeries.

PubMed

Rickett, Todd A; Amoozgar, Zohreh; Tuchek, Chad A; Park, Joonyoung; Yeo, Yoon; Shi, Riyi

2011-01-10

Restoring continuity to severed peripheral nerves is crucial to regeneration and enables functional recovery. However, the two most common agents for coaptation, sutures and fibrin glues, have drawbacks such as inflammation, pathogenesis, and dehiscence. Chitosan-based adhesives are a promising alternative, reported to have good cytocompatibility and favorable immunogenicity. A photo-cross-linkable hydrogel based on chitosan is proposed as a new adhesive for peripheral nerve anastomosis. Two Az-chitosans were synthesized by conjugating 4-azidobenzoic acid with low (LMW, 15 kDa) and high (HMW, 50-190 kDa) molecular weight chitosans. These solutions formed a hydrogel in less than 1 min under UV light. The LMW Az-chitosan was more tightly cross-linked than the HMW variant, undergoing significantly less swelling and possessing a higher rheological storage modulus, and both Az-chitosan gels were stiffer than commercial fibrin glue. Severed nerves repaired by Az-chitosan adhesives tolerated longitudinal forces comparable or superior to fibrin glue. Adhesive exposure to intact nerves and neural cell culture showed both Az-chitosans to be nontoxic in the acute (minutes) and chronic (days) time frames. These results demonstrate that Az-chitosan hydrogels are cytocompatible and mechanically suitable for use as bioadhesives in peripheral neurosurgeries.

Management of peripheral facial nerve palsy

PubMed Central

2008-01-01

Peripheral facial nerve palsy (FNP) may (secondary FNP) or may not have a detectable cause (Bell’s palsy). Three quarters of peripheral FNP are primary and one quarter secondary. The most prevalent causes of secondary FNP are systemic viral infections, trauma, surgery, diabetes, local infections, tumor, immunological disorders, or drugs. The diagnosis of FNP relies upon the presence of typical symptoms and signs, blood chemical investigations, cerebro-spinal-fluid-investigations, X-ray of the scull and mastoid, cerebral MRI, or nerve conduction studies. Bell’s palsy may be diagnosed after exclusion of all secondary causes, but causes of secondary FNP and Bell’s palsy may coexist. Treatment of secondary FNP is based on the therapy of the underlying disorder. Treatment of Bell’s palsy is controversial due to the lack of large, randomized, controlled, prospective studies. There are indications that steroids or antiviral agents are beneficial but also studies, which show no beneficial effect. Additional measures include eye protection, physiotherapy, acupuncture, botulinum toxin, or possibly surgery. Prognosis of Bell’s palsy is fair with complete recovery in about 80% of the cases, 15% experience some kind of permanent nerve damage and 5% remain with severe sequelae. PMID:18368417

ARA 290 improves symptoms in patients with sarcoidosis-associated small nerve fiber loss and increases corneal nerve fiber density.

PubMed

Dahan, Albert; Dunne, Ann; Swartjes, Maarten; Proto, Paolo L; Heij, Lara; Vogels, Oscar; van Velzen, Monique; Sarton, Elise; Niesters, Marieke; Tannemaat, Martijn R; Cerami, Anthony; Brines, Michael

2013-11-08

Small nerve fiber loss and damage (SNFLD) is a frequent complication of sarcoidosis that is associated with autonomic dysfunction and sensory abnormalities, including pain syndromes that severely degrade the quality of life. SNFLD is hypothesized to arise from the effects of immune dysregulation, an essential feature of sarcoidosis, on the peripheral and central nervous systems. Current therapy of sarcoidosis-associated SNFLD consists primarily of immune suppression and symptomatic treatment; however, this treatment is typically unsatisfactory. ARA 290 is a small peptide engineered to activate the innate repair receptor that antagonizes inflammatory processes and stimulates tissue repair. Here we show in a blinded, placebo-controlled trial that 28 d of daily subcutaneous administration of ARA 290 in a group of patients with documented SNFLD significantly improves neuropathic symptoms. In addition to improved patient-reported symptom-based outcomes, ARA 290 administration was also associated with a significant increase in corneal small nerve fiber density, changes in cutaneous temperature sensitivity, and an increased exercise capacity as assessed by the 6-minute walk test. On the basis of these results and of prior studies, ARA 290 is a potential disease-modifying agent for treatment of sarcoidosis-associated SNFLD.

ARA 290 Improves Symptoms in Patients with Sarcoidosis-Associated Small Nerve Fiber Loss and Increases Corneal Nerve Fiber Density

PubMed Central

Dahan, Albert; Dunne, Ann; Swartjes, Maarten; Proto, Paolo L; Heij, Lara; Vogels, Oscar; van Velzen, Monique; Sarton, Elise; Niesters, Marieke; Tannemaat, Martijn R; Cerami, Anthony; Brines, Michael

2013-01-01

Small nerve fiber loss and damage (SNFLD) is a frequent complication of sarcoidosis that is associated with autonomic dysfunction and sensory abnormalities, including pain syndromes that severely degrade the quality of life. SNFLD is hypothesized to arise from the effects of immune dysregulation, an essential feature of sarcoidosis, on the peripheral and central nervous systems. Current therapy of sarcoidosis-associated SNFLD consists primarily of immune suppression and symptomatic treatment; however, this treatment is typically unsatisfactory. ARA 290 is a small peptide engineered to activate the innate repair receptor that antagonizes inflammatory processes and stimulates tissue repair. Here we show in a blinded, placebo-controlled trial that 28 d of daily subcutaneous administration of ARA 290 in a group of patients with documented SNFLD significantly improves neuropathic symptoms. In addition to improved patient-reported symptom-based outcomes, ARA 290 administration was also associated with a significant increase in corneal small nerve fiber density, changes in cutaneous temperature sensitivity, and an increased exercise capacity as assessed by the 6-minute walk test. On the basis of these results and of prior studies, ARA 290 is a potential disease-modifying agent for treatment of sarcoidosis-associated SNFLD. PMID:24136731

Nanoparticles as a Novel Delivery Vehicle for Therapeutics Targeting Erectile Dysfunction

PubMed Central

Han, George; Tar, Moses; Kuppam, Dwaraka S. R.; Friedman, Adam; Melman, Arnold; Friedman, Joel; Davies, Kelvin P.

2010-01-01

Introduction Nanoparticles represent a potential novel mechanism for transdermal delivery of erectogenic agents directly to the penis. Aim To determine if nanoparticles encapsulating known erectogenic agents (tadalafil, sialorphin, and nitric oxide [NO]) can improve erectile function in a rat model of erectile dysfunction (ED) as a result of aging (the Sprague-Dawley retired breeder rat). Methods Nanoparticles encapsulating the erectogenic agents were applied as a gel to the glans and penile shaft of anesthetized Sprague-Dawley rats and the intracorporal pressure/blood pressure (ICP/BP) monitored for up to 2 hours with or without stimulation of the cavernous nerve. Control nanoparticles were made without encapsulating erectogenic agents and applied in a similar manner in separate experiments. Results Nanoparticles encapsulating NO caused spontaneous visible erections in the rat, with an average time of onset of 4.5 minutes, duration of 1.42 minutes, and ICP/BP of 0.67 ± 0.14. The sialorphin nanoparticles also caused visible spontaneous erections after an average of 4.5 minutes, with a duration of 8 minutes and ICP/BP ratio of 0.72 ± 0.13. The difference in the erectile response between groups of animals treated with NO or sialorphin nanoparticles was significantly different from the control group treated with empty nanoparticles (P < 0.05) Tadalafil nanoparticles showed a significant increase in the mean ICP/BP (0.737 ± 0.029) following stimulation of the cavernous nerve (4 mA) 1 hour after application of the nanoparticles with a visibly improved erectile response. Conclusions Nanoparticles encapsulating three different erectogenic agents resulted in increased erectile function when applied to the penis of a rat model of ED. Nanoparticles represent a potential novel route for topical delivery of erectogenic agents which could improve the safety profile for existing orally administered drugs by avoiding effects of absorption and first-pass metabolism, and would be less hazardous than injection. PMID:19765204

Nanoparticles as a novel delivery vehicle for therapeutics targeting erectile dysfunction.

PubMed

Han, George; Tar, Moses; Kuppam, Dwaraka S R; Friedman, Adam; Melman, Arnold; Friedman, Joel; Davies, Kelvin P

2010-01-01

Nanoparticles represent a potential novel mechanism for transdermal delivery of erectogenic agents directly to the penis. To determine if nanoparticles encapsulating known erectogenic agents (tadalafil, sialorphin, and nitric oxide [NO]) can improve erectile function in a rat model of erectile dysfunction (ED) as a result of aging (the Sprague-Dawley retired breeder rat). Nanoparticles encapsulating the erectogenic agents were applied as a gel to the glans and penile shaft of anesthetized Sprague-Dawley rats and the intracorporal pressure/blood pressure (ICP/BP) monitored for up to 2 hours with or without stimulation of the cavernous nerve. Control nanoparticles were made without encapsulating erectogenic agents and applied in a similar manner in separate experiments. Nanoparticles encapsulating NO caused spontaneous visible erections in the rat, with an average time of onset of 4.5 minutes, duration of 1.42 minutes, and ICP/BP of 0.67 +/- 0.14. The sialorphin nanoparticles also caused visible spontaneous erections after an average of 4.5 minutes, with a duration of 8 minutes and ICP/BP ratio of 0.72 +/- 0.13. The difference in the erectile response between groups of animals treated with NO or sialorphin nanoparticles was significantly different from the control group treated with empty nanoparticles (P < 0.05) Tadalafil nanoparticles showed a significant increase in the mean ICP/BP (0.737 +/- 0.029) following stimulation of the cavernous nerve (4 mA) 1 hour after application of the nanoparticles with a visibly improved erectile response. Nanoparticles encapsulating three different erectogenic agents resulted in increased erectile function when applied to the penis of a rat model of ED. Nanoparticles represent a potential novel route for topical delivery of erectogenic agents which could improve the safety profile for existing orally administered drugs by avoiding effects of absorption and first-pass metabolism, and would be less hazardous than injection.

Electrospinning of poly(glycerol sebacate)-based nanofibers for nerve tissue engineering.

PubMed

Hu, Jue; Kai, Dan; Ye, Hongye; Tian, Lingling; Ding, Xin; Ramakrishna, Seeram; Loh, Xian Jun

2017-01-01

Nerve tissue engineering (TE) requires biomimetic scaffolds providing essential chemical and topographical cues for nerve regeneration. Poly(glycerol sebacate) (PGS) is a biodegradable and elastic polymer that has gained great interest as a TE scaffolding biomaterial. However, uncured PGS is difficult to be electrospun into nanofibers. PGS would, therefore, require the addition of electrospinning agents. In this study, we modified PGS by using atom transfer radical polymerization (ATRP) to synthesize PGS-based copolymers with methyl methacrylate (MMA). The synthesized PGS-PMMA copolymer showed a molecular weight of 82kDa and a glass transition temperature of 115°C. More importantly, the PGS-PMMA could be easily electrospun into nanofiber with a fiber diameter of 167±33nm. Blending gelatin into PGS-PMMA nanofibers was found to increase its hydrophilicity and biocompatibility. Rat PC12 cells were seeded onto the PGS-PMMA/gelatin nanofibers to investigate their potential for nerve regeneration. It was found that gelatin-containing PGS-based nanofibers promoted cell proliferation. The elongated cell morphology observed on such nanofibers indicated that the scaffolds could induce the neurite outgrowth of the nerve stem cells. Overall, our study suggested that the synthesis of PGS-based copolymers might be a promising approach to enhance their processability, and therefore advancing bioscaffold engineering for various TE applications. Copyright © 2016 Elsevier B.V. All rights reserved.

Neuroleptic-induced "painful legs and moving toes" syndrome: successful treatment with clonazepam and baclofen.

PubMed

Sandyk, R

1990-12-01

The syndrome of "painful legs and moving toes" is characterised by spontaneous causalgic pain in the lower extremities associated with peculiar involuntary movements of the toes and feet. It has been observed after a variety of lesions affecting the posterior nerve roots, the spinal ganglia and the peripheral nerves. The pathophysiology of the syndrome is unknown. I report a patient who developed the syndrome during treatment for schizophrenia with the antipsychotic agent molindone hydrochloride. The patient's response to the combination of clonazepam and baclofen suggests that the pathophysiology of the "painful legs and moving toes" may be linked to impairment of spinal serotonergic and GABA functions.

Chemical terrorism for the intensivist.

PubMed

Chalela, Julio A; Burnett, Thomas

2012-05-01

The use of chemical agents for terrorist attacks or military warfare is a major concern at the present time. Chemical agents can cause significant morbidity, are relatively inexpensive, and are easy to store and use. Weaponization of chemical agents is only limited by the physicochemical properties of some agents. Recent incidents involving toxic industrial chemicals and chemical terrorist attacks indicate that critical care services are frequently utilized. For obvious reasons, the critical care literature on chemical terrorism is scarce. This article reviews the clinical aspects of diagnosing and treating victims of chemical terrorism while emphasizing the critical care management. The intensivist needs to be familiar with the chemical agents that could be used in a terrorist attack. The military classification divides agents into lung agents, blood agents, vesicants, and nerve agents. Supportive critical care is the cornerstone of treatment for most casualties, and dramatic recovery can occur in many cases. Specific antidotes are available for some agents, but even without the antidote, aggressive intensive care support can lead to favorable outcome in many cases. Critical care and emergency services can be overwhelmed by a terrorist attack as many exposed but not ill will seek care.

Stable-carbon isotope ratios for sourcing the nerve-agent precursor methylphosphonic dichloride and its products

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moran, James J.; Fraga, Carlos G.; Nims, Megan K.

The ability to connect a chemical threat agent to a specific batch of a synthetic precursor can provide a fingerprint to contribute to effective forensic investigations. Stable isotope analysis can leverage intrinsic, natural isotopic variability within the molecules of a threat agent to unlock embedded chemical fingerprints in the material. Methylphosphonic dichloride (DC) is a chemical precursor to the nerve agent sarin. It is converted to methylphosphonic difluoride (DF) as part of the sarin synthesis process. We used a suite of commercially available DC stocks to both evaluate the potential for δ13C analysis to be used as a fingerprinting toolmore » in sarin-related investigations and to develop sample preparation techniques (using chemical hydrolysis) that can simplify isotopic analysis of DC and its synthetic products. We demonstrate that natural isotopic variability in DC results in at least three distinct, isotope-resolved clusters within the thirteen stocks we analyzed. Isotopic variability in the carbon feedstock (i.e., methanol) used for DC synthesis is likely inherited by the DC samples we measured. We demonstrate that the hydrolysis of DC and DF to methylphosphonic acid (MPA) can be used as a preparative step for isotopic analysis because the reaction does not impart a measureable isotopic fractionation. MPA is more chemically stable, less toxic, and easier to handle than DC or DF. Further, the hydrolysis method we demonstrated can be applied to a suite of other precursors or to sarin itself, thereby providing a potentially valuable forensic tool.« less

Stable-Carbon Isotope Ratios for Sourcing the Nerve-Agent Precursor Methylphosphonic Dichloride and Its Products

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moran, James J.; Fraga, Carlos G.; Nims, Megan K.

The ability to connect a chemical threat agent to a specific batch of a synthetic precursor can provide a fingerprint to contribute to effective forensic investigations. Stable isotope analysis can leverage intrinsic, natural isotopic variability within the molecules of a threat agent to unlock embedded chemical fingerprints in the material. Methylphosphonic dichloride (DC) is a chemical precursor to the nerve agent sarin. DC is converted to methylphosphonic difluoride (DF) as part of the sarin synthesis process. We used a suite of commercially available DC stocks to both evaluate the potential for δ 13C analysis to be used as a fingerprintingmore » tool in sarin-related investigations and to develop sample preparation techniques (using chemical hydrolysis) that can simplify isotopic analysis of DC and its synthetic products. We demonstrate that natural isotopic variability in DC results in at least three distinct, isotope-resolved clusters within the thirteen stocks we analyzed. Isotopic variability in the carbon feedstock (i.e., methanol) used for DC synthesis is likely inherited by the DC samples we measured. Here, we demonstrate that the hydrolysis of DC and DF to methylphosphonic acid (MPA) can be used as a preparative step for isotopic analysis because the reaction does not impart a significant isotopic fractionation. MPA is more chemically stable, less toxic, and easier to handle than DC or DF. Further, the hydrolysis method we demonstrated can be applied to a suite of other precursors or to sarin itself, thereby providing a potentially valuable forensic tool.« less

Neurotoxic disorders of organophosphorus compounds and their managements.

PubMed

Balali-Mood, Mahdi; Balali-Mood, Kia

2008-01-01

Organophosphorus compounds have been used as pesticides and as chemical warfare nerve agents. The mechanism of toxicity of organophosphorus compounds is the inhibition of acetylcholinesterase, which results in accumulation of acetylcholine and the continued stimulation of acetylcholine receptors. Therefore, they are also called anticholinesterase agents. Organophosphorus pesticides have largely been used worldwide, and poisoning by these agents, particularly in developing countries, is a serious health problem. Organophosphorus nerve agents were used by Iraqi army against Iranian combatants and even civilian population in 1983 - 1988. They were also used for chemical terrorism in Japan in 1994 - 1995. Their use is still a constant threat to the population. Therefore, medical and health professionals should be aware and learn more about the toxicology and proper management of organophosphorus poisoning. Determination of acetylcholinesterase and butyrylcholinesterase activity in blood remains a mainstay for the fast initial screening of organophosphorus compounds but lacks sensitivity and specificity. Quantitative analysis of organophosphorus compounds and their degradation products in plasma and urine by mass spectrometric methods may prove exposure but is expensive and is limited to specialized laboratories. However, history of exposure to organophosphorous compounds and clinical manifestations of a cholinergic syndrome are sufficient for management of the affected patients. The standard management of poisoning with organophosphorous compounds consists of decontamination, and injection of atropine sulfate with an oxime. Recent advances on treatment of organophosphorus pesticides poisoning revealed that blood alkalinization with sodium bicarbonate and also magnesium sulfate as adjunctive therapies are promising. Patients who receive prompt proper treatment usually recover from acute toxicity but may suffer from neurologic complications.

Stable-Carbon Isotope Ratios for Sourcing the Nerve-Agent Precursor Methylphosphonic Dichloride and Its Products

DOE PAGES

Moran, James J.; Fraga, Carlos G.; Nims, Megan K.

2018-04-01

The ability to connect a chemical threat agent to a specific batch of a synthetic precursor can provide a fingerprint to contribute to effective forensic investigations. Stable isotope analysis can leverage intrinsic, natural isotopic variability within the molecules of a threat agent to unlock embedded chemical fingerprints in the material. Methylphosphonic dichloride (DC) is a chemical precursor to the nerve agent sarin. DC is converted to methylphosphonic difluoride (DF) as part of the sarin synthesis process. We used a suite of commercially available DC stocks to both evaluate the potential for δ 13C analysis to be used as a fingerprintingmore » tool in sarin-related investigations and to develop sample preparation techniques (using chemical hydrolysis) that can simplify isotopic analysis of DC and its synthetic products. We demonstrate that natural isotopic variability in DC results in at least three distinct, isotope-resolved clusters within the thirteen stocks we analyzed. Isotopic variability in the carbon feedstock (i.e., methanol) used for DC synthesis is likely inherited by the DC samples we measured. Here, we demonstrate that the hydrolysis of DC and DF to methylphosphonic acid (MPA) can be used as a preparative step for isotopic analysis because the reaction does not impart a significant isotopic fractionation. MPA is more chemically stable, less toxic, and easier to handle than DC or DF. Further, the hydrolysis method we demonstrated can be applied to a suite of other precursors or to sarin itself, thereby providing a potentially valuable forensic tool.« less

Preliminary assessment of the health and environmental impacts of continuing to store M55 rockets at Lexington-Blue Grass Depot Activity, Anniston Army Depot, Umatilla Depot Activity, Pine Bluff Arsenal, and Tooele Army Depot

DOE Office of Scientific and Technical Information (OSTI.GOV)

Boyette, J.A.; Breck, J.E.; Coleman, P.R.

1986-03-01

The purpose is to provide an assessment of the potential health and environmental impacts of continuing to store M55 rockets filled with nerve agent GB or VX at their current storage locations at Anniston Army Depot in Alabama, Lexington-Blue Grass Depot Activity in Kentucky, Pine Bluff Arsenal in Arkansas, Tooele Army Depot in Utah, and Umatilla Depot Activity in Oregon. The assessment considers the possible impacts of (1) normal storage (with no release to the environment) and (2) two postulated accidents on the air quality, ground and surface water, aquatic ecology, terrestrial ecology, human health, and cultural and socioeconomic resourcesmore » in and around the various storage depots. The analysis considers three basic scenarios during storage: (1) normal operations; (2) a minor spill of agent (the contents of one rocket released to the biosphere); and (3) a maximum credible event or MCE. The MCE is an igloo fire resulting in the aerosolization of a small (in the case of GB) or an extremely small (in the case of VX) percentage of the igloo's nerve agent contents to the biosphere. The extremely low probabilities of such accidents, which are reported elsewhere, are noted. Our assessments of the impacts of a minor spill and of an MCE consider two sets of meteorological conditions: conservative most likely and worst-case. In addition, we assume that an agent plume would travel toward the area of highest population density. 21 figs., 47 tabs.« less

Enzyme-linked immunosorbent assay for detection of organophosphorylated butyrylcholinesterase: A biomarker of exposure to organophosphate agents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Liming; Du, Dan; Lu, Donglai

2011-05-05

A sandwich enzyme-linked immunosorbent assay (sELISA) is developed for detection of organophosphorylated butyrylcholinesterase (OP-BChE), a potential biomarker for human exposure to organophosphate insecticides and nerve agents. A pair of antibodies specific to OP-BChE adduct were identified through systematic screening of several anti BChE antibodies (anti-BChE) and anti-phosphoserine antibodies (anti-Pser) from different sources. The selected anti-BChE (set as capture antibody) antibodies recognize both phosphorylated and nonphosphorylated BChE. These antibodies can therefore be used to capture both BChE and OP-BChE from the sample matrices. The anti- Pser (set as detecting antibody) was used to recognize the OP moiety of OP-BChE adducts. Withmore » the combination of the selected antibody pair, several key parameters (such as the concentration of anti-BChE and anti-Pser, and the blocking agent) were optimized to enhance the sensitivity and selectivity of the sELISA. Under the optimal conditions, the sELISA has shown a wide linear range from 0.03 nM to 30 nM, with a detection limit of 0.03 nM. Furthermore, the sELISA was successfully applied to detect OP-BChE using in-vitro biological samples such as rat plasma spiked with OP-BChE with excellent adduct recovery (z>99 %). These results demonstrate that this novel approach holds great promise to develop an ELISA kit and offers a simple and cost-effective tool for screening/evaluating exposure to organophosphate insecticides and nerve agents.« less

Stable-carbon isotope ratios for sourcing the nerve-agent precursor methylphosphonic dichloride and its products.

PubMed

Moran, James J; Fraga, Carlos G; Nims, Megan K

2018-08-15

The ability to connect a chemical threat agent to a specific batch of a synthetic precursor can provide a fingerprint to contribute to effective forensic investigations. Stable isotope analysis can leverage intrinsic, natural isotopic variability within the molecules of a threat agent to unlock embedded chemical fingerprints in the material. Methylphosphonic dichloride (DC) is a chemical precursor to the nerve agent sarin. DC is converted to methylphosphonic difluoride (DF) as part of the sarin synthesis process. We used a suite of commercially available DC stocks to both evaluate the potential for δ 13 C analysis to be used as a fingerprinting tool in sarin-related investigations and to develop sample preparation techniques (using chemical hydrolysis) that can simplify isotopic analysis of DC and its synthetic products. We demonstrate that natural isotopic variability in DC results in at least three distinct, isotope-resolved clusters within the thirteen stocks we analyzed. Isotopic variability in the carbon feedstock (i.e., methanol) used for DC synthesis is likely inherited by the DC samples we measured. We demonstrate that the hydrolysis of DC and DF to methylphosphonic acid (MPA) can be used as a preparative step for isotopic analysis because the reaction does not impart a significant isotopic fractionation. MPA is more chemically stable, less toxic, and easier to handle than DC or DF. Further, the hydrolysis method we demonstrated can be applied to a suite of other precursors or to sarin itself, thereby providing a potentially valuable forensic tool. Copyright © 2018. Published by Elsevier B.V.

Schizophrenia: a review of neuropharmacology.

PubMed

Lyne, J; Kelly, B D; O'Connor, W T

2004-01-01

The last few decades have seen significant advances in our understanding of the neurochemical basis of schizophrenia. To describe the neurotransmitter systems and nerve circuits implicated in schizophrenia; to compare the neuropharmacology of typical and atypical anti-psychotic agents; and to describe recent developments in the pharmacological treatment of schizophrenia. Relevant pharmacological, neurophysiological and psychiatric literature was examined and reviewed. Schizophrenia is associated with abnormalities of multiple neurotransmitter systems, including dopamine, serotonin, gamma-aminobutyric acid and glutamate. Typical and atypical antipsychotic agents differ in their receptor-binding affinities, which are related to their differing side-effect profiles. Novel therapeutic strategies include normalisation of synaptic dopamine or serotonin levels, serotonin receptor antagonism and modulation of cerebral protein synthesis. The ideal treatment for schizophrenia may not be a single pharmacological agent but several agents that match the different expressions of the illness, in combination with psycho-social interventions.

Bioscavenger is effective as a delayed therapeutic intervention following percutaneous VX poisoning in the guinea-pig.

PubMed

Mann, T M; Price, M E; Whitmore, C L; Perrott, R L; Laws, T R; McColm, R R; Emery, E R; Tattersall, J E H; Green, A C; Rice, H

2017-11-26

The prolonged systemic exposure that follows skin contamination with low volatility nerve agents, such as VX, requires treatment to be given over a long time due to the relatively short half-lives of the therapeutic compounds used. Bioscavengers, such as butyrylcholinesterase (BChE), have been shown to provide effective post-exposure protection against percutaneous nerve agent when given immediately on signs of poisoning and to reduce reliance on additional treatments. In order to assess the benefits of administration of bioscavenger at later times, its effectiveness was assessed when administration was delayed for 2h after the appearance of signs of poisoning in guinea-pigs challenged with VX (4×LD 50 ). VX-challenged animals received atropine, HI-6 and avizafone on signs of poisoning and 2h later the same combination with or without bioscavenger. Five out of 6 animals which received BChE 2h after the appearance of signs of poisoning survived to the end of the study at 48h, compared with 6 out of 6 which received BChE immediately on signs. All the animals (n=6+6) that received only MedCM, without the addition of BChE, died within 10h of poisoning. The toxicokinetics of a sub-lethal challenge of percutaneous VX were determined in untreated animals. Blood VX concentration peaked at approximately 4h after percutaneous dosing with 0.4×LD 50 ; VX was still detectable at 36h and had declined to levels below the lower limit of quantification (10pg/mL) by 48h in 7 of 8 animals, with the remaining animal having a concentration of 12pg/mL. These studies confirm the persistent systemic exposure to nerve agent following percutaneous poisoning and demonstrate that bioscavenger can be an effective component of treatment even if its administration is delayed. Copyright © 2017. Published by Elsevier B.V.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Du, Dan; Wang, Jun; Wang, Limin

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 themore » 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.« less

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.

A rat model of nerve agent exposure applicable to the pediatric population: The anticonvulsant efficacies of atropine and GluK1 antagonists.

PubMed

Miller, Steven L; Aroniadou-Anderjaska, Vassiliki; Figueiredo, Taiza H; Prager, Eric M; Almeida-Suhett, Camila P; Apland, James P; Braga, Maria F M

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 LD50 of 62μg/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 2mg/kg, administered 20 min after soman exposure (1.2×LD50), terminated seizures. ATS at 0.5mg/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 1h 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 90days 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 1h post-exposure, prevents brain pathology and behavioral deficits. Published by Elsevier Inc.

Reinnervating the penis in spina bifida patients in the United States: ilioinguinal-to-dorsal-penile neurorrhaphy in two cases.

PubMed

Jacobs, Micah A; Avellino, Anthony M; Shurtleff, David; Lendvay, Thomas S

2013-10-01

Penile sensation is absent in some patients with myelomeningocele owing to the dysfunction of the pudendal nerve. Here, we describe the introduction of penile sensation via ilioinguinal-to-dorsal-penile neurorrhaphy in two patients with penile anesthesia due to neural tube defects. To establish penile sensation via ilioinguinal-to-dorsal-penile-nerve neurorrhaphy. A 20-year-old and a 35-year-old male with L5/S1 myelomeningocele were both highly functioning and ambulatory, with intact ilioinguinal nerve distribution sensation but anesthesia of the penis and glans. They were sexually active and able to ejaculate antegrade. Both had high International Index of Erectile Function scores for confidence to achieve erection sufficient for intercourse. An incision was made from anterior superior iliac crest to the glans penis to expose the inguinal canal and ilioinguinal nerve. The ilioinguinal and dorsal penile nerve were transected and anastomosed. The anastomotic site was then wrapped in a hemostatic agent and a drain was left in place. For penile rehabilitation, both patients were instructed to stimulate the penis while looking at the genitalia to encourage redistribution of perceived sensation. Presence of erogenous penile sensation was tested by neurologic examination and patient feedback, and patients completed sexual health questionnaires. Both patients reported paresthesias of the groin with penile stimulation 1 month after surgery. Both patients are now 24 months postoperative and have erogenous sensation on the ipsilateral glans and shaft during intercourse. Neither patient has difficulty achieving or maintaining erections. We present two patients with dorsal penile reinnervation via the ilioinguinal nerve. Although nerve reinnervation has been used in urological procedures, this is the first description of an attempt to resupply penile sensation via the dorsal penile nerve in the United States with a minimum of 18 months follow-up. Early follow-up suggests successful neuronal remapping and regained sensation of the penis. © 2013 International Society for Sexual Medicine.

Nanoparticle-Based Immunochromatographic Test Strip with Fluorescent Detector for Quantification of Phosphorylated Acetycholinesterase: An Exposure Biomarker of Organophosphorous Agents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Weiying; Ge, Xiaoxiao; Tang, Yong

A nanoparticle-based fluorescence immunochromatographic test strip (FITS) coupled with a hand-held detector for highly selective and sensitive detection of phosphorylated acetylcholinesterase (AChE), an exposure biomarker of organophosphate (OP) pesticides and nerve agents, is reported. In this approach, OP-AChE adducts were selectively captured by quantum dot-tagged anti-AChE antibodies (Qdot-anti-AChE) and zirconia nanoparticles (ZrO2 NPs). The sandwich-like immunoreactions were performed among the Qdot-anti-AChE, OP-AChE and ZrO2 NPs to form Qdot-anti-AChE/OP-AChE/ZrO2 complex, which was detected by recording the fluorescence intensity of Qdot captured on the test line. Paraoxon was used as the model OP pesticides. Under optimal conditions, this portable FITS immunosensor demonstratesmore » a highly linear absorption response over the range of 0.01 nM to 10 nM OP-AChE, with a detection limit of 4 pM, coupled with a good reproducibility. Moreover, the FITS immunosensor has been validated with OP-AChE spiked human plasma samples. This is the first report on the development of ZrO2 NPs-based FITS for detection of OP-AChE adduct. The FITS immunosensor provides a sensitive and low-cost sensing platform for on-site screening/evaluating OP pesticides and nerve agents poisoning.« less

The Incidence of Intravascular Needle Entrance during Inferior Alveolar Nerve Block Injection.

PubMed

Taghavi Zenouz, Ali; Ebrahimi, Hooman; Mahdipour, Masoumeh; Pourshahidi, Sara; Amini, Parisa; Vatankhah, Mahdi

2008-01-01

Dentists administer thousands of local anesthetic injections every day. Injection to a highly vascular area such as pterygomandibular space during an inferior alveolar nerve block has a high risk of intravascular needle entrance. Accidental intravascular injection of local anesthetic agent with vasoconstrictor may result in cardiovascular and central nervous system toxicity, as well as tachycardia and hypertension. There are reports that indicate aspiration is not performed in every injection. The aim of the present study was to assess the incidence of intravascular needle entrance in inferior alveolar nerve block injections. Three experienced oral and maxillofacial surgeons performed 359 inferior alveolar nerve block injections using direct or indirect techniques, and reported the results of aspiration. Aspirable syringes and 27 gauge long needles were used, and the method of aspiration was similar in all cases. Data were analyzed using t-test. 15.3% of inferior alveolar nerve block injections were aspiration positive. Intravascular needle entrance was seen in 14.2% of cases using direct and 23.3% of cases using indirect block injection techniques. Of all injections, 15.8% were intravascular on the right side and 14.8% were intravascular on the left. There were no statistically significant differences between direct or indirect block injection techniques (P = 0.127) and between right and left injection sites (P = 0.778). According to our findings, the incidence of intravascular needle entrance during inferior alveolar nerve block injection was relatively high. It seems that technique and maneuver of injection have no considerable effect in incidence of intravascular needle entrance.

The Incidence of Intravascular Needle Entrance during Inferior Alveolar Nerve Block Injection

PubMed Central

Taghavi Zenouz, Ali; Ebrahimi, Hooman; Mahdipour, Masoumeh; Pourshahidi, Sara; Amini, Parisa; Vatankhah, Mahdi

2008-01-01

Background and aims Dentists administer thousands of local anesthetic injections every day. Injection to a highly vascular area such as pterygomandibular space during an inferior alveolar nerve block has a high risk of intravascular needle entrance. Accidental intravascular injection of local anesthetic agent with vasoconstrictor may result in cardiovascular and central nervous system toxicity, as well as tachycardia and hypertension. There are reports that indicate aspiration is not performed in every injection. The aim of the present study was to assess the incidence of intravascular needle entrance in inferior alveolar nerve block injections. Materials and methods Three experienced oral and maxillofacial surgeons performed 359 inferior alveolar nerve block injections using direct or indirect techniques, and reported the results of aspiration. Aspirable syringes and 27 gauge long needles were used, and the method of aspiration was similar in all cases. Data were analyzed using t-test. Results 15.3% of inferior alveolar nerve block injections were aspiration positive. Intravascular needle entrance was seen in 14.2% of cases using direct and 23.3% of cases using indirect block injection techniques. Of all injections, 15.8% were intravascular on the right side and 14.8% were intravascular on the left. There were no statistically significant differences between direct or indirect block injection techniques (P = 0.127) and between right and left injection sites (P = 0.778). Conclusion According to our findings, the incidence of intravascular needle entrance during inferior alveolar nerve block injection was relatively high. It seems that technique and maneuver of injection have no considerable effect in incidence of intravascular needle entrance. PMID:23285329

The effect of routine reversal of neuromuscular blockade on adequacy of recurrent laryngeal nerve stimulation during thyroid surgery.

PubMed

Marshall, S D; Boden, E; Serpell, J

2015-07-01

Testing of the integrity of the recurrent laryngeal nerve during thyroid surgery has become routine practice for many surgeons to aid dissection and minimise the chance of inadvertent nerve injury. We hypothesised that routine reversal of an intermediate-acting, non-depolarising neuromuscular blocking agent would improve conditions for stimulation of the recurrent laryngeal nerve. We conducted a single-centre, randomised, double-blind placebo-controlled trial of patients undergoing thyroid surgery by the same surgeon. After randomisation, the participants received either neostigmine 2.5 mg with glycopyrrolate 0.4 mg or placebo, at 30 minutes after induction of anaesthesia and administration of 0.4 mg/kg of atracurium. The primary outcome was the subjective assessment by the surgeon as to whether the neuromuscular function was adequate for stimulation of the recurrent laryngeal nerve using a neuromuscular integrity monitor (NIM). Time to NIM stimulation was 44.6 minutes in the placebo group and 41.4 minutes in the intervention group (P=0.268). Of the 21 patients who received the neuromuscular blockade reversal, 20 (95.2%) had adequate surgical conditions for NIM stimulation, compared to 9 out of 18 patients (50%) in the placebo group (P=0.002). Three of the ten patients (30%) with inadequate reversal showed no evidence of residual blockade assessed peripherally. The routine reversal of neuromuscular blockade at 30 minutes post induction appears to result in adequate surgical conditions for safe stimulation of the recurrent laryngeal nerve. Return of neuromuscular function at a peripheral site does not guarantee adequate laryngeal muscle function for use of the NIM.

A Descriptive Morphometric Approach of the Skull and Mandible of the Common Opossum (Didelphis Marsupialis Linnaeus, 1758) in the Caribbean and its Clinical Application during Regional Anaesthesia.

PubMed

Mohamed, Reda

2018-03-09

The aim of this study was to determine the morphometric values of the skull and the mandible of the common opossum from the Caribbean island of Trinidad and Tobago. The skulls and mandibles were obtained from ten opossums captured for research purposes. The skulls and mandibles were prepared and cleaned using standard method. Some anatomical landmarks of the skulls and mandibles were identified and measured. The results were important for identification of the common opossum via comparison and discussion of our results with that of other marsupial species. Furthermore, the results had clinical importance with regard to regional nerve blocks of the infraorbital, inferior alveolar, and mental nerves for dental extraction and head surgery. This study concluded that by using the anatomical landmarks of the infraorbital and mental foramina it will be easier for the veterinarian surgeons during the application of local anesthetic agent for the infraorbital, inferior alveolar, and mental nerve blocks.

A Descriptive Morphometric Approach of the Skull and Mandible of the Common Opossum (Didelphis Marsupialis Linnaeus, 1758) in the Caribbean and its Clinical Application during Regional Anaesthesia

PubMed Central

Mohamed, Reda

2018-01-01

The aim of this study was to determine the morphometric values of the skull and the mandible of the common opossum from the Caribbean island of Trinidad and Tobago. The skulls and mandibles were obtained from ten opossums captured for research purposes. The skulls and mandibles were prepared and cleaned using standard method. Some anatomical landmarks of the skulls and mandibles were identified and measured. The results were important for identification of the common opossum via comparison and discussion of our results with that of other marsupial species. Furthermore, the results had clinical importance with regard to regional nerve blocks of the infraorbital, inferior alveolar, and mental nerves for dental extraction and head surgery. This study concluded that by using the anatomical landmarks of the infraorbital and mental foramina it will be easier for the veterinarian surgeons during the application of local anesthetic agent for the infraorbital, inferior alveolar, and mental nerve blocks. PMID:29522485

Single-particle aerosol mass spectrometry for the detection and identification of chemical warfare agent simulants.

PubMed

Martin, Audrey N; Farquar, George R; Frank, Matthias; Gard, Eric E; Fergenson, David P

2007-08-15

Single-particle aerosol mass spectrometry (SPAMS) was used for the real-time detection of liquid nerve agent simulants. A total of 1000 dual-polarity time-of-flight mass spectra were obtained for micrometer-sized single particles each of dimethyl methyl phosphonate, diethyl ethyl phosphonate, diethyl phosphoramidate, and diethyl phthalate using laser fluences between 0.58 and 7.83 nJ/microm2, and mass spectral variation with laser fluence was studied. The mass spectra obtained allowed identification of single particles of the chemical warfare agent (CWA) simulants at each laser fluence used although lower laser fluences allowed more facile identification. SPAMS is presented as a promising real-time detection system for the presence of CWAs.

Geotechnical Containment Alternatives for Industrial Waste Basin F, Rocky Mountain Arsenal, Denver, Colorado. A quantitative Evaluation

DTIC Science & Technology

1979-09-01

RMA have included the production of GB nerve gas, lewisite, mustard gas, arsenic chloride, anticrop agents , and chlorine - gas, as well as the...fabrication if munitions containing white phosphorus and chemical warfare agents . The demilitarization of GB munitions and mustard-filled munitions and the...i , i iSndy S BLUE of .4 I i i lly G BLOE -GRE ii 0 ir i Grntl C - -- - I WHITE Sh__ O ickeft dit SL ML B~d~ 0 20 40 60 80 too Ovd’ted o LL IOU,O

Optimization of Therapeutic Strategies for Organophosphate Poisoning

DTIC Science & Technology

2008-03-01

chemical (Szinicz, 2005:173). Researchers later created various forms of the organophosphate and applied the chemicals as insecticides (Szinicz, 2005:173...of organophosphorus insecticides and nerve agents (Cannard, 2006:87). Organophosphates poison an estimated 100,000 people each year throughout the...quantifiable result in order to facilitate comparison among different therapeutic strategies. Justification and Applicability Organophosphorus insecticides are

Severe necrotic dermatitis in the combs of line 6-3 chickens is associated with Marek's disease virus-induced immunosuppression

USDA-ARS?s Scientific Manuscript database

Marek’s disease (MD), a lymphoproliferative disorder of domestic chickens is characterized by bursal–thymic atrophy and rapid onset of T-cell lymphomas that infiltrate lymphoid tissues, visceral organs, and peripheral nerves. Marek’s disease virus (MDV), the etiological agent of MD, is a highly cel...

SPECIFIC ADHESION TO CELLULOSE AND HYDROLYSIS OF ORGANOPHOSPHATE NERVE AGENTS BY A GENETICALLY ENGINEERED E. COLI WITH SURFACE-EXPRESSED CELLULOSE-BINDING DOMAIN AND ORGANOPHOSPHORUS HYDROLASE. (R827227)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

M Current-Based Therapies for Nerve Agent Seizures

DTIC Science & Technology

2012-07-01

2012.235820. Third goal was to test whether drugs that open M channels wouterminate status epilepticus induced by an organophosphate and cholinergic...agonist (Li/Pilocarpine). Two modelof organophasphate-induced seizures were characterized and published: Characterization of status epilepticus induced...terminates refractory status epilepticus in two models. . 15. SUBJECT TERMS- Seizures, status epilepticus Cholinergic, M Current, Synaptoic

M Current-Based Therapies for Nerve Agent Seizures

DTIC Science & Technology

2013-07-01

Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT 15. SUBJECT TERMS Seizures, status epilepticus Cholinergic, M Current...Channel openers in cholinergic overstimulation-induced status epilepticus . Body: We proposed to study the effects of organophosphates and muscarinic...test whether drugs that open M channels would terminate status epilepticus induced by an organophosphate and cholinergic agonist (Li/Pilocarpine). Two

MICROBIAL BIOSENSOR FOR DIRECT DETERMINATION OF ORGANOPHOSPHATE NERVE AGENTS USING RECOMBINANT ESCHERICHIA COLI WITH SURFACE-EXPRESSED ORGANOPHOSPHORUS HYDROLASE. 2. FIBER-OPTIC MICROBIAL BIOSENSOR. (R823663)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

Mass casualty chemical exposure and implications for respiratory failure.

PubMed

Muskat, Peter C

2008-01-01

Exposure to chemical agents, both deliberate and accidental, over the past 100 years has resulted in the deaths of thousands and a significant number of casualties requiring hospitalization. The respiratory system is an important portal of entry into the human body for many of these agents, and pulmonary symptoms are a hallmark of many chemical exposures. The 4 major chemical warfare agents are: lung-damaging, blood, blister, and nerve compounds. The review will cover historical exposures, signs and symptoms, treatment, and long-term consequences. There are numerous examples of deliberate (as well as accidental) exposure to harmful chemicals, and each incident requires the provider to understand the signs and symptoms of the particular chemical so that the correct treatment is provided. The respiratory implications of these agents appear to be dose and timing dependent, with full recovery often seen if supportive measures and appropriate antidotes are administered in a timely fashion.

Botulinum Toxin Injection and Phenol Nerve Block for Reduction of End-of-Life Pain

PubMed Central

Ngo, An; Shin, Ki; Bruera, Eduardo

2013-01-01

Abstract Background: Injectable antispasticity agents have been utilized for the reduction of pain. However, there are no reports of its use for end-of-life pain. Patient Case: A 62-year-old female with a history of progressive left frontotemporal glioblastoma status post gross total resection, radiation, and chemotherapy presented to the physical medicine and rehabilitation (PM&R) clinic for management of spastic quadriplegia and pain. At the time of presentation to the PM&R clinic she was no longer eligible for further cancer treatment. The patient had been declining neurologically with cognitive changes, weakness, and increasing spasticity. The patient had an Edmonton Symptom Assessment Scale (ESAS) pain score of 8/10 at her visit, as reported by her husband. She exhibited mild to moderate spasticity during the exam. Cognitively, she was unable to follow commands and would fluctuate between being awake for a few minutes and sleeping during the exam. She was not on any oral muscle relaxants and none were started due to her state of hypoarousal. Nine days after the initial consultation she received 700 units of onabotulinum toxin into her bilateral upper limbs and left thigh and a phenol nerve block to her left tibial nerve. At a follow-up visit 28 days later in the palliative care clinic, the ESAS pain score was 0. The patient died 51 days post-injection. Conclusion: The case report demonstrates the use of injectable antispasticity agents in the reduction of end-of-life pain in a glioblastoma patient. PMID:24236959

Chlorpyrifos, chlorpyrifos-oxon, and diisopropylfluorophosphate inhibit kinesin-dependent microtubule motility

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gearhart, Debra A.; Sickles, Dale W.; Buccafusco, Jerry J.

2007-01-01

Diisopropylfluorophosphate, originally developed as a chemical warfare agent, is structurally similar to nerve agents, and chlorpyrifos has extensive worldwide use as an agricultural pesticide. While inhibition of cholinesterases underlies the acute toxicity of these organophosphates, we previously reported impaired axonal transport in the sciatic nerves from rats treated chronically with subthreshold doses of chlorpyrifos. Those data indicate that chlorpyrifos (and/or its active metabolite, chlorpyrifos-oxon) might directly affect the function of kinesin and/or microtubules-the principal proteins that mediate anterograde axonal transport. The current report describes in vitro assays to assess the concentration-dependent effects of chlorpyrifos (0-10 {mu}M), chlorpyrifos-oxon (0-10 {mu}M), andmore » diisopropylfluorophosphate (0-0.59 nM) on kinesin-dependent microtubule motility. Preincubating bovine brain microtubules with the organophosphates did not alter kinesin-mediated microtubule motility. In contrast, preincubation of bovine brain kinesin with diisopropylfluorophosphate, chlorpyrifos, or chlorpyrifos-oxon produced a concentration-dependent increase in the number of locomoting microtubules that detached from the kinesin-coated glass cover slip. Our data suggest that the organophosphates-chlorpyrifos-oxon, chlorpyrifos, and diisopropylfluorophosphate-directly affect kinesin, thereby disrupting kinesin-dependent transport on microtubules. Kinesin-dependent movement of vesicles, organelles, and other cellular components along microtubules is fundamental to the organization of all eukaryotic cells, especially in neurons where organelles and proteins synthesized in the cell body must move down long axons to pre-synaptic sites in nerve terminals. We postulate that disruption of kinesin-dependent intracellular transport could account for some of the long-term effects of organophosphates on the peripheral and central nervous system.« less

Peripheral Nerve Block as a Supplement to Light or Deep General Anesthesia in Elderly Patients Receiving Total Hip Arthroplasty: A Prospective Randomized Study.

PubMed

Mei, Bin; Zha, Hanning; Lu, Xiaolong; Cheng, Xinqi; Chen, Shishou; Liu, Xuesheng; Li, Yuanhai; Gu, Erwei

2017-12-01

Peripheral nerve block combined with general anesthesia is a preferable anesthesia method for elderly patients receiving hip arthroplasty. The depth of sedation may influence patient recovery. Therefore, we investigated the influence of peripheral nerve blockade and different intraoperative sedation levels on the short-term recovery of elderly patients receiving total hip arthroplasty. Patients aged 65 years and older undergoing total hip arthroplasty were randomized into 3 groups: a general anesthesia without lumbosacral plexus block group, and 2 general anesthesia plus lumbosacral plexus block groups, each with a different level of sedation (light or deep). The extubation time and intraoperative consumption of propofol, sufentanil, and vasoactive agent were recorded. Postoperative delirium and early postoperative cognitive dysfunction were assessed using the Confusion Assessment Method and Mini-Mental State Examination, respectively. Postoperative analgesia was assessed by the consumption of patient-controlled analgesics and visual analog scale scores. Discharge time and complications over a 30-day period were also recorded. Lumbosacral plexus block reduced opioid intake. With lumbosacral plexus block, intraoperative deep sedation was associated with greater intake of propofol and vasoactive agent. In contrast, patients with lumbosacral plexus block and intraoperative light sedation had lower incidences of postoperative delirium and postoperative cognitive decline, and earlier discharge readiness times. The 3 groups showed no difference in complications within 30 days of surgery. Lumbosacral plexus block reduced the need for opioids and offered satisfactory postoperative analgesia. It led to better postoperative outcomes in combination with intraoperative light sedation (high bispectral index).

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. Published by Elsevier B.V.

Intrafascicular injection of ammonium sulfate and bupivacaine in peripheral nerves of neonatal and juvenile rats.

PubMed

Hertl, M C; Hagberg, P K; Hunter, D A; Mackinnon, S E; Langer, J C

1998-01-01

Regional nerve blocks are often used for the treatment of postoperative pain in children. Ammonium sulfate is a non-narcotic anesthetic agent, which has been reported to provide pain relief lasting days to weeks, with few reported side effects in adult studies. Prior to considering clinical use in children, the neurotoxicity of ammonium sulfate in 4-day and 3-week old rats was assessed and compared with that of bupivacaine. Each rat received a posterior tibial nerve intrafascicular injection (0.01 mL in 4-day-old and 0.02 mL in 3-week-old rats) using either 10% ammonium sulfate (n = 24 per age group), 0.5% bupivacaine (n = 18 per age group), 0.9% saline (n = 18 per age group), or 5% phenol (n = 18 per age group). A functional assessment by serial walking track analysis and a morphologic assessment by neurohistology were made. No abnormalities in serial walking track analysis and no structural nerve damage were detected after ammonium sulfate, bupivacaine, or saline injection. Bupivacaine caused mild focal changes in both age groups, which recovered by 8 weeks. Intrafascicular injection of ammonium sulfate was as safe as bupivacaine in this animal model. Further animal studies must be made before human trials are initiated.

How Is Acetylcholinesterase Phosphonylated by Soman? An Ab Initio QM/MM Molecular Dynamics Study

PubMed Central

2015-01-01

Acetylcholinesterase (AChE) is a crucial enzyme in the cholinergic nerve system that hydrolyzes acetylcholine (ACh) and terminates synaptic signals by reducing the effective concentration of ACh in the synaptic clefts. Organophosphate compounds irreversibly inhibit AChEs, leading to irreparable damage to nerve cells. By employing Born–Oppenheimer ab initio QM/MM molecular dynamics simulations with umbrella sampling, a state-of-the-art approach to simulate enzyme reactions, we have characterized the covalent inhibition mechanism between AChE and the nerve toxin soman and determined its free energy profile for the first time. Our results indicate that phosphonylation of the catalytic serine by soman employs an addition–elimination mechanism, which is highly associative and stepwise: in the initial addition step, which is also rate-limiting, His440 acts as a general base to facilitate the nucleophilic attack of Ser200 on the soman’s phosphorus atom to form a trigonal bipyrimidal pentacovalent intermediate; in the subsequent elimination step, Try121 of the catalytic gorge stabilizes the leaving fluorine atom prior to its dissociation from the active site. Together with our previous characterization of the aging mechanism of soman inhibited AChE, our simulations have revealed detailed molecular mechanistic insights into the damaging function of the nerve agent soman. PMID:24786171

Neural control of renal function: role of renal alpha adrenoceptors.

PubMed

DiBona, G F

1985-01-01

Adrenoceptors of various subtypes mediate the renal functional responses to alterations in efferent renal sympathetic nerve activity, the neural component, and renal arterial plasma catecholamine concentrations, the humoral component, of the sympathoadrenergic nervous system. Under normal physiologic as well as hypertensive conditions, the influence of the renal sympathetic nerves predominates over that of circulating plasma catecholamines. In most mammalian species, increases in efferent renal sympathetic nerve activity elicit renal vasoconstrictor responses mediated predominantly by renal vascular alpha-1 adrenoceptors, increases in renin release mediated largely by renal juxtaglomerular granular cell beta-1 adrenoceptors with involvement of renal vascular alpha-1 adrenoceptors only when renal vasoconstriction occurs, and direct increases in renal tubular sodium and water reabsorption mediated predominantly by renal tubular alpha-1 adrenoceptors. In most mammalian species, alpha-2 adrenoceptors do not play a significant role in the renal vascular or renin release responses to renal sympathoadrenergic stimulation. Although renal tubular alpha-2 adrenoceptors do not mediate the increases in renal tubular sodium and water reabsorption produced by increases in efferent renal sympathetic nerve activity, they may be involved through their inhibitory effect on adenylate cyclase in modulating the response to other hormonal agents that influence renal tubular sodium and water reabsorption via stimulation of adenylate cyclase.

Carvedilol prevents functional deficits in peripheral nerve mitochondria of rats with oxaliplatin-evoked painful peripheral neuropathy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Areti, Aparna; Komirishetty, Prashanth; Kumar, Ash

Oxaliplatin use as chemotherapeutic agent is frequently limited by cumulative neurotoxicity which may compromise quality of life. Reports relate this neurotoxic effect to oxidative stress and mitochondrial dysfunction in peripheral nerves and dorsal root ganglion (DRG). Carvedilol is an antihypertensive drug, has also been appreciated for its antioxidant and mitoprotective properties. Carvedilol co-treatment did not reduce the anti-tumor effects of oxaliplatin in human colon cancer cells (HT-29), but exhibited free radical scavenging activity against oxaliplatin-induced oxidative stress in neuronal cells (Neuro-2a). Hence, the present study was designed to investigate the effect of carvedilol in the experimental model of oxaliplatin-induced peripheralmore » neuropathy (OIPN) in Sprague-Dawley rats. Oxaliplatin reduced the sensory nerve conduction velocity and produced the thermal and mechanical nociception. Carvedilol significantly (P < 0.001) attenuated these functional and sensorimotor deficits. It also counteracted oxidative/nitrosative stress by reducing the levels of nitrotyrosine and improving the mitochondrial superoxide dismutase expression in both sciatic nerve and DRG tissues. It improved the mitochondrial function and prevented the oxaliplatin-induced alteration in mitochondrial membrane potential in sciatic nerve thus prevented loss of intra epidermal nerve fiber density in the foot pads. Together the results prompt the use of carvedilol along with chemotherapy with oxaliplatin to prevent the peripheral neuropathy. - Graphical abstract: Schematic representation neuroprotective mechanisms of carvedilol in oxaliplatin-induced peripheral neuropathy. - Highlights: • Oxaliplatin-induced mitochondrial dysfunction causes neurotoxicity. • Mitochondrial dysfunction leads to bioenergetic and functional deficits. • Carvedilol alleviated oxaliplatin-induced behavioural and functional changes. • Targeting mitochondria with carvedilol attenuated neuropathic pain.« less

Peripheral Neuropathy Induced by Microtubule-Targeted Chemotherapies: Insights into Acute Injury and Long-term Recovery.

PubMed

Wozniak, Krystyna M; Vornov, James J; Wu, Ying; Liu, Ying; Carozzi, Valentina A; Rodriguez-Menendez, Virginia; Ballarini, Elisa; Alberti, Paola; Pozzi, Eleonora; Semperboni, Sara; Cook, Brett M; Littlefield, Bruce A; Nomoto, Kenichi; Condon, Krista; Eckley, Sean; DesJardins, Christopher; Wilson, Leslie; Jordan, Mary A; Feinstein, Stuart C; Cavaletti, Guido; Polydefkis, Michael; Slusher, Barbara S

2018-02-01

Chemotherapy-induced peripheral neuropathy (CIPN) is a major cause of disability in cancer survivors. CIPN investigations in preclinical model systems have focused on either behaviors or acute changes in nerve conduction velocity (NCV) and amplitude, but greater understanding of the underlying nature of axonal injury and its long-term processes is needed as cancer patients live longer. In this study, we used multiple independent endpoints to systematically characterize CIPN recovery in mice exposed to the antitubulin cancer drugs eribulin, ixabepilone, paclitaxel, or vinorelbine at MTDs. All of the drugs ablated intraepidermal nerve fibers and produced axonopathy, with a secondary disruption in myelin structure within 2 weeks of drug administration. In addition, all of the drugs reduced sensory NCV and amplitude, with greater deficits after paclitaxel and lesser deficits after ixabepilone. These effects correlated with degeneration in dorsal root ganglia (DRG) and sciatic nerve and abundance of Schwann cells. Although most injuries were fully reversible after 3-6 months after administration of eribulin, vinorelbine, and ixabepilone, we observed delayed recovery after paclitaxel that produced a more severe, pervasive, and prolonged neurotoxicity. Compared with other agents, paclitaxel also displayed a unique prolonged exposure in sciatic nerve and DRG. The most sensitive indicator of toxicity was axonopathy and secondary myelin changes accompanied by a reduction in intraepidermal nerve fiber density. Taken together, our findings suggest that intraepidermal nerve fiber density and changes in NCV and amplitude might provide measures of axonal injury to guide clinical practice. Significance: This detailed preclinical study of the long-term effects of widely used antitubulin cancer drugs on the peripheral nervous system may help guide clinical evaluations to improve personalized care in limiting neurotoxicity in cancer survivors. Cancer Res; 78(3); 817-29. ©2017 AACR . ©2017 American Association for Cancer Research.

Local Anesthetic Peripheral Nerve Block Adjuvants for Prolongation of Analgesia: A Systematic Qualitative Review

PubMed Central

Kirksey, Meghan A.; Haskins, Stephen C.; Cheng, Jennifer; Liu, Spencer S.

2015-01-01

Background The use of peripheral nerve blocks for anesthesia and postoperative analgesia has increased significantly in recent years. Adjuvants are frequently added to local anesthetics to prolong analgesia following peripheral nerve blockade. Numerous randomized controlled trials and meta-analyses have examined the pros and cons of the use of various individual adjuvants. Objectives To systematically review adjuvant-related randomized controlled trials and meta-analyses and provide clinical recommendations for the use of adjuvants in peripheral nerve blocks. Methods Randomized controlled trials and meta-analyses that were published between 1990 and 2014 were included in the initial bibliographic search, which was conducted using Medline/PubMed, Cochrane Central Register of Controlled Trials, and EMBASE. Only studies that were published in English and listed block analgesic duration as an outcome were included. Trials that had already been published in the identified meta-analyses and included adjuvants not in widespread use and published without an Investigational New Drug application or equivalent status were excluded. Results Sixty one novel clinical trials and meta-analyses were identified and included in this review. The clinical trials reported analgesic duration data for the following adjuvants: buprenorphine (6), morphine (6), fentanyl (10), epinephrine (3), clonidine (7), dexmedetomidine (7), dexamethasone (7), tramadol (8), and magnesium (4). Studies of perineural buprenorphine, clonidine, dexamethasone, dexmedetomidine, and magnesium most consistently demonstrated prolongation of peripheral nerve blocks. Conclusions Buprenorphine, clonidine, dexamethasone, magnesium, and dexmedetomidine are promising agents for use in prolongation of local anesthetic peripheral nerve blocks, and further studies of safety and efficacy are merited. However, caution is recommended with use of any perineural adjuvant, as none have Food and Drug Administration approval, and concerns for side effects and potential toxicity persist. PMID:26355598

Integrated Lateral Flow Test Strip with Electrochemical Sensor for Quantification of Phosphorylated Cholinesterase: Biomarker of Exposure to Organophosphorus Agents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Du, Dan; Wang, Jun; Wang, Limin

An integrated lateral flow test strip with electrochemical sensor (LFTSES) device with rapid, selective and sensitive response for quantification of exposure to organophosphorus (OP) pesticides and nerve agents has been developed. The principle of this approach is based on parallel measurements of post-exposure and baseline acetylcholinesterase (AChE) enzyme activity, where reactivation of the phosphorylated AChE is exploited to enable measurement of total amount of AChE (including inhibited and active) which is used as a baseline for calculation of AChE inhibition. Quantitative measurement of phosphorylated adduct (OP-AChE) was realized by subtracting the active AChE from the total amount of AChE. Themore » proposed LFTSES device integrates immunochromatographic test strip technology with electrochemical measurement using a disposable screen printed electrode which is located under the test zone. It shows linear response between AChE enzyme activity and enzyme concentration from 0.05 to 10 nM, with detection limit of 0.02 nM. Based on this reactivation approach, the LFTSES device has been successfully applied for in vitro red blood cells inhibition studies using chlorpyrifos oxon as a model OP agent. This approach not only eliminates the difficulty in screening of low-dose OP exposure because of individual variation of normal AChE values, but also avoids the problem in overlapping substrate specificity with cholinesterases and avoids potential interference from other electroactive species in biological samples. It is baseline free and thus provides a rapid, sensitive, selective and inexpensive tool for in-field and point-of-care assessment of exposures to OP pesticides and nerve agents.« less

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

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

PubMed

Moshiri, Mohammd; Darchini-Maragheh, Emadodin; Balali-Mood, Mahdi

2012-11-28

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.

Nonthermal ablation with microbubble-enhanced focused ultrasound close to the optic tract without affecting nerve function.

PubMed

McDannold, Nathan; Zhang, Yong-Zhi; Power, Chanikarn; Jolesz, Ferenc; Vykhodtseva, Natalia

2013-11-01

Tumors at the skull base are challenging for both resection and radiosurgery given the presence of critical adjacent structures, such as cranial nerves, blood vessels, and brainstem. Magnetic resonance imaging-guided thermal ablation via laser or other methods has been evaluated as a minimally invasive alternative to these techniques in the brain. Focused ultrasound (FUS) offers a noninvasive method of thermal ablation; however, skull heating limits currently available technology to ablation at regions distant from the skull bone. Here, the authors evaluated a method that circumvents this problem by combining the FUS exposures with injected microbubble-based ultrasound contrast agent. These microbubbles concentrate the ultrasound-induced effects on the vasculature, enabling an ablation method that does not cause significant heating of the brain or skull. In 29 rats, a 525-kHz FUS transducer was used to ablate tissue structures at the skull base that were centered on or adjacent to the optic tract or chiasm. Low-intensity, low-duty-cycle ultrasound exposures (sonications) were applied for 5 minutes after intravenous injection of an ultrasound contrast agent (Definity, Lantheus Medical Imaging Inc.). Using histological analysis and visual evoked potential (VEP) measurements, the authors determined whether structural or functional damage was induced in the optic tract or chiasm. Overall, while the sonications produced a well-defined lesion in the gray matter targets, the adjacent tract and chiasm had comparatively little or no damage. No significant changes (p > 0.05) were found in the magnitude or latency of the VEP recordings, either immediately after sonication or at later times up to 4 weeks after sonication, and no delayed effects were evident in the histological features of the optic nerve and retina. This technique, which selectively targets the intravascular microbubbles, appears to be a promising method of noninvasively producing sharply demarcated lesions in deep brain structures while preserving function in adjacent nerves. Because of low vascularity--and thus a low microbubble concentration--some large white matter tracts appear to have some natural resistance to this type of ablation compared with gray matter. While future work is needed to develop methods of monitoring the procedure and establishing its safety at deep brain targets, the technique does appear to be a potential solution that allows FUS ablation of deep brain targets while sparing adjacent nerve structures.

Nonthermal ablation with microbubble-enhanced focused ultrasound close to the optic tract without affecting nerve function

PubMed Central

McDannold, Nathan; Zhang, Yong-Zhi; Power, Chanikarn; Jolesz, Ferenc; Vykhodtseva, Natalia

2014-01-01

Object Tumors at the skull base are challenging for both resection and radiosurgery given the presence of critical adjacent structures, such as cranial nerves, blood vessels, and brainstem. Magnetic resonance imaging–guided thermal ablation via laser or other methods has been evaluated as a minimally invasive alternative to these techniques in the brain. Focused ultrasound (FUS) offers a noninvasive method of thermal ablation; however, skull heating limits currently available technology to ablation at regions distant from the skull bone. Here, the authors evaluated a method that circumvents this problem by combining the FUS exposures with injected microbubble-based ultrasound contrast agent. These microbubbles concentrate the ultrasound-induced effects on the vasculature, enabling an ablation method that does not cause significant heating of the brain or skull. Methods In 29 rats, a 525-kHz FUS transducer was used to ablate tissue structures at the skull base that were centered on or adjacent to the optic tract or chiasm. Low-intensity, low-duty-cycle ultrasound exposures (sonications) were applied for 5 minutes after intravenous injection of an ultrasound contrast agent (Definity, Lantheus Medical Imaging Inc.). Using histological analysis and visual evoked potential (VEP) measurements, the authors determined whether structural or functional damage was induced in the optic tract or chiasm. Results Overall, while the sonications produced a well-defined lesion in the gray matter targets, the adjacent tract and chiasm had comparatively little or no damage. No significant changes (p > 0.05) were found in the magnitude or latency of the VEP recordings, either immediately after sonication or at later times up to 4 weeks after sonication, and no delayed effects were evident in the histological features of the optic nerve and retina. Conclusions This technique, which selectively targets the intravascular microbubbles, appears to be a promising method of noninvasively producing sharply demarcated lesions in deep brain structures while preserving function in adjacent nerves. Because of low vascularity—and thus a low microbubble concentration—some large white matter tracts appear to have some natural resistance to this type of ablation compared with gray matter. While future work is needed to develop methods of monitoring the procedure and establishing its safety at deep brain targets, the technique does appear to be a potential solution that allows FUS ablation of deep brain targets while sparing adjacent nerve structures. PMID:24010975

USSR Report, Life Sciences, Biomedical and Behavioral Sciences

DTIC Science & Technology

1985-02-06

Breathing Altered Gas Medium (N. V. Sanotskaya, D. D. Matsiyevskly; BYULLETEN’ EKSPERIMENTAL’NOY BIOLOGII I MEDITSINY, No 3, Mar 84) 132...Antldromlc Electrical Activity of Motor Terminations of Nerve - Muscle Synapses of Rats With Acetylchollnesterase Inhibition (I. Ya. Serdyuchenko...Eoslnophil Kinetics (T. M. Zukhbaya; RADIOBIOLOGIYA, No 4, Jul-Aug 84) . ...... 205 Radioprotective Effects of Certain Hypotenslve Agents (V. V

Neuroprotection for Nerve Agent-Induced Brain Damage

DTIC Science & Technology

2002-01-01

fosphenytoin), antioxidants and free radical scavengers (trilazad, ebselen, nitrones ), other ion channel inhibitors (clomethiazole, MBQX, GM1...dihydrolipoic acid, free radical traps such as nitrones and inhibitors of N- acetylaspartylglutamate (NAAG) peptidase to reduce the formation of glutamate...1999). When administered 40 min after onset of seizures and despite having no effect on the severity or duration of the seizure activity HU-211

Acetylcholinesterases of Rhipicephalus (Boophilus) microplus – Multiple gene expression presents an opportune model system for elucidation of multiple functions of AChEs.

USDA-ARS?s Scientific Manuscript database

Acetylcholinesterase (AChE) is a key neural enzyme of both vertebrates and invertebrates, and is the biochemical target of organophosphate and carbamate pesticides for invertebrates, as well as vertebrate nerve agents, e.g., soman, tabun, VX, and others. AChE inhibitors are also key drugs among thos...

Effect of toxic threat nerve agents on anesthetic requirements of representative pr-anesthetic medicants and inhalant and parenteral general anesthetic in the cat. Annual report, 15 July 1985-14 July 1986

DOE Office of Scientific and Technical Information (OSTI.GOV)

Webb, A.I.

1986-07-30

The effect of soman on anesthetic requirements of halothane and isoflurane was studied before and after administration of acepromazine maleate (0.2 mg/kg). Insufficient data has been obtained to date to draw conclusions on any possible drug interactions.

Higher concentration local anaesthetics causing prolonged anaesthesia. Do they? A literature review and case reports.

PubMed

Kingon, A; Sambrook, P; Goss, A

2011-12-01

Higher concentration dental local anaesthetics (3% and 4%) have become more available in Australia in recent years. Benefits claimed include a faster onset of anaesthesia and improved success with injections compared to 2% solutions. Recent reports suggest that the higher concentration carries a greater risk of prolonged anaesthesia to the mandibular and particularly the lingual nerves. The literature was reviewed and those studies which demonstrated adverse effects of different concentrations of local anaesthetics were analysed. Recent cases are presented. There is an extensive international literature which confirms increased concentration of local anaesthetic does show an increased risk, by about ×6, of prolonged anaesthesia. Five case reports illustrate the impact of this complication on patients' quality of life. Careful consideration needs to be given before using higher concentration local anaesthetic agents for mandibular and lingual blocks as lower concentration local anaesthetics are safer. If acceptable to individual patients, avoidance of block injections or any local anaesthetic for minor restorative tasks could be encouraged given the severity of the complication. It is safe to use the higher concentration agents for infiltrations away from major nerves. © 2011 Australian Dental Association.

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

Simultaneous quantification of VX and its toxic metabolite in blood and plasma samples and its application for in vivo and in vitro toxicological studies.

PubMed

Reiter, Georg; Mikler, John; Hill, Ira; Weatherby, Kendal; Thiermann, Horst; Worek, Franz

2011-09-15

The present study was initiated to develop a sensitive and highly selective method for the simultaneous quantification of the nerve agent VX (O-ethyl S-[2(diisopropylamino)ethyl] methylphosphonothioate) and its toxic metabolite (EA-2192) in blood and plasma samples in vivo and in vitro. For the quantitative detection of VX and EA-2192 the resolution was realized on a HYPERCARB HPLC phase. A specific procedure was developed to isolate both toxic analytes from blood and plasma samples. The limit of detection was 0.1 pg/ml and the absolute recovery of the overall sample preparation procedure was 74% for VX and 69% for EA-2192. After intravenous and percutaneous administration of a supralethal doses of VX in anaesthetised swine both VX and EA-2192 could be quantified over 540 min following exposure. This study is the first to verify the in vivo formation of the toxic metabolite EA-2192 after poisoning with the nerve agent VX. Further toxicokinetic and therapeutic studies are required in order to determine the impact of EA-2192 on the treatment of acute VX poisoning. Copyright © 2011 Elsevier B.V. All rights reserved.

Simultaneous Time-concentration Analysis of Soman and VX Adducts to Butyrylcholinesterase and Albumin by LC-MS-MS.

PubMed

Lee, Jin Young; Kim, Changhwan; Lee, Yong Han

2018-06-01

A sensitive method for the purification and determination of two protein adducts, organophosphorus (OP)-BChE and OP-albumin adducts, in a single sample using a simultaneous sample preparation method was developed and validated using liquid chromatography-tandem mass spectrometry. First, we isolated O-ethyl S-2-diisopropylaminoethyl methyl phosphonothiolate (VX) and O-pinacolyl methylphosphonofluoridate (soman, GD)-BChE adducts using an immunomagnetic separation (IMS) method and the HiTrap™ Blue affinity column was subsequently used to isolate and purify VX and GD-albumin adducts from the plasma of rhesus monkeys exposed to nerve agents. Additionally, we examined the time-concentration profiles of two biomarkers, VX and GD-nonapeptides and VX and GD-tyrosines, derived from OP-BChE and OP-albumin adducts up to 8 weeks after exposure. Based on the results, we determined that VX and GD-tyrosine is more suitable than VX and GD-nonapeptide as a biomarker owing to its longevity. This integrated approach is expected to be applicable for the quantification of other OP-BChE and OP-albumin adducts in human plasma, thus serving as a potential generic assay for exposure to nerve agents.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

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

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 formore » 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.« less

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Baowei; Shah, Saumil S.; Shin, Yongsoon

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)-FMSmore » 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.« less

The success rate of bupivacaine and lidocaine as anesthetic agents in inferior alveolar nerve block in teeth with irreversible pulpitis without spontaneous pain.

PubMed

Parirokh, Masoud; Yosefi, Mohammad Hosein; Nakhaee, Nouzar; Abbott, Paul V; Manochehrifar, Hamed

2015-05-01

Achieving adequate anesthesia with inferior alveolar nerve blocks (IANB) is of great importance during dental procedures. The aim of the present study was to assess the success rate of two anesthetic agents (bupivacaine and lidocaine) for IANB when treating teeth with irreversible pulpitis. Sixty volunteer male and female patients who required root canal treatment of a mandibular molar due to caries participated in the present study. The inclusion criteria included prolonged pain to thermal stimulus but no spontaneous pain. The patients were randomly allocated to receive either 2% lidocaine with 1:80,000 epinephrine or 0.5% bupivacaine with 1:200,000 epinephrine as an IANB injection. The sensitivity of the teeth to a cold test as well as the amount of pain during access cavity preparation and root canal instrumentation were recorded. Results were statistically analyzed with the Chi-Square and Fischer's exact tests. At the final step, fifty-nine patients were included in the study. The success rate for bupivacaine and lidocaine groups were 20.0% and 24.1%, respectively. There was no significant difference between the two groups at any stage of the treatment procedure. There was no difference in success rates of anesthesia when bupivacaine and lidocaine were used for IANB injections to treat mandibular molar teeth with irreversible pulpitis. Neither agent was able to completely anesthetize the teeth effectively. Therefore, practitioners should be prepared to administer supplemental anesthesia to overcome pain during root canal treatment.

Sensitive and comprehensive detection of chemical warfare agents in air by atmospheric pressure chemical ionization ion trap tandem mass spectrometry with counterflow introduction.

PubMed

Seto, Yasuo; Sekiguchi, Hiroshi; Maruko, Hisashi; Yamashiro, Shigeharu; Sano, Yasuhiro; Takayama, Yasuo; Sekioka, Ryoji; Yamaguchi, Shintaro; Kishi, Shintaro; Satoh, Takafumi; Sekiguchi, Hiroyuki; Iura, Kazumitsu; Nagashima, Hisayuki; Nagoya, Tomoki; Tsuge, Kouichiro; Ohsawa, Isaac; Okumura, Akihiko; Takada, Yasuaki; Ezawa, Naoya; Watanabe, Susumu; Hashimoto, Hiroaki

2014-05-06

A highly sensitive and specific real-time field-deployable detection technology, based on counterflow air introduction atmospheric pressure chemical ionization, has been developed for a wide range of chemical warfare agents (CWAs) comprising gaseous (two blood agents, three choking agents), volatile (six nerve gases and one precursor agent, five blister agents), and nonvolatile (three lachrymators, three vomiting agents) agents in air. The approach can afford effective chemical ionization, in both positive and negative ion modes, for ion trap multiple-stage mass spectrometry (MS(n)). The volatile and nonvolatile CWAs tested provided characteristic ions, which were fragmented into MS(3) product ions in positive and negative ion modes. Portions of the fragment ions were assigned by laboratory hybrid mass spectrometry (MS) composed of linear ion trap and high-resolution mass spectrometers. Gaseous agents were detected by MS or MS(2) in negative ion mode. The limits of detection for a 1 s measurement were typically at or below the microgram per cubic meter level except for chloropicrin (submilligram per cubic meter). Matrix effects by gasoline vapor resulted in minimal false-positive signals for all the CWAs and some signal suppression in the case of mustard gas. The moisture level did influence the measurement of the CWAs.

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. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia

PubMed Central

Pavlov, Valentin A.; Ochani, Mahendar; Gallowitsch-Puerta, Margot; Ochani, Kanta; Huston, Jared M.; Czura, Christopher J.; Al-Abed, Yousef; Tracey, Kevin J.

2006-01-01

TNF has a critical mediator role in inflammation and is an important therapeutic target. We recently discovered that TNF production is regulated by neural signals through the vagus nerve. Activation of this “cholinergic antiinflammatory pathway” inhibits the production of TNF and other cytokines and protects animals from the inflammatory damage caused by endotoxemia and severe sepsis. Here, we describe a role for central muscarinic acetylcholine receptors in the activation of the cholinergic antiinflammatory pathway. Central muscarinic cholinergic activation by muscarine, the M1 receptor agonist McN-A-343, and the M2 receptor antagonist methoctramine inhibited serum TNF levels significantly during endotoxemia. Centrally administered methoctramine stimulated vagus-nerve activity measured by changes in instantaneous heart-rate variability. Blockade of peripheral muscarinic receptors did not abolish antiinflammatory signaling through the vagus nerve, indicating that peripheral muscarinic receptors on immune cells are not required for the cytokine-regulating activities of the cholinergic antiinflammatory pathway. The role of central muscarinic receptors in activating the cholinergic antiinflammatory pathway is of interest for the use of centrally acting muscarinic cholinergic enhancers as antiinflammatory agents. PMID:16549778

Ganglioneuritis causing high mortalities in farmed Australian abalone (Haliotis laevigata and Haliotis rubra).

PubMed

Hooper, C; Hardy-Smith, P; Handlinger, J

2007-05-01

To investigate an outbreak of sudden severe mortality in farmed abalone from coastal Victoria. The outbreaks occurred almost simultaneously in three farms following abalone movements from the wild and between farms. The initial on farm investigation identified a number of features that when considered together were highly suggestive of an infectious aetiology. In many cases, dead abalone had no significant gross lesions. Others had swollen mouths and some had prolapse and eversion of the radula. Histologically, the lesions centred on the nerves innervating the labial apparatus, primarily the cerebral and buccal ganglia, cerebral commissure and peripheral nerve branches arising from these. Nervous tissue necrosis and haemocyte infiltration were the dominant lesions seen microscopically in affected nerves. A recent outbreak of mortality in Australian abalone was associated with neurotropic lesions, which have not previously been described in this country. The on farm and between farm pattern of spread of the outbreak, a history of abalone movements linking farms, clinical observation of moribund and dead abalone were all highly suggestive of a virulent infectious agent.

Mechanosensilla in the adult abdomen of Drosophila: engrailed and slit help to corral the peripheral sensory axons into segmental bundles.

PubMed

Fabre, Caroline C G; Casal, José; Lawrence, Peter A

2010-09-01

The abdomen of adult Drosophila bears mechanosensory bristles with axons that connect directly to the CNS, each hemisegment contributing a separate nerve bundle. Here, we alter the amount of Engrailed protein and manipulate the Hedgehog signalling pathway in clones of cells to study their effects on nerve pathfinding within the peripheral nervous system. We find that high levels of Engrailed make the epidermal cells inhospitable to bristle neurons; sensory axons that are too near these cells are either deflected or fail to extend properly or at all. We then searched for the engrailed-dependent agent responsible for these repellent properties. We found slit to be expressed in the P compartment and, using genetic mosaics, present evidence that Slit is the responsible molecule. Blocking the activity of the three Robo genes (putative receptors for Slit) with RNAi supported this hypothesis. We conclude that, during normal development, gradients of Slit protein repel axons away from compartment boundaries - in consequence, the bristles from each segment send their nerves to the CNS in separated sets.

MK-801 and dextromethorphan block microglial activation and protect against methamphetamine-induced neurotoxicity.

PubMed

Thomas, David M; Kuhn, Donald M

2005-07-19

Methamphetamine causes long-term toxicity to dopamine nerve endings of the striatum. Evidence is emerging that microglia can contribute to the neuronal damage associated with disease, injury, or inflammation, but their role in methamphetamine-induced neurotoxicity has received relatively little attention. Lipopolysaccharide (LPS) and the neurotoxic HIV Tat protein, which cause dopamine neuronal toxicity after direct infusion into brain, cause activation of cultured mouse microglial cells as evidenced by increased expression of intracellular cyclooxygenase-2 and elevated secretion of tumor necrosis factor-alpha. MK-801, a non-competitive NMDA receptor antagonist that is known to protect against methamphetamine neurotoxicity, prevents microglial activation by LPS and HIV Tat. Dextromethorphan, an antitussive agent with NMDA receptor blocking properties, also prevents microglial activation. In vivo, MK-801 and dextromethorphan reduce methamphetamine-induced activation of microglia in striatum and they protect dopamine nerve endings against drug-induced nerve terminal damage. The present results indicate that the ability of MK-801 and dextromethorphan to protect against methamphetamine neurotoxicity is related to their common property as blockers of microglial activation.

Ischemic optic neuropathy as a model of neurodegenerative disorder: A review of pathogenic mechanism of axonal degeneration and the role of neuroprotection.

PubMed

Khalilpour, Saba; Latifi, Shahrzad; Behnammanesh, Ghazaleh; Majid, Amin Malik Shah Abdul; Majid, Aman Shah Abdul; Tamayol, Ali

2017-04-15

Optic neuropathy is a neurodegenerative disease which involves optic nerve injury. It is caused by acute or intermittent insults leading to visual dysfunction. There are number of factors, responsible for optic neuropathy, and the optic nerve axon is affected in all type which causes the loss of retinal ganglion cells. In this review we will highlight various mechanisms involved in the cell loss cascades during axonal degeneration as well as ischemic optic neuropathy. These mechanisms include oxidative stress, excitotoxicity, angiogenesis, neuroinflammation and apoptosis following retinal ischemia. We will also discuss the effect of neuroprotective agents in attenuation of the negative effect of factors involve in the disease occurrence and progression. Copyright © 2016. Published by Elsevier B.V.

Reevaluation of 1999 Health-Based Environmental Screening Levels (HBESLs) for Chemical Warfare Agents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Watson, Annetta Paule; Dolislager, Fredrick G

2007-05-01

This report evaluates whether new information and updated scientific models require that changes be made to previously published health-based environmental soil screening levels (HBESLs) and associated environmental fate/breakdown information for chemical warfare agents (USACHPPM 1999). Specifically, the present evaluation describes and compares changes that have been made since 1999 to U.S. Environmental Protection Agency (EPA) risk assessment models, EPA exposure assumptions, as well as to specific chemical warfare agent parameters (e.g., toxicity values). Comparison was made between screening value estimates recalculated with current assumptions and earlier health-based environmental screening levels presented in 1999. The chemical warfare agents evaluated include themore » G-series and VX nerve agents and the vesicants sulfur mustard (agent HD) and Lewisite (agent L). In addition, key degradation products of these agents were also evaluated. Study findings indicate that the combined effect of updates and/or changes to EPA risk models, EPA default exposure parameters, and certain chemical warfare agent toxicity criteria does not result in significant alteration to the USACHPPM (1999) health-based environmental screening level estimates for the G-series and VX nerve agents or the vesicant agents HD and L. Given that EPA's final position on separate Tier 1 screening levels for indoor and outdoor worker screening assessments has not yet been released as of May 2007, the study authors find that the 1999 screening level estimates (see Table ES.1) are still appropriate and protective for screening residential as well as nonresidential sites. As such, risk management decisions made on the basis of USACHPPM (1999) recommendations do not require reconsideration. While the 1999 HBESL values are appropriate for continued use as general screening criteria, the updated '2007' estimates (presented below) that follow the new EPA protocols currently under development are also protective. When EPA finalizes and documents a position on the matter of indoor and outdoor worker screening assessments, site-specific risk assessments should make use of modified models and criteria. Screening values such as those presented in this report may be used to assess soil or other porous media to determine whether chemical warfare agent contamination is present as part of initial site investigations (whether due to intentional or accidental releases) and to determine whether weather/decontamination has adequately mitigated the presence of agent residual to below levels of concern. However, despite the availability of scientifically supported health-based criteria, there are significant resources needs that should be considered during sample planning. In particular, few analytical laboratories are likely to be able to meet these screening levels. Analyses will take time and usually have limited confidence at these concentrations. Therefore, and particularly for the more volatile agents, soil/destructive samples of porous media should be limited and instead enhanced with headspace monitoring and presence-absence wipe sampling.« less

Relationship Between Organophosphate Toxicity and Choline Metabolism

DTIC Science & Technology

1986-06-06

E.M.G. Voltage and motor nerve conduction velocity in organophosphorus Pesticide factroy workers. Int. Arch. Occup. Environ. Health 36: 267-274. 62...internal standard, and prepared for the determination of the concentration of choline by pyrolysis gas chromatography (18,19). The rate of choline...those by which they affect ACh metabolism. Diisopropylfluorophosphate (DFP) is the agent most often studied, and data show that after acute or

Public Health Surveillance: A Local Health Department Perspective

DTIC Science & Technology

2002-04-03

vomiting – Diarrhea (+/-bloody) • Rash and fever – Vesicular – Petechial • Neurologic – cranial nerve palsies, HA, fever , confusion • Septic Shock...Francisella tularensis (tularemia) • Viral hemorrhagic fever Agents of Concern: CDC Category B • Coxiella burnetti (Q fever ) • Brucella species...Concern: CDC Category C • Nipah virus • hantaviruses • tickborne hemorrhagic fever viruses • yellow fever • multidrug-resistant tuberculosis

New England Bioterrorism Preparedness Workshop

DTIC Science & Technology

2002-04-04

Hypoxia • GI – Fever – Nausea/vomiting – Diarrhea (+/-bloody) • Rash and fever – Vesicular – Petechial • Neurologic – cranial nerve palsies, HA...plague) • variola major (smallpox) • Francisella tularensis (tularemia) • Viral hemorrhagic fever Agents of Concern: CDC Category B • Coxiella...burnetti (Q fever ) • Brucella species (brucellosis) • Burkholderia mallei (glanders) • ricin toxin from Ricinus communis (castor beans) • epsilon toxin of

Breaking Down Chemical Weapons by Metal-Organic Frameworks.

PubMed

Mondal, Suvendu Sekhar; Holdt, Hans-Jürgen

2016-01-04

Seek and destroy: Filtration schemes and self-detoxifying protective fabrics based on the Zr(IV)-containing metal-organic frameworks (MOFs) MOF-808 and UiO-66 doped with LiOtBu have been developed that capture and hydrolytically detoxify simulants of nerve agents and mustard gas. Both MOFs function as highly catalytic elements in these applications. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Development of Optimized Guidelines for Therapeutic Strategies for Organophosphate Poisoning

DTIC Science & Technology

2011-03-01

compounds (Cannard, 2006). Pyridostigmine bromide , a pretreatment for a potential soman exposure, is a member of the carbamate family (Cannard, 2006...others, 2005) and later expanded that model to incorporate the nerve agent pretreatment by carbamates such as pyridostigmine (Worek and others, 2007...model developed in 2005 to incorporate pretreatment by a carbamate such as pyridostigmine (Worek and others, 2007). Both sets of researchers show

Essentials of Endodontic Microsurgery

DTIC Science & Technology

2010-04-01

protocol is divided into regional and local injections and are as follows: 1. The administration of a long-acting anesthetic agent such as bupivicaine (Mar...mandibular anterior teeth receive bilateral mental nerve blocks. All of these can be supplemented, as need be, with corresponding palatal or lingual...infiltrations of the same anesthetic . In studies examining the effectiveness of lidocaine versus bupivicaine, it was shown that lidocaine was faster in

Promethazine as a Novel Prophylaxis and Treatment for Nerve Agent Poisoning

DTIC Science & Technology

2008-12-01

mitochondrial dysfunction. Mitochondrial damage after seizure activity has been previously documented (Cock et al., 2002), and mitochondrial...McDonough et al., 1998), the lack of brain pathology in surviving animals is solely due to the secondary anticholinergic activity of promethazine...rats, Experientia, 41(11), 1457-1458. Department of Health, Expert group on the management of chemical casualties by terrorist activity , 2003: Use

Modeling, Simulation, and Analysis for State and Local Emergency Planning and Response. Operational Requirements Document

DTIC Science & Technology

2009-01-01

pro- gram requirements, and administering local and federal funding. Emergency services—organizations that provide for public safety by the...chemicals Nerve agent Chlorine tank explosion Major earthquake Major hurricane Radiological dispersal device Improvised explosive device Food ...state Locally Developed Software 1 city 1 county 1 city 1 county 3 states Lotus Notes Suite 1 NGO MABAS.ORG 1 county

European Science Notes. Volume 39, Number 3.

DTIC Science & Technology

1985-03-01

on the body by measuring the inhi- from a nearby outstation of the UK’s bition of the hydrolytic activity of the Meteorological Office using both stan...process work on materials for time without undergoing the deteriora- defense which are unavailable from com- tion in catalytic activity common with mercial...contaminated protec- When a nerve agent is used in the tive clothing. Ultra- high

Toxic Industrial Chemicals: A Future Weapons of Mass Destruction Threat

DTIC Science & Technology

2002-05-31

1937 by Dr. Gerhard Schrader, a chemist conducting insecticide research with organophosphates (Stockholm International Peace Research Institute 1971...International Peace Research Institute 1971 and 1973). Phosgene oxime is known as “ nettle gas,” so named because of its property of intensely irritating...as a WMD. Common TICs Effects of CW Agents Organophosphate Insecticide Nerve Dimethyl Sulfate Blister Methyl Isocyanate Blood Anhydrous Ammonia

Infrared Spectra and Binding Energies of Chemical Warfare Nerve Agent Simulants on the Surface of Amorphous Silica

DTIC Science & Technology

2013-06-24

Limited TPD of Water from Zeolite Linde 4A. Thermochim. Acta 1998, 319 (1), 177−184. (43) Palermo, A.; Löffler, D. G. Kinetics of Water Desorption...from Pelletized 4A and 5A Zeolites . Thermochim. Acta 1990, 159, 171−176. (44) Gorte, R. J. Design Parameters for Temperature Programmed Desorption from

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

minced finely with scissors, and transferred to a pre-cooled hand-held glass dounce homogenizer. The pestle was passed through the dounce until the...Nakajima, Sarin experiences in Japan : acute toxicity and long-term effects. Journal of the Neurological Sciences, 2006. 249(1): p. 76-85. 9. Shih, T.-M

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

DTIC Science & Technology

2002-03-16

3,000 Canadian Gulf War veterans found an combustion of jet fuel , and other weapons depots that may increased prevalence (4.7 percent) of self-reported...Hereditary and idiopathic peripheral neuropathy 11 47 0.72 0.37,1.39 0.72 0.37, 1.40 357 Inflammatory and toxic neuropathy 9 23 1.34 0.62, 2.90 1.36 0.63

Pediatric Susceptibility to Nerve Agent-Induced Seizures and Effectiveness of Anticonvulsant Treatments

DTIC Science & Technology

2014-12-01

poisoning can result in status epilepticus (SE), which can become pharmacoresistant if treatment is delayed. Virtually no data exist on OP-induced...are needed to characterize models of P7 and P14 DFP-induced SE. 15. SUBJECT TERMS Status Epilepticus , seizure, organophosphate, DFP, pediatric...5 Introduction Organophosphate (OP) exposure can lead to continuous, repetitive seizures (i.e., status epilepticus , SE), which are

Teaching resources. The Sherlock Holmes lab: investigations in neurophysiology.

PubMed

Adler, Elizabeth M; Schwartz, Paul J

2006-05-09

This Teaching Resource describes a research project that can be used in an advanced undergraduate course in neurobiology that covers basic electrophysiology and synaptic transmission. A thought experiment is provided that can be used to assess student understanding of (i) the scientific method, (ii) the process whereby nerve stimulation leads to muscle contraction, and (iii) the use of pharmacological agents to analyze a physiological system.

Chemical Terrorism for the Intensivist

DTIC Science & Technology

2012-05-01

used in the ICU, and the clinician needs to be mindful of this interaction (nerve agents and neuromuscular blockers ).6 Chemical and biological attacks...Frothy Sputum Headache, Fatigue, Anxiety , Irritability, Cardiac Arrest, Dyspnea Coma, Seizures Conjunctivitis, Sore Throat, Epistaxis, Erythema, Skin...Steroids and beta -agonists are com- monly used, and although there is no strong human clinical data to support this practice, there is some animal evidence

Combating Terrorism Technology Support Office 2006 Review

DTIC Science & Technology

2006-01-01

emplaced beyond the control point, activated manually or automatically , with warning lights and an audible alarm to alert innocent pedestrians. The...throughout a vehicle. When a tamper event is detected, SERVANT automatically records sensor data and surveillance video and sends an alert to the security...exposure to organophosphate nerve agents, botulinum toxin, cyanide, and carbon monoxide and will be packaged into a portable , lightweight, mobile hand

Chemical and Biological Defense: Designated Entity Needed to Identify, Align, and Manage DOD’s Infrastructure

DTIC Science & Technology

2015-06-01

Designated Leader, GAO-10-645 (Washington, D.C.: June 30, 2010). 35See GAO, Biological Defense: DOD Has Strengthened Coordination on Medical... on track to be designated a Leadership in Energy and Environmental Design facility. metabolic poisons, and pulmonary toxicants; nerve agent...CHEMICAL AND BIOLOGICAL DEFENSE Designated Entity Needed to Identify, Align, and Manage DOD’s Infrastructure

Structural Insights into the Dual Activities of the Nerve Agent Degrading Organophosphate Anhydrolase/Prolidase

DTIC Science & Technology

2009-12-11

class of bimetalloenzymes that hydrolyze a variety of toxic acetylcholinesterase-inhibiting organophosphorus compounds, including fluorine ... electrophilicity of the phosphorus center. Similar interactions and functions have been proposed for the carbonyl oxygen of the scissile peptide bond...163, 261–276. 2. Mazur, A. (1946) An enzyme in animal tissues capable of hydrolyzing the phosphorus- fluorine bond of alkyl fluorophosphate. J. Biol

Combating Terrorism in a Globalized World

DTIC Science & Technology

2002-05-01

warhead is detonated in London or a smallpox outbreak in Tokyo or a nerve agent is introduced into the Washington, DC, subway system. An initiative...and convey a more positive image of the Western world. Furthermore, the civilized world should work together to provide disen- franchised youth...59 Economic growth in developing countries leads to reduced poverty, increased food security, and higher standards of living, including better health

Developing Extracellular Matrix Technology to Treat Retinal or Optic Nerve Injury

PubMed Central

van der Merwe, Yolandi

2015-01-01

Abstract Adult mammalian CNS neurons often degenerate after injury, leading to lost neurologic functions. In the visual system, retinal or optic nerve injury often leads to retinal ganglion cell axon degeneration and irreversible vision loss. CNS axon degeneration is increasingly linked to the innate immune response to injury, which leads to tissue-destructive inflammation and scarring. Extracellular matrix (ECM) technology can reduce inflammation, while increasing functional tissue remodeling, over scarring, in various tissues and organs, including the peripheral nervous system. However, applying ECM technology to CNS injuries has been limited and virtually unstudied in the visual system. Here we discuss advances in deriving fetal CNS-specific ECMs, like fetal porcine brain, retina, and optic nerve, and fetal non-CNS-specific ECMs, like fetal urinary bladder, and the potential for using tissue-specific ECMs to treat retinal or optic nerve injuries in two platforms. The first platform is an ECM hydrogel that can be administered as a retrobulbar, periocular, or even intraocular injection. The second platform is an ECM hydrogel and polymer “biohybrid” sheet that can be readily shaped and wrapped around a nerve. Both platforms can be tuned mechanically and biochemically to deliver factors like neurotrophins, immunotherapeutics, or stem cells. Since clinical CNS therapies often use general anti-inflammatory agents, which can reduce tissue-destructive inflammation but also suppress tissue-reparative immune system functions, tissue-specific, ECM-based devices may fill an important need by providing naturally derived, biocompatible, and highly translatable platforms that can modulate the innate immune response to promote a positive functional outcome. PMID:26478910

Single treatment of VX poisoned guinea pigs with the phosphotriesterase mutant C23AL: Intraosseous versus intravenous injection.

PubMed

Wille, Timo; Neumaier, Katharina; Koller, Marianne; Ehinger, Christina; Aggarwal, Nidhi; Ashani, Yacov; Goldsmith, Moshe; Sussman, Joel L; Tawfik, Dan S; Thiermann, Horst; Worek, Franz

2016-09-06

The recent attacks with the nerve agent sarin in Syria reveal the necessity of effective countermeasures against highly toxic organophosphorus compounds. Multiple studies provide evidence that a rapid onset of antidotal therapy might be life-saving but current standard antidotal protocols comprising reactivators and competitive muscarinic antagonists show a limited efficacy for several nerve agents. We here set out to test the newly developed phosphotriesterase (PTE) mutant C23AL by intravenous (i.v.), intramuscular (i.m.; model for autoinjector) and intraosseous (i.o.; model for intraosseous insertion device) application in an in vivo guinea pig model after VX challenge (∼2LD50). C23AL showed a Cmax of 0.63μmolL(-1) after i.o. and i.v. administration of 2mgkg(-1) providing a stable plasma profile up to 180min experimental duration with 0.41 and 0.37μmolL(-1) respectively. The i.m. application of C23AL did not result in detectable plasma levels. All animals challenged with VX and subsequent i.o. or i.v. C23AL therapy survived although an in part substantial inhibition of erythrocyte, brain and diaphragm AChE was detected. Theoretical calculation of the time required to hydrolyze in vivo 96.75% of the toxic VX enantiomer is consistent with previous studies wherein similar activity of plasma containing catalytic scavengers of OPs resulted in non-lethal protection although accompanied with a variable severity of cholinergic symptoms. The relatively low C23AL plasma level observed immediately after its i.v. or i.o load, point at a possible volume of distribution greater than the guinea pig plasma content, and thus underlines the necessity of in vivo experiments in antidote research. In conclusion the i.o. application of PTE is efficient and resulted in comparable plasma levels to the i.v. application at a given time. Thus, i.o. vascular access systems could improve the post-exposure PTE therapy of nerve agent poisoning. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Adenosine A(2A) receptor antagonists are broad facilitators of antinicotinic neuromuscular blockade monitored either with 2 Hz train-of-four or 50 Hz tetanic stimuli.

PubMed

Pereira, Monalisa W; Correia-de-Sá, Paulo; Alves-Do-Prado, Wilson

2012-10-01

1. The 2 Hz train-of-four ratio (TOF(ratio)) is used to monitor the degree of patient curarization. Using a rat phrenic nerve-hemidiaphragm preparation, we showed that antinicotinic agents, such as hexamethonium, d-tubocurarine and pancuronium, but not cisatracurium, decreased contractions produced by physiological nerve activity patterns (50 Hz) more efficiently than those caused by 2 Hz trains. Uncertainty about the usefulness of the TOF(ratio) to control safe recovery from curarization prompted us to investigate the muscarinic and adenosine neuromodulation of tetanic (50 Hz) fade induced by antinicotinic agents at concentrations that cause a 25% reduction in the TOF(ratio) (TOF(fade)). 2. Tetanic fade caused by d-tubocurarine (1.1 μmol/L), pancuronium (3 μmol/L) and hexamethonium (5.47 mmol/L) was attenuated by blocking presynaptic inhibitory muscarinic M(2) and adenosine A(1) receptors with methoctramine (1 μmol/L) and 1,3-dipropyl-8-cyclopentylxanthine (2.5 nmol/L), respectively. These compounds enhanced rather than decreased tetanic fade induced by cisatracurium (2.2 μmol/L), but they consistently attenuated cisatracurium-induced TOF(fade). The effect of the M(1) receptor antagonist pirenzepine (10 nmol/L) on fade produced by antinicotinic agents at 50 Hz was opposite to that observed with TOF stimulation. Blockade of adenosine A(2A) receptors with ZM 241385 (10 nmol/L) attenuated TOF(fade) caused by all antinicotinic drugs tested, with the exception of the 'pure' presynaptic nicotinic antagonist hexamethonium. ZM 241385 was the only compound tested in this series that facilitated recovery from tetanic fade produced by cisatracurium. 3. The data suggest that distinct antinicotinic relaxants interfere with fine-tuning neuromuscular adaptations to motor nerve stimulation patterns via activation of presynaptic muscarinic and adenosine receptors. These results support the use of A(2A) receptor antagonists together with atropine to facilitate recovery from antinicotinic neuromuscular blockade. © 2012 The Authors Clinical and Experimental Pharmacology and Physiology © 2012 Wiley Publishing Asia Pty Ltd.

Role of water in aging of human butyrylcholinesterase inhibited by echothiophate: the crystal structure suggests two alternative mechanisms of aging.

PubMed

Nachon, Florian; Asojo, Oluwatoyin A; Borgstahl, Gloria E O; Masson, Patrick; Lockridge, Oksana

2005-02-01

Organophosphorus poisons (OP) bind covalently to the active-site serine of cholinesterases. The inhibited enzyme can usually be reactivated with powerful nucleophiles such as oximes. However, the covalently bound OP can undergo a suicide reaction (termed aging) yielding nonreactivatable enzyme. In human butyrylcholinesterase (hBChE), aging involves the residues His438 and Glu197 that are proximal to the active-site serine (Ser198). The mechanism of aging is known in detail for the nerve gases soman, sarin, and tabun as well as the pesticide metabolite isomalathion. Aging of soman- and sarin-inhibited acetylcholinesterase occurs by C-O bond cleavage, whereas that of tabun- and isomalathion-inhibited acetylcholinesterase occurs by P-N and P-S bond cleavage, respectively. In this work, the crystal structures of hBChE inhibited by the ophthalmic reagents echothiophate (nonaged and aged) and diisopropylfluorophosphate (aged) were solved and refined to 2.1, 2.25, and 2.2 A resolution, respectively. No appreciable shift in the position of the catalytic triad histidine was observed between the aged and nonaged conjugates of hBChE. This absence of shift contrasts with the aged and nonaged crystal structures of Torpedo californica acetylcholinesterase inhibited by the nerve agent VX. The nonaged hBChE structure shows one water molecule interacting with Glu197 and the catalytic triad histidine (His438). Interestingly, this water molecule is ideally positioned to promote aging by two mechanisms: breaking either a C-O bond or a P-O bond. Pesticides and certain stereoisomers of nerve agents are expected to undergo aging by breaking the P-O bond.

Enkephalin modulation of neural transmission in the cat stellate ganglion: pharmacological actions of exogenous opiates.

PubMed

Prosdocimi, M; Finesso, M; Gorio, A

1986-11-01

Neural ganglionic transmission was studied in vivo in the cat, using closed chest anesthetized preparations. The right stellate ganglion and its branches were exposed retropleurally and prepared for electrical stimulation of pre- and postganglionic nerve fibers. The axillary artery was cannulated allowing direct administration of drugs in the arterial blood supplying the ganglion. Stimulation of postjunctional receptors could thus be obtained by local administration of selective agents. Local administration of nicotinic, muscarinic or histaminergic agents increased heart rate and blood pressure. Opiates were given either i.v. or locally through the axillary artery: we tested the effects of morphine, Leu-enkephalin (Leu-enk), Met-enkephalin (Met-enk), [D-ala2]-Met-enkephalinamide (DAME) and etorphine. When given locally, Leu-enk (from 10 micrograms), Met-enk (from 20 micrograms), DAME (from 5 micrograms) and etorphine (from 0.2 micrograms) inhibited tachycardia induced by preganglionic stimulation and reduced the amplitude of the compound action potential recorded from the postganglionic nerve. Morphine (10-200 micrograms) had no effect. On the other hand, tachycardia induced by postganglionic nerve stimulation was unaffected by opiates in the same experimental conditions. Intravenous administration of similar doses of opiates had no effect on ganglionic transmission. When tachycardia was induced by chemical stimulation of nicotinic (DMPP), muscarinic (McN-A-343-11) or histamine receptors in the stellate ganglia, opiates were still active in reducing the effect of these chemicals. These data provide evidence that exogenous opiates exert a depressing action on postsynaptic responses of sympathetic ganglia tested in vivo, although an additional action on presynaptic terminals is not excluded. As endogenous opiates are normally present in various sympathetic ganglia, including the stellate ganglion of the cat, it is possible that they play some modulatory role on ganglionic transmission in physiological conditions.

Decontamination of adsorbed chemical warfare agents on activated carbon using hydrogen peroxide solutions.

PubMed

Osovsky, Ruth; Kaplan, Doron; Nir, Ido; Rotter, Hadar; Elisha, Shmuel; Columbus, Ishay

2014-09-16

Mild treatment with hydrogen peroxide solutions (3-30%) efficiently decomposes adsorbed chemical warfare agents (CWAs) on microporous activated carbons used in protective garments and air filters. Better than 95% decomposition of adsorbed sulfur mustard (HD), sarin, and VX was achieved at ambient temperatures within 1-24 h, depending on the H2O2 concentration. HD was oxidized to the nontoxic HD-sulfoxide. The nerve agents were perhydrolyzed to the respective nontoxic methylphosphonic acids. The relative rapidity of the oxidation and perhydrolysis under these conditions is attributed to the microenvironment of the micropores. Apparently, the reactions are favored due to basic sites on the carbon surface. Our findings suggest a potential environmentally friendly route for decontamination of adsorbed CWAs, using H2O2 without the need of cosolvents or activators.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

C-11 hydroxy ephedrine, introduced as the first clinically usable norepinephrine analogue, studies employing normal volunteers and patients with various cardiac disorders was found to valuable as a nonadreneric tracer. Simultaneously, animal studies been used to assess its use following ischemic injury in order to define neuronal damage. Current research focuses on the comparison of C-11 hydroxyephedrine with other neurotransmitters such as C-11 epinephrine and C-11 threohydroxyephedrine. Epinephrine is primarily stored in vesicles of the nerve terminal, while threo-hydroxyephedrine is only substrate to uptake I mechanism. Such a combination of radiotracers may allow the dissection of uptake I mechanism as wellmore » as vesicular storage. In parallel to the refinement of presynaptic tracers for the sympathetic nervous system, we are developing radiopharmaceuticals to delineate the adrenergic receptors in the heart. The combined evaluation of pre- and postsynaptic nerve function will improve our ability to identify abnormalides. We are currently developing a new radiosynthesis of the hydrophilic adrenergic receptor antagonist C-11 CGP-12177 which has been used by others for the visualization of adrenergic receptors in the heart. We are developing radiopharmaceuticals, for the delineation of presynaptic cholinergic nerve terminals. Derivatives of benzovesamicol have been labeled in our institution and are currently under investigation. The most promising agent is F-18 benzovesamicol (FEBOBV) which allows the visualization of parasympathetic nerve terminals in the canine heart as demonstrated by, preliminary PET data.« less

Agent neutralization studies III. Detoxification of VX in aqueous persulfate. Final report, May-August 1993

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hovanec, J.W.; Albizo, J.M.; Henderson, V.D.

1994-06-01

Aqueous solutions of persulfate salts are frequently used to mineralize organic substrates in the course of total organic carbon analyses. A study has been conducted at the U.S. Army Edgewood Research, Development and Engineering Center to determine whether this approach may be useful to neutralize the nerve agent VX. VX was reacted with aqueous ammonium persulfate at 90 deg C and 70 deg C. The concentration of agent and the acidity of the mixture were varied. 31P-NMR was used to monitor the destruction of VX as well as the formation and degradation of the phosphorus-containing products. A titration procedure usingmore » ferrous sulfate and ceric ammonium nitrate was used to monitor the consumption of persulfate. The products formed and their stabilities were found to vary significantly with the acidity of the solution. Nuclear magnetic resonance, Oxidation, VX, Ammonium persulfate, Mineralization, Temperature effects, Chemical agent disposal.« less

A review of multi-threat medical countermeasures against chemical warfare and terrorism.

PubMed

Cowan, Fred M; Broomfield, Clarence A; Stojiljkovic, Milos P; Smith, William J

2004-11-01

The Multi-Threat Medical Countermeasure (MTMC) hypothesis has been proposed with the aim of developing a single countermeasure drug with efficacy against different pathologies caused by multiple classes of chemical warfare agents. Although sites and mechanisms of action and the pathologies caused by different chemical insults vary, common biochemical signaling pathways, molecular mediators, and cellular processes provide targets for MTMC drugs. This article will review the MTMC hypothesis for blister and nerve agents and will expand the scope of the concept to include other chemicals as well as briefly consider biological agents. The article will also consider how common biochemical signaling pathways, molecular mediators, and cellular processes that contribute to clinical pathologies and syndromes may relate to the toxicity of threat agents. Discovery of MTMC provides the opportunity for the integration of diverse researchers and clinicians, and for the exploitation of cutting-edge technologies and drug discovery. The broad-spectrum nature of MTMC can augment military and civil defense to combat chemical warfare and chemical terrorism.

A small effect of adding antiviral agents in treating patients with severe Bell palsy.

PubMed

van der Veen, Erwin L; Rovers, Maroeska M; de Ru, J Alexander; van der Heijden, Geert J

2012-03-01

In this evidence-based case report, the authors studied the following clinical question: What is the effect of adding antiviral agents to corticosteroids in the treatment of patients with severe or complete Bell palsy? The search yielded 250 original research articles. The 6 randomized trials of these that could be used all reported low-quality data for answering the clinical question; apart from apparent flaws, they did not primarily include patients with severe or complete Bell palsy. Complete functional facial nerve recovery was seen in 75% of the patients receiving prednisolone only and in 83% with additional antiviral treatment. The pooled risk difference of 7% (95% confidence interval, -1% to 15%) results in a number needed to treat of 14 (ie, slightly favors adding an antiviral agent). The authors conclude that although a strong recommendation for adding antiviral agents to corticosteroids to further improve the recovery of patients with severe Bell palsy is precluded by the lack of robust evidence, it should be discussed with the patient.

Topical tranexamic Acid does not affect electrophysiologic or neurovascular sciatic nerve markers in an animal model.

PubMed

Schwarzkopf, Ran; Dang, Phuc; Luu, Michele; Mozaffar, Tahseen; Gupta, Ranjan

2015-03-01

Tranexamic acid is a safe and effective antifibrinolytic agent used systemically and topically to reduce blood loss and transfusion rate in patients having TKA or THA. As the hip does not have a defined capsule, topical application of tranexamic acid may entirely envelop the sciatic nerve during THA. Accidental application of tranexamic acid onto the spinal cord in spinal anesthesia has been shown to produce seizures; therefore, we sought to investigate if topical application of tranexamic acid on the sciatic nerve has a deleterious effect. We explored whether there were any short- or long-term alterations in (1) electrophysiologic measures, (2) macrophage recruitment, or (3) blood-nerve barrier permeability. Our hypothesis was that local application of tranexamic acid would have a transient effect or no effect on histologic features and function of the sciatic nerve. We used a rat protocol to model sciatic nerve exposure in THA to determine the effects of tranexamic acid on neural histologic features and function. We evaluated 35 rats by the dorsal gluteal splitting approach to expose the sciatic nerve for topical use of control and tranexamic acid. We evaluated EMG changes (distal latency, amplitude, nerve conduction velocity), histologic signs of nerve injury via macrophage recruitment, and changes in blood-nerve barrier permeability at early (4 days) and late (1 month) times after surgery, after application of subtherapeutic (1 mg/kg body weight [1.6 mg]), therapeutic (10 mg/kg [16 mg]), and supratherapeutic (100 mg/kg [160 mg]) concentrations of tranexamic acid. Differences in blood-nerve barrier permeability, macrophage recruitment, and EMG between normal and tranexamic acid-treated nerves were calculated using one-way ANOVA, with Newman-Keuls post hoc analyses, at each time. A post hoc power calculation showed that with the numbers available, we had 16% power to detect a 50% difference in EMG changes between the control, 1 mg/kg group, 10 mg/kg group, and 100 mg/kg group. At the early and late times, with the numbers available, there were no differences in EMG except for distal latency at 4 days, macrophage recruitment, or changes in blood-nerve barrier between control rats and those with tranexamic acid-treated nerves. The distal latency in the 1 mg tranexamic acid-treated animals at 4 days was 1.06 ± 0.15 ms (p = 0.0036 versus all other groups, 95% CI, 0.89-1.25), whereas the distal latencies in the control, the 10 mg/kg, and 100 mg/kg tranexamic acid-treated animals were 0.83 ± 0.11, 0.89 ± 0.05, and 0.87 ± 0.13, respectively. Distal latencies were not increased in any of the groups at 1 month with the numbers available (0.81 ± 0.10, 0.89 ± 0.03, 0.81 ± 0.06, and 0.83 ± 0.08 ms, respectively, for controls; 1 mg/kg, 10 mg/kg, and 100 mg/kg for the tranexamic acid-treated groups). In our in vivo rat model study, tranexamic acid did not appear to have any clinically relevant effect on the sciatic nerve resulting from topical administration up to 1 month. However, because our statistical power was low, these data should be considered hypothesis-generating pilot data for larger, more-definitive studies. Topical tranexamic acid is effective in decreasing patient blood loss during THA, and results from our in vivo rat model study suggest there may be no electrophysiologic and histologic effects on the sciatic nerve, with the numbers available, up to 1 month.

Destruction of chemical warfare agents using metal-organic frameworks

NASA Astrophysics Data System (ADS)

Mondloch, Joseph E.; Katz, Michael J.; Isley, William C., III; Ghosh, Pritha; Liao, Peilin; Bury, Wojciech; Wagner, George W.; Hall, Morgan G.; Decoste, Jared B.; Peterson, Gregory W.; Snurr, Randall Q.; Cramer, Christopher J.; Hupp, Joseph T.; Farha, Omar K.

2015-05-01

Chemical warfare agents containing phosphonate ester bonds are among the most toxic chemicals known to mankind. Recent global military events, such as the conflict and disarmament in Syria, have brought into focus the need to find effective strategies for the rapid destruction of these banned chemicals. Solutions are needed for immediate personal protection (for example, the filtration and catalytic destruction of airborne versions of agents), bulk destruction of chemical weapon stockpiles, protection (via coating) of clothing, equipment and buildings, and containment of agent spills. Solid heterogeneous materials such as modified activated carbon or metal oxides exhibit many desirable characteristics for the destruction of chemical warfare agents. However, low sorptive capacities, low effective active site loadings, deactivation of the active site, slow degradation kinetics, and/or a lack of tailorability offer significant room for improvement in these materials. Here, we report a carefully chosen metal-organic framework (MOF) material featuring high porosity and exceptional chemical stability that is extraordinarily effective for the degradation of nerve agents and their simulants. Experimental and computational evidence points to Lewis-acidic ZrIV ions as the active sites and to their superb accessibility as a defining element of their efficacy.

Destruction of chemical warfare agents using metal-organic frameworks.

PubMed

Mondloch, Joseph E; Katz, Michael J; Isley, William C; Ghosh, Pritha; Liao, Peilin; Bury, Wojciech; Wagner, George W; Hall, Morgan G; DeCoste, Jared B; Peterson, Gregory W; Snurr, Randall Q; Cramer, Christopher J; Hupp, Joseph T; Farha, Omar K

2015-05-01

Chemical warfare agents containing phosphonate ester bonds are among the most toxic chemicals known to mankind. Recent global military events, such as the conflict and disarmament in Syria, have brought into focus the need to find effective strategies for the rapid destruction of these banned chemicals. Solutions are needed for immediate personal protection (for example, the filtration and catalytic destruction of airborne versions of agents), bulk destruction of chemical weapon stockpiles, protection (via coating) of clothing, equipment and buildings, and containment of agent spills. Solid heterogeneous materials such as modified activated carbon or metal oxides exhibit many desirable characteristics for the destruction of chemical warfare agents. However, low sorptive capacities, low effective active site loadings, deactivation of the active site, slow degradation kinetics, and/or a lack of tailorability offer significant room for improvement in these materials. Here, we report a carefully chosen metal-organic framework (MOF) material featuring high porosity and exceptional chemical stability that is extraordinarily effective for the degradation of nerve agents and their simulants. Experimental and computational evidence points to Lewis-acidic Zr(IV) ions as the active sites and to their superb accessibility as a defining element of their efficacy.

The success rate of bupivacaine and lidocaine as anesthetic agents in inferior alveolar nerve block in teeth with irreversible pulpitis without spontaneous pain

PubMed Central

Yosefi, Mohammad Hosein; Nakhaee, Nouzar

2015-01-01

Objectives Achieving adequate anesthesia with inferior alveolar nerve blocks (IANB) is of great importance during dental procedures. The aim of the present study was to assess the success rate of two anesthetic agents (bupivacaine and lidocaine) for IANB when treating teeth with irreversible pulpitis. Materials and Methods Sixty volunteer male and female patients who required root canal treatment of a mandibular molar due to caries participated in the present study. The inclusion criteria included prolonged pain to thermal stimulus but no spontaneous pain. The patients were randomly allocated to receive either 2% lidocaine with 1:80,000 epinephrine or 0.5% bupivacaine with 1:200,000 epinephrine as an IANB injection. The sensitivity of the teeth to a cold test as well as the amount of pain during access cavity preparation and root canal instrumentation were recorded. Results were statistically analyzed with the Chi-Square and Fischer's exact tests. Results At the final step, fifty-nine patients were included in the study. The success rate for bupivacaine and lidocaine groups were 20.0% and 24.1%, respectively. There was no significant difference between the two groups at any stage of the treatment procedure. Conclusions There was no difference in success rates of anesthesia when bupivacaine and lidocaine were used for IANB injections to treat mandibular molar teeth with irreversible pulpitis. Neither agent was able to completely anesthetize the teeth effectively. Therefore, practitioners should be prepared to administer supplemental anesthesia to overcome pain during root canal treatment. PMID:25984478

Purinergic and cholinergic components of bladder contractility and flow.

PubMed

Theobald, R J

1995-01-01

The role of ATP as a neurotransmitter/neuromodulator in the urinary tract has been the subject of much study, particularly whether ATP has a functional role in producing urine flow. Recent studies suggested significant species variation, specifically a variation between cat and other species. This study was performed to determine the in vivo response of cat urinary bladder to pelvic nerve stimulation (PNS) and to the exogenous administration of cholinergic and purinergic agents. In anesthetized cats, bladder contractions and fluid expulsion was measured in response to PNS and to the exogenous administration of cholinergic and purinergic agents. Fluid was instilled into the bladder and any fluid expelled by bladder contractions induced by PNS or exogenous agents was collected in a beaker. The volume was measured in a graduated cylinder and recorded. PNS, carbachol and APPCP produced sustained contractions with significant expulsion of fluid. ATP, ACh and hypogastric nerve stimulation did not produce any significant expulsion of fluid. Atropine, a cholinergic antagonist, inhibited PNS contractions and fluid expulsion with no effect on purinergic actions. There was a significant relationship between the magnitude of the contraction, duration of the contractions and volume of fluid expelled. The data and information from other studies, strongly suggests a functional role for ATP as a cotransmitter in the lower urinary tract different from ACh's role. ATP stimulation of a specific purinergic receptor plays a role in initiation of bladder contractions and perhaps in the initiation of urine flow from the bladder. ACh's role is functionally different and appears to be more involved in maintenance of contractile activity and flow.

Detection/classification/quantification of chemical agents using an array of surface acoustic wave (SAW) devices

NASA Astrophysics Data System (ADS)

Milner, G. Martin

2005-05-01

ChemSentry is a portable system used to detect, identify, and quantify chemical warfare (CW) agents. Electro chemical (EC) cell sensor technology is used for blood agents and an array of surface acoustic wave (SAW) sensors is used for nerve and blister agents. The combination of the EC cell and the SAW array provides sufficient sensor information to detect, classify and quantify all CW agents of concern using smaller, lighter, lower cost units. Initial development of the SAW array and processing was a key challenge for ChemSentry requiring several years of fundamental testing of polymers and coating methods to finalize the sensor array design in 2001. Following the finalization of the SAW array, nearly three (3) years of intensive testing in both laboratory and field environments were required in order to gather sufficient data to fully understand the response characteristics. Virtually unbounded permutations of agent characteristics and environmental characteristics must be considered in order to operate against all agents and all environments of interest to the U.S. military and other potential users of ChemSentry. The resulting signal processing design matched to this extensive body of measured data (over 8,000 agent challenges and 10,000 hours of ambient data) is considered to be a significant advance in state-of-the-art for CW agent detection.

Corticosterone primes the neuroinflammatory response to DFP in mice: potential animal model of Gulf War Illness.

PubMed

O'Callaghan, James P; Kelly, Kimberly A; Locker, Alicia R; Miller, Diane B; Lasley, Steve M

2015-06-01

Gulf War Illness (GWI) is a multi-symptom disorder with features characteristic of persistent sickness behavior. Among conditions encountered in the Gulf War (GW) theater were physiological stressors (e.g., heat/cold/physical activity/sleep deprivation), prophylactic treatment with the reversible AChE inhibitor, pyridostigmine bromide (PB), the insect repellent, N,N-diethyl-meta-toluamide (DEET), and potentially the nerve agent, sarin. Prior exposure to the anti-inflammatory glucocorticoid, corticosterone (CORT), at levels associated with high physiological stress, can paradoxically prime the CNS to produce a robust proinflammatory response to neurotoxicants and systemic inflammation; such neuroinflammatory effects can be associated with sickness behavior. Here, we examined whether CORT primed the CNS to mount neuroinflammatory responses to GW exposures as a potential model of GWI. Male C57BL/6 mice were treated with chronic (14 days) PB/ DEET, subchronic (7-14 days) CORT, and acute exposure (day 15) to diisopropyl fluorophosphate (DFP), a sarin surrogate and irreversible AChE inhibitor. DFP alone caused marked brain-wide neuroinflammation assessed by qPCR of tumor necrosis factor-α, IL6, chemokine (C-C motif) ligand 2, IL-1β, leukemia inhibitory factor, and oncostatin M. Pre-treatment with high physiological levels of CORT greatly augmented (up to 300-fold) the neuroinflammatory responses to DFP. Anti-inflammatory pre-treatment with minocycline suppressed many proinflammatory responses to CORT+DFP. Our findings are suggestive of a possible critical, yet unrecognized interaction between the stressor/environment of the GW theater and agent exposure(s) unique to this war. Such exposures may in fact prime the CNS to amplify future neuroinflammatory responses to pathogens, injury, or toxicity. Such occurrences could potentially result in the prolonged episodes of sickness behavior observed in GWI. Gulf War (GW) veterans were exposed to stressors, prophylactic medicines and, potentially, nerve agents in theater. Subsequent development of GW Illness, a persistent multi-symptom disorder with features characteristic of sickness behavior, may be caused by priming of the CNS resulting in exaggerated neuroinflammatory responses to pathogens/insults. Nerve agent, diisopropyl fluorophosphate (DFP), produced a neuroinflammatory response that was exacerbated by pre-treatment with levels of corticosterone simulating heightened stressor conditions. While prophylactic treatments reduced DFP-induced neuroinflammation, this effect was negated when those treatments were combined with corticosterone. © 2015 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of The International Society for Neurochemistry.

Prophylaxis and Therapy Against Chemical Agents

DTIC Science & Technology

2009-11-01

relationship of stress to neurologic function and the overall role of cholinergic neuropharmacology. These efforts were all directed on finding new ...high concentration in plasma; plasma CaE is synthesized in the liver and secreted into the circulation via the Golgi apparatus of hepatocytes [76...group and held in 1999, 2000, 2002, 2003 and 2005. The report also includes a summary report on bioscavengers as a new pre-treatment for nerve

Applying Genomic and Genetic Tools to Understand and Mitigate Damage from Exposure to Toxins

DTIC Science & Technology

2011-10-01

Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Use of the pyridostigmine bromide during the 1991 Gulf War has been implicated as a contributing...2 EXECUTIVE SUMMARY Treatment of soldiers of the 1991 Gulf War with the drug pyridostigmine bromide for pretreatment against nerve agents has...organism for the characterization of the effects of pyridostigmine bromide (PB) on gene expression using unbiased, high-throughput techniques, specifically

Analysis of Urinary Metabolites of Nerve and Blister Chemical Warfare Agents

DTIC Science & Technology

2014-08-01

of CWAs. The analysis methods use UHPLC-MS/MS in Multiple Reaction Monitoring ( MRM ) mode to enhance the selectivity and sensitivity of the method...Chromatography Mass Spectrometry LOD Limit Of Detection LOQ Limit of Quantitation MRM Multiple Reaction Monitoring MSMS Tandem mass...urine [1]. Those analysis methods use UHPLC- MS/MS in Multiple Reaction Monitoring ( MRM ) mode to enhance the selectivity and sensitivity of the method

An Evaluation of the Eclox Chemiluminescence Test, Hach Pesticide/Nerve Agent Test Strips, and Agri-Screen Test Tickets

DTIC Science & Technology

2010-06-30

Interference Testing Our testing shows that it is unlikely that the Eclox Chemiluminescence Test will respond to the common disinfectant chloramine ...common disinfectants (chlorine and chloramine ), cyanobacterial byproducts (geosmin and MIB) or water quality parameters (humic/fulvic acids or water...toxicity sensor testing Table 2-2: Interferences Test Chemicals Concentration (mg/L) Chlorine 10 Chloramines 10 Geosmin 0.0001 Methyl-isoborneol

Circadian Rhythms of Heart Rate and Locomotion After Treatment With Low-Dose Acetylcholinesterase Inhibitors

DTIC Science & Technology

2006-01-01

with pyridostigmine bromide (PB), a carbamate AChE by air conditioned vans and air-freight to the Laboratory inhibitor that does not cross the blood ...15. SUBJECT TERMS Nerve agents, sarin, pyridostigmine bromide, cerebral glucose utilization, cerebrovascular circulation, low dose cholinesterase ...March 2006" Accepted 12 May 2006 ABSTRACT: This study tested the hypothesis that repeated exposure to low levels of sarin, pyridostigmine bromide (PB