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.

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.

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

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.

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

PubMed

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

2015-01-01

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

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.

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

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.

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

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

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

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.

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.

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

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.

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

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.

Stable adducts of nerve agents sarin, soman and cyclosarin with TRIS, TES and related buffer compounds--characterization by LC-ESI-MS/MS and NMR and implications for analytical chemistry.

PubMed

Gäb, Jürgen; John, Harald; Melzer, Marco; Blum, Marc-Michael

2010-05-15

Buffering compounds like TRIS are frequently used in chemical, biochemical and biomedical applications to control pH in solution. One of the prerequisites of a buffer compound, in addition to sufficient buffering capacity and pH stability over time, is its non-reactivity with other constituents of the solution. This is especially important in the field of analytical chemistry where analytes are to be determined quantitatively. Investigating the enzymatic hydrolysis of G-type nerve agents sarin, soman and cyclosarin in buffered solution we have identified stable buffer adducts of TRIS, TES and other buffer compounds with the nerve agents. We identified the molecular structure of these adducts as phosphonic diesters using 1D (1)H-(31)P HSQC NMR and LC-ESI-MS/MS techniques. Reaction rates with TRIS and TES are fast enough to compete with spontaneous hydrolysis in aqueous solution and to yield substantial amounts (up to 20-40%) of buffer adduct over the course of several hours. A reaction mechanism is proposed in which the amino function of the buffer serves as an intramolecular proton acceptor rendering the buffer hydroxyl groups nucleophilic enough for attack on the phosphorus atom of the agents. Results show that similar buffer adducts are formed with a range of hydroxyl and amino function containing buffers including TES, BES, TRIS, BIS-TRIS, BIS-TRIS propane, Tricine, Bicine, HEPES and triethanol amine. It is recommended to use alternative buffers like MOPS, MES and CHES when working with G-type nerve agents especially at higher concentrations and over prolonged times. Copyright (c) 2010 Elsevier B.V. All rights reserved.

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.

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.

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.

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

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

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

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

Essential Function of Protein 4.1G in Targeting of Membrane Protein Palmitoylated 6 into Schmidt-Lanterman Incisures in Myelinated Nerves

PubMed Central

Saitoh, Yurika; Ohno, Nobuhiko; Komada, Masayuki; Saitoh, Sei; Peles, Elior; Ohno, Shinichi

2012-01-01

Protein 4.1G is a membrane skeletal protein found in specific subcellular structures in myelinated Schwann cells and seminiferous tubules. Here, we show that in the mouse sciatic nerve, protein 4.1G colocalized at Schmidt-Lanterman incisures (SLI) and the paranodes with a member of the membrane-associated guanylate kinase (MAGUK) family, membrane protein palmitoylated 6 (MPP6). Coimmunoprecipitation experiments revealed that MPP6 was interacting with protein 4.1G. In contrast to wild-type nerves, in 4.1G knockout mice, MPP6 was found largely in the cytoplasm near Schwann cell nuclei, indicating an abnormal protein transport. Although the SLI remained in the 4.1G knockout sciatic nerves, as confirmed by E-cadherin immunostaining, their shape was altered in aged 4.1G knockout nerves compared to their shape in wild-type nerves. In the seminiferous tubules, MPP6 was localized similarly to protein 4.1G along cell membranes of the spermatogonium and early spermatocytes. However, in contrast to myelinated peripheral nerves, the specific localization of MPP6 in the seminiferous tubules was unaltered in the absence of protein 4.1G. These results indicate that 4.1G has a specific role in the targeting of MPP6 to the SLI and the assembly of these subcellular structures. PMID:22025680

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...

Nerve ultrasound shows subclinical peripheral nerve involvement in neurofibromatosis type 2.

PubMed

Telleman, Johan A; Stellingwerff, Menno D; Brekelmans, Geert J; Visser, Leo H

2018-02-01

Neurofibromatosis type 2 (NF2) is mainly associated with central nervous system (CNS) tumors. Peripheral nerve involvement is described in symptomatic patients, but evidence of subclinical peripheral nerve involvement is scarce. We conducted a cross-sectional pilot study in 2 asymptomatic and 3 minimally symptomatic patients with NF2 to detect subclinical peripheral nerve involvement. Patients underwent clinical examination, nerve conduction studies (NCS), and high-resolution ultrasonography (HRUS). A total of 30 schwannomas were found, divided over 20 nerve segments (33.9% of all investigated nerve segments). All patients had at least 1 schwannoma. Schwannomas were identified with HRUS in 37% of clinically unaffected nerve segments and 50% of nerve segments with normal NCS findings. HRUS shows frequent subclinical peripheral nerve involvement in NF2. Clinicians should consider peripheral nerve involvement as a cause of weakness and sensory loss in the extremities in patients with this disease. Muscle Nerve 57: 312-316, 2018. © 2017 Wiley Periodicals, Inc.

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.

[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.

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.

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

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

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

Morphometric analysis of the diameter and g-ratio of the myelinated nerve fibers of the human sciatic nerve during the aging process.

PubMed

Ugrenović, Sladjana; Jovanović, Ivan; Vasović, Ljiljana; Kundalić, Braca; Čukuranović, Rade; Stefanović, Vladisav

2016-06-01

Myelinated nerve fibers suffer from different degrees of atrophy with age. The success of subsequent regeneration varies. The aim of this research was to analyze myelinated fibers of the human sciatic nerve during the aging process. Morphometric analysis was performed on 17 cases with an age range from 9 to 93 years. The outer and inner diameter of 100 randomly selected nerve fibers was measured in each of the cases evaluated, and the g-ratio (axonal diameter/outer diameter of the whole nerve fiber) of each was calculated. Scatter plots of the diameters and g-ratios of the analyzed fibers were then analyzed. Nerve fibers of each case were classified into three groups according to the g-ratio values: group I (g-ratio lower than 0.6), group II (g-ratio from 0.6 to 0.7) and group III (g-ratio higher than 0.7). Afterwards, nerve fibers of group II were further classified into small and large subgroups. The percentages of each group of nerve fibers were computed for each case and these values were used for correlational and bivariate linear regression analysis. The percentage of myelinated nerve fibers with large diameter and optimal g-ratio of the sciatic nerve declines significantly with age. This is accompanied by a simultaneous significant increase in the percentage of small myelinated fibers with g-ratio values close to 1 that occupy the upper left quadrant of the scatter plot. It can be concluded that aging of the sciatic nerve is associated with significant atrophy of large myelinated fibers. Additionally, a significant increase in regenerated nerve fibers with thinner myelin sheath is observed with age, which, together with the large myelinated fiber atrophy, might be the cause of the age-related decline in conduction velocity. A better understanding of the changes in aging peripheral nerves might improve interpretation of their pathological changes, as well as comprehension of their regeneration in individuals of different age.

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

Study of efficacy of reactivator HI 6 in reactivation of immobilized acetylcholinesterase, inhibited by organophosphorus chemical warfare agents of the "G" series.

PubMed

Hoskovcová, Monika; Halámek, Emil; Kobliha, Zbynĕk

2009-01-01

Reactivation with bis quaternary aldoxime HI-6, chemical formula 1-(2-hydroxyamino-methylpyridinium)-3-(4-carbamoylpyridinium)-2-oxapropane dichloride of immobilized enzyme acetylcholinesterase inhibited by nerve agent type "G" was studied. This aldoxime is effective in reactivation of sarin-inhibited acetylcholinesterase. Substantially lower reactivation potency was observed with cyclosarin-inhibited enzyme and almost no effect was found for that acetylcholinesterase is the enzyme complex. HI 6 is completely ineffective towards the soman-inhibited enzyme: After a 2-minute inhibition of the enzyme with soman no ability to define reactivator the inhibited enzymes and complexes.

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.

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

PubMed Central

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

2015-01-01

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

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.

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.

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

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...

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 ...

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 ...

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...

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.

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

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

Maxwell, Donald M.; Koplovitz, Irwin; Worek, Franz

2008-09-01

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

Abducens Nerve in Patients with Type 3 Duane’s Retraction Syndrome

PubMed Central

Hwang, Jeong-Min

2016-01-01

Background We have previously reported that the presence of the abducens nerve was variable in patients with type 3 Duane’s retraction syndrome (DRS), being present in 2 of 5 eyes (40%) and absent in 3 (60%) on magnetic resonance imaging (MRI). The previous study included only 5 eyes with unilateral DRS type 3. Objectives To supplement existing scarce pathologic information by evaluating the presence of the abducens nerve using high resolution thin-section MRI system in a larger number of patients with DRS type 3, thus to provide further insight into the pathogenesis of DRS. Data Extraction A retrospective review of medical records on ophthalmologic examination and high resolution thin-section MRI at the brainstem level and orbit was performed. A total of 31 patients who showed the typical signs of DRS type 3, including abduction and adduction deficit, globe retraction, narrowing of fissure on adduction and upshoot and/or downshoot, were included. The abducens nerve and any other extraocular muscle abnormalities discovered by MRI were noted. Results DRS was unilateral in 26 patients (84%) and bilateral in 5 patients (16%). Two out of 5 bilateral patients had DRS type 3 in the right eye and DRS type 1 in the left eye. Of the 34 affected orbits with DRS type 3 in 31 patients, the abducens nerve was absent or hypoplastic in 31 eyes (91%) and present in 3 eyes (9%). Patients with a present abducens nerve showed more limitation in adduction compared to patients with an absent abducens nerve (P = 0.030). Conclusions The abducens nerve is absent or hypoplastic in 91% of DRS type 3. Patients with a present abducens nerve showed more prominent limitation of adduction. As DRS type 3 partly share the same pathophysiology with type 1 and 2 DRS, the classification of DRS may have to be revised according to MRI findings. PMID:27352171

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.

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

Impaired peripheral nerve regeneration in type-2 diabetic mouse model.

PubMed

Pham, Vuong M; Tu, Nguyen Huu; Katano, Tayo; Matsumura, Shinji; Saito, Akira; Yamada, Akihiro; Furue, Hidemasa; Ito, Seiji

2018-01-01

Peripheral neuropathy is one of the most common and serious complications of type-2 diabetes. Diabetic neuropathy is characterized by a distal symmetrical sensorimotor polyneuropathy, and its incidence increases in patients 40 years of age or older. In spite of extensive research over decades, there are few effective treatments for diabetic neuropathy besides glucose control and improved lifestyle. The earliest changes in diabetic neuropathy occur in sensory nerve fibers, with initial degeneration and regeneration resulting in pain. To seek its effective treatment, here we prepared a type-2 diabetic mouse model by giving mice 2 injections of streptozotocin and nicotinamide and examining the ability for nerve regeneration by using a sciatic nerve transection-regeneration model previously established by us. Seventeen weeks after the last injection, the mice exhibited symptoms of type-2 diabetes, that is, impaired glucose tolerance, decreased insulin level, mechanical hyperalgesia, and impaired sensory nerve fibers in the plantar skin. These mice showed delayed functional recovery and nerve regeneration by 2 weeks compared with young healthy mice and by 1 week compared with age-matched non-diabetic mice after axotomy. Furthermore, type-2 diabetic mice displayed increased expression of PTEN in their DRG neurons. Administration of a PTEN inhibitor at the cutting site of the nerve for 4 weeks promoted the axonal transport and functional recovery remarkably. This study demonstrates that peripheral nerve regeneration was impaired in type-2 diabetic model and that its combination with sciatic nerve transection is suitable for the study of the pathogenesis and treatment of early diabetic neuropathy. © 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

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....

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.

Asymmetric type F botulism with cranial nerve demyelination.

PubMed

Filozov, Alina; Kattan, Jessica A; Jitendranath, Lavanya; Smith, C Gregory; Lúquez, Carolina; Phan, Quyen N; Fagan, Ryan P

2012-01-01

We report a case of type F botulism in a patient with bilateral but asymmetric neurologic deficits. Cranial nerve demyelination was found during autopsy. Bilateral, asymmetric clinical signs, although rare, do not rule out botulism. Demyelination of cranial nerves might be underrecognized during autopsy of botulism patients.

G-CSF prevents caspase 3 activation in Schwann cells after sciatic nerve transection, but does not improve nerve regeneration.

PubMed

Frost, Hanna K; Kodama, Akira; Ekström, Per; Dahlin, Lars B

2016-10-15

Exogenous granulocyte-colony stimulating factor (G-CSF) has emerged as a drug candidate for improving the outcome after peripheral nerve injuries. We raised the question if exogenous G-CSF can improve nerve regeneration following a clinically relevant model - nerve transection and repair - in healthy and diabetic rats. In short-term experiments, distance of axonal regeneration and extent of injury-induced Schwann cell death was quantified by staining for neurofilaments and cleaved caspase 3, respectively, seven days after repair. There was no difference in axonal outgrowth between G-CSF-treated and non-treated rats, regardless if healthy Wistar or diabetic Goto-Kakizaki (GK) rats were examined. However, G-CSF treatment caused a significant 13% decrease of cleaved caspase 3-positive Schwann cells at the lesion site in healthy rats, but only a trend in diabetic rats. In the distal nerve segments of healthy rats a similar trend was observed. In long-term experiments of healthy rats, regeneration outcome was evaluated at 90days after repair by presence of neurofilaments, wet weight of gastrocnemius muscle, and perception of touch (von Frey monofilament testing weekly). The presence of neurofilaments distal to the suture line was similar in G-CSF-treated and non-treated rats. The weight ratio of ipsi-over contralateral gastrocnemius muscles, and perception of touch at any time point, were likewise not affected by G-CSF treatment. In addition, the inflammatory response in short- and long-term experiments was studied by analyzing ED1 stainable macrophages in healthy rats, but in neither case was any attenuation seen at the injury site or distal to it. G-CSF can prevent caspase 3 activation in Schwann cells in the short-term, but does not detectably affect the inflammatory response, nor improve early or late axonal outgrowth or functional recovery. Copyright © 2016 IBRO. Published by Elsevier Ltd. 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

Asymmetric Type F Botulism with Cranial Nerve Demyelination

PubMed Central

Kattan, Jessica A.; Jitendranath, Lavanya; Smith, C. Gregory; Lúquez, Carolina; Phan, Quyen N.; Fagan, Ryan P.

2012-01-01

We report a case of type F botulism in a patient with bilateral but asymmetric neurologic deficits. Cranial nerve demyelination was found during autopsy. Bilateral, asymmetric clinical signs, although rare, do not rule out botulism. Demyelination of cranial nerves might be underrecognized during autopsy of botulism patients. PMID:22257488

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

Impact of keyboard typing on the morphological changes of the median nerve

PubMed Central

Yeap Loh, Ping; Liang Yeoh, Wen; Nakashima, Hiroki; Muraki, Satoshi

2017-01-01

Objectives: The primary objective was to investigate the effects of continuous typing on median nerve changes at the carpal tunnel region at two different keyboard slopes (0° and 20°). The secondary objective was to investigate the differences in wrist kinematics and the changes in wrist anthropometric measurements when typing at the two different keyboard slopes. Methods: Fifteen healthy right-handed young men were recruited. A randomized sequence of the conditions (control, typing I, and typing II) was assigned to each participant. Wrist anthropometric measurements, wrist kinematics data collection and ultrasound examination to the median nerve was performed at designated time block. Results: Typing activity and time block do not cause significant changes to the wrist anthropometric measurements. The wrist measurements remained similar across all the time blocks in the three conditions. Subsequently, the wrist extensions and ulnar deviations were significantly higher in both the typing I and typing II conditions than in the control condition for both wrists (p<0.05). Additionally, the median nerve cross-sectional area (MNCSA) significantly increased in both the typing I and typing II conditions after the typing task than before the typing task. The MNCSA significantly decreased in the recovery phase after the typing task. Conclusions: This study demonstrated the immediate changes in the median nerve after continuous keyboard typing. Changes in the median nerve were greater during typing using a keyboard tilted at 20° than during typing using a keyboard tilted at 0°. The main findings suggest wrist posture near to neutral position caused lower changes of the median nerve. PMID:28701627

Impact of keyboard typing on the morphological changes of the median nerve.

PubMed

Yeap Loh, Ping; Liang Yeoh, Wen; Nakashima, Hiroki; Muraki, Satoshi

2017-09-28

The primary objective was to investigate the effects of continuous typing on median nerve changes at the carpal tunnel region at two different keyboard slopes (0° and 20°). The secondary objective was to investigate the differences in wrist kinematics and the changes in wrist anthropometric measurements when typing at the two different keyboard slopes. Fifteen healthy right-handed young men were recruited. A randomized sequence of the conditions (control, typing I, and typing II) was assigned to each participant. Wrist anthropometric measurements, wrist kinematics data collection and ultrasound examination to the median nerve was performed at designated time block. Typing activity and time block do not cause significant changes to the wrist anthropometric measurements. The wrist measurements remained similar across all the time blocks in the three conditions. Subsequently, the wrist extensions and ulnar deviations were significantly higher in both the typing I and typing II conditions than in the control condition for both wrists (p<0.05). Additionally, the median nerve cross-sectional area (MNCSA) significantly increased in both the typing I and typing II conditions after the typing task than before the typing task. The MNCSA significantly decreased in the recovery phase after the typing task. This study demonstrated the immediate changes in the median nerve after continuous keyboard typing. Changes in the median nerve were greater during typing using a keyboard tilted at 20° than during typing using a keyboard tilted at 0°. The main findings suggest wrist posture near to neutral position caused lower changes of the median nerve.

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

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

PubMed

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

2015-09-01

A treatment regimen consisting of HI-6, levetiracetam, and procyclidine (termed the triple regimen) has previously been shown to work as a universal therapy against soman poisoning in rats, since it has capacities to function as both prophylactic and therapeutic measure. The purpose of the present study was to examine whether the triple regimen may have antidotal efficacy against intoxication by other classical nerve agents than soman. The treatment was given 1 and 5 min after exposure to a supralethal dose of nerve agents, and the results showed that the triple regimen successfully prevented or terminated seizures and preserved the lives of rats exposed to 5×LD50 of soman, sarin, cyclosarin, or VX, but solely 3×LD50 of tabun was managed by this regimen. To meet the particular antidotal requirements of tabun, the triple regimen was reinforced with obidoxime and was made to a quadruple regimen that effectively treated rats intoxicated by 5×LD50 of tabun. The rats recovered very well and the majority gained pre-exposure body weight within 7 days. Neuropathology was seen in all groups regardless of whether the rats seized or not. The most extensive damage was produced by sarin and cyclosarin. Differentiation between the nerve agents' potency to cause lesions was probably seen because the efficacious treatments ensured survival of supralethal poisoning. A combination of 2 oximes and 2 anticonvulsants may be a prerequisite to counteract effectively high levels of poisoning by any classical nerve agent. Copyright © 2015 Elsevier Inc. All rights reserved.

APOBEC3G: a Double Agent in Defense

PubMed Central

Smith, Harold C.

2011-01-01

APOBEC3G (A3G) is an effective cellular host defense factor under experimental conditions in which a functional form of the HIV-encoded protein Vif cannot be expressed. Wild type Vif targets A3G for proteasomal degradation and along with it, any host defense advantage A3G might provide is severely diminished or lost. Recent evidence cast doubt on the potency of A3G in host defense and suggested that it could, under some circumstances, promote the emergence of more virulent HIV strains. In this article, I argue that it is time to recognize that A3G has the potential to act as a double agent. The path forward relies on understanding how cellular and viral regulatory mechanisms enable A3G antiviral function and on developing novel research reagents to explore these pathways. PMID:21239176

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

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

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.

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 ...

CORRELATION BETWEEN MARKERS OF PERIPHERAL NERVE FUNCTION AND STRUCTURE IN TYPE 1 DIABETES.

PubMed

Borire, Adeniyi A; Issar, Tushar; Kwai, Natalie C; Visser, Leo H; Simon, Neil G; Poynten, Ann M; Kiernan, Matthew C; Krishnan, Arun V

2018-06-01

Clinical and experimental studies in patients with type 1 and type 2 diabetes have demonstrated changes in ion channel function and nerve structure. In this study, we investigated the relationship between axonal dysfunction and morphological change in diabetic polyneuropathy using neuromuscular ultrasound and nerve excitability techniques. We also explored possible differences in this relationship between type 1 and type 2 diabetes. Nerve ultrasound and corresponding motor excitability studies were undertaken in 110 diabetes patients (50 type 1;60 type 2) and 60 age-matched controls (30 for each group). Neuropathy severity was assessed using Total Neuropathy Score. Median and tibial nerve cross-sectional areas were measured at non-entrapment sites using high resolution linear probe. Median and tibial nerve cross-sectional areas were significantly higher in diabetes patients compared to controls: Type1 (Median=7.6±0.2mm 2 vs. 6.3±0.1mm 2 ; Tibial=14.5±0.7mm 2 vs. 10.8±0.3mm 2 ,p<0.05) and Type 2 (Median=9.1±0.3mm 2 vs. 7.2±0.1mm 2 ; Tibial=18.5±1.0mm 2 vs. 12.8±0.5mm 2 ,p<0.05). In the type 1 cohort, significant correlations were found between nerve cross-sectional area and excitability parameters including resting current-threshold slope (Median: r=0.523,p<0.0001; Tibial: r=-0.571,p=0.004) and depolarizing threshold electrotonus at 90-100ms (Median: 0.424,p<0.01; Tibial: r=0.435,p=0.030). In contrast, there was no relationship between excitability values and nerve cross-sectional area in the type 2 cohort. This study has identified correlation between markers of axonal membrane function and structural abnormalities in peripheral nerves of type 1 diabetes patients. The differential relationship in nerve function and structure between Type 1 and Type 2 diabetes provides clinical evidence that different pathophysiological mechanisms underlie the development of neuropathy in these patient groups. This article is protected by copyright. All rights reserved.

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

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.

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.

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

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

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

Loss of G2 subunit of vacuolar-type proton transporting ATPase leads to G1 subunit upregulation in the brain

PubMed Central

Kawamura, Nobuyuki; Sun-Wada, Ge-Hong; Wada, Yoh

2015-01-01

Vacuolar-type ATPase (V-ATPase) is a primary proton pump with versatile functions in various tissues. In nerve cells, V-ATPase is required for accumulation of neurotransmitters into secretory vesicles and subsequent release at the synapse. Neurons express a specific isoform (G2) of the G subunit of V-ATPase constituting the catalytic sector of the enzyme complex. Using gene targeting, we generated a mouse lacking functional G2 (G2 null), which showed no apparent disorders in architecture and behavior. In the G2-null mouse brain, a G1 subunit isoform, which is ubiquitously expressed in neuronal and non-neuronal tissues, accumulated more abundantly than in wild-type animals. This G1 upregulation was not accompanied by an increase in mRNA. These results indicate that loss of function of neuron-specific G2 isoform was compensated by an increase in levels of the G1 isoform without apparent upregulation of the G1 mRNA. PMID:26353914

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

Different nerve ultrasound patterns in charcot-marie-tooth types and hereditary neuropathy with liability to pressure palsies.

PubMed

Padua, Luca; Coraci, Daniele; Lucchetta, Marta; Paolasso, Ilaria; Pazzaglia, Costanza; Granata, Giuseppe; Cacciavillani, Mario; Luigetti, Marco; Manganelli, Fiore; Pisciotta, Chiara; Piscosquito, Giuseppe; Pareyson, Davide; Briani, Chiara

2018-01-01

Nerve ultrasound in Charcot-Marie-Tooth (CMT) disease has focused mostly on the upper limbs. We performed an evaluation of a large cohort of CMT patients in which we sonographically characterized nerve abnormalities in different disease types, ages, and nerves. Seventy patients affected by different CMT types and hereditary neuropathy with liability to pressure palsies (HNPP) were evaluated, assessing median, ulnar, fibular, tibial, and sural nerves bilaterally. Data were correlated with age. Nerve dimensions were correlated with CMT type, age, and nerve site. Nerves were larger in demyelinating than in axonal neuropathies. Nerve involvement was symmetric. CMT1 patients had larger nerves than did patients with other CMT types. Patients with HNPP showed enlargement at entrapment sites. Our study confirms the general symmetry of ultrasound nerve patterns in CMT. When compared with ultrasound studies of nerves of the upper limbs, evaluation of the lower limbs did not provide additional information. Muscle Nerve 57: E18-E23, 2018. © 2017 Wiley Periodicals, Inc.

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

Comparison of Extracellular Striatal Acetylcholine and Brain Seizure Activity Following Acute Exposure to the Nerve Agents Cyclosarin and Tabun in Freely Moving Guinea Pigs

DTIC Science & Technology

2010-01-01

Literature 3. DATES COVERED (From - To) 4. TITLE AND SUBTITLE Comparison of extracellular striatal acetylcholine and brain seizure activity following...lethality; nerve agents; organophosphorus compounds; seizure activity ; tabun 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER...acetylcholine and brain seizure activity following acute exposure to the nerve agents cyclosarin and tabun in freely moving guinea pigs John C

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.

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

DTIC Science & Technology

2013-01-01

times the median lethal dose (LD50) of the OP nerve agents tabun (GA), sarin (GB), soman (GD), and cyclosarin (GF), or chlorpyrifos oxon, the toxic...metabolite of the OP pesticide chlorpyrifos . In the second model, mice were infected with an adenovirus that induced expression of HuPON1 and then...mice are dramati- cally more susceptible to the toxic metabolites of the OP pesticides diazinon and chlorpyrifos (diazoxon and chlorpyrifos oxon

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.

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.

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

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

Types of neural guides and using nanotechnology for peripheral nerve reconstruction

PubMed Central

Biazar, Esmaeil; Khorasani, MT; Montazeri, Naser; Pourshamsian, Khalil; Daliri, Morteza; T, Mostafa Rezaei; B, Mahmoud Jabarvand; Khoshzaban, Ahad; K, Saeed Heidari; Jafarpour, Mostafa; Roviemiab, Ziba

2010-01-01

Peripheral nerve injuries can lead to lifetime loss of function and permanent disfigurement. Different methods, such as conventional allograft procedures and use of biologic tubes present problems when used for damaged peripheral nerve reconstruction. Designed scaffolds comprised of natural and synthetic materials are now widely used in the reconstruction of damaged tissues. Utilization of absorbable and nonabsorbable synthetic and natural polymers with unique characteristics can be an appropriate solution to repair damaged nerve tissues. Polymeric nanofibrous scaffolds with properties similar to neural structures can be more effective in the reconstruction process. Better cell adhesion and migration, more guiding of axons, and structural features, such as porosity, provide a clearer role for nanofibers in the restoration of neural tissues. In this paper, basic concepts of peripheral nerve injury, types of artificial and natural guides, and methods to improve the performance of tubes, such as orientation, nanotechnology applications for nerve reconstruction, fibers and nanofibers, electrospinning methods, and their application in peripheral nerve reconstruction are reviewed. PMID:21042546

QUANTITATIVE ASSESSMENT OF INTEGRATED PHRENIC NERVE ACTIVITY

PubMed Central

Nichols, Nicole L.; Mitchell, Gordon S.

2016-01-01

Integrated electrical activity in the phrenic nerve is commonly used to assess within-animal changes in phrenic motor output. Because of concerns regarding the consistency of nerve recordings, activity is most often expressed as a percent change from baseline values. However, absolute values of nerve activity are necessary to assess the impact of neural injury or disease on phrenic motor output. To date, no systematic evaluations of the repeatability/reliability have been made among animals when phrenic recordings are performed by an experienced investigator using standardized methods. We performed a meta-analysis of studies reporting integrated phrenic nerve activity in many rat groups by the same experienced investigator; comparisons were made during baseline and maximal chemoreceptor stimulation in 14 wild-type Harlan and 14 Taconic Sprague Dawley groups, and in 3 pre-symptomatic and 11 end-stage SOD1G93A Taconic rat groups (an ALS model). Meta-analysis results indicate: 1) consistent measurements of integrated phrenic activity in each sub-strain of wild-type rats; 2) with bilateral nerve recordings, left-to-right integrated phrenic activity ratios are ~1.0; and 3) consistently reduced activity in end-stage SOD1G93A rats. Thus, with appropriate precautions, integrated phrenic nerve activity enables robust, quantitative comparisons among nerves or experimental groups, including differences caused by neuromuscular disease. PMID:26724605

Quantitative assessment of integrated phrenic nerve activity.

PubMed

Nichols, Nicole L; Mitchell, Gordon S

2016-06-01

Integrated electrical activity in the phrenic nerve is commonly used to assess within-animal changes in phrenic motor output. Because of concerns regarding the consistency of nerve recordings, activity is most often expressed as a percent change from baseline values. However, absolute values of nerve activity are necessary to assess the impact of neural injury or disease on phrenic motor output. To date, no systematic evaluations of the repeatability/reliability have been made among animals when phrenic recordings are performed by an experienced investigator using standardized methods. We performed a meta-analysis of studies reporting integrated phrenic nerve activity in many rat groups by the same experienced investigator; comparisons were made during baseline and maximal chemoreceptor stimulation in 14 wild-type Harlan and 14 Taconic Sprague Dawley groups, and in 3 pre-symptomatic and 11 end-stage SOD1(G93A) Taconic rat groups (an ALS model). Meta-analysis results indicate: (1) consistent measurements of integrated phrenic activity in each sub-strain of wild-type rats; (2) with bilateral nerve recordings, left-to-right integrated phrenic activity ratios are ∼1.0; and (3) consistently reduced activity in end-stage SOD1(G93A) rats. Thus, with appropriate precautions, integrated phrenic nerve activity enables robust, quantitative comparisons among nerves or experimental groups, including differences caused by neuromuscular disease. Copyright © 2015 Elsevier B.V. All rights reserved.

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

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...

Modeling neuropeptide transport in various types of nerve terminals containing en passant boutons.

PubMed

Kuznetsov, I A; Kuznetsov, A V

2015-03-01

We developed a mathematical model for simulating neuropeptide transport inside dense core vesicles (DCVs) in axon terminals containing en passant boutons. The motivation for this research is a recent experimental study by Levitan and colleagues (Bulgari et al., 2014) which described DCV transport in nerve terminals of type Ib and type III as well as in nerve terminals of type Ib with the transcription factor DIMM. The goal of our modeling is validating the proposition put forward by Levitan and colleagues that the dramatic difference in DCV number in type Ib and type III terminals can be explained by the difference in DCV capture in type Ib and type III boutons rather than by differences in DCV anterograde transport and half-life of resident DCVs. The developed model provides a tool for studying the dynamics of DCV transport in various types of nerve terminals. The model is also an important step in gaining a better mechanistic understanding of transport processes in axons and identifying directions for the development of new models in this area. Copyright © 2014 Elsevier Inc. All rights reserved.

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

PubMed

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

2012-11-01

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

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

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.

External laryngeal nerve in thyroid surgery: is the nerve stimulator necessary?

PubMed

Aina, E N; Hisham, A N

2001-09-01

To find out the incidence and type of external laryngeal nerves during operations on the thyroid, and to assess the role of a nerve stimulator in detecting them. Prospective, non-randomised study. Teaching hospital, Malaysia. 317 patients who had 447 dissections between early January 1998 and late November 1999. Number and type of nerves crossing the cricothyroid space, and the usefulness of the nerve stimulator in finding them. The nerve stimulator was used in 206/447 dissections (46%). 392 external laryngeal nerves were seen (88%), of which 196/206 (95%) were detected with the stimulator. However, without the stimulator 196 nerves were detected out of 241 dissections (81%). The stimulator detected 47 (23%) Type I nerves (nerve > 1 cm from the upper edge of superior pole); 86 (42%) Type IIa nerves (nerve < 1 cm from the upper edge of superior pole); and 63 (31%) Type IIb nerves (nerve below upper edge of superior pole). 10 nerves were not detected. When the stimulator was not used the corresponding figures were 32 (13%), 113 (47%), and 51 (21%), and 45 nerves were not seen. If the nerve cannot be found we recommend dissection of capsule close to the medial border of the upper pole of the thyroid to avoid injury to the nerve. Although the use of the nerve stimulator seems desirable, it confers no added advantage in finding the nerve. In the event of uncertainty about whether a structure is the nerve, the stimulator may help to confirm it. However, exposure of the cricothyroid space is most important for good exposure in searching for the external laryngeal nerve.

Morphological and immunohistochemical comparison of intrapancreatic nerves between chronic pancreatitis and type 1 autoimmune pancreatitis.

PubMed

Kato, Kota; Ikeura, Tsukasa; Yanagawa, Masato; Tomiyama, Takashi; Fukui, Toshiro; Uchida, Kazushige; Takaoka, Makoto; Nishio, Akiyoshi; Uemura, Yoshiko; Satoi, Sohei; Yamada, Hisao; Okazaki, Kazuichi

The abdominal pain associated with chronic pancreatitis (CP) may be related to the increased number and size of intrapancreatic nerves. On the other hand, patients with type 1 autoimmune pancreatitis (AIP) rarely suffer from the pain syndrome, and there are no previous studies concerning the histopathological findings of intrapancreatic nerves in patients with type 1 AIP. The current study is aimed at investigating the differences in the histopathological and immunohistochemical findings of intrapancreatic nerves in patients with CP and type 1 AIP. Neuroanatomical differences between CP and type 1 AIP were assessed by immunostaining with a pan-neuronal marker, protein gene product 9.5 (PGP9.5). The number (neural density) and area (neural hypertrophy) of PGP9.5-immunopositive nerves were quantitatively analyzed. Furthermore, the expression of nerve growth factor (NGF), and a high affinity receptor for NGF, tyrosine kinase receptor A (TrkA), was assessed by immunohistochemistry. Both neural density and hypertrophy were significantly greater in pancreatic tissue samples from patients with CP than those with normal pancreas or type 1 AIP. NGF expression was stronger in type 1 AIP than in CP, whereas TrkA expression in type 1 AIP was poorer than in CP. Although CP and type 1 AIP are both characterized by the presence of sustained pancreatic inflammation, they are different in terms of the density and hypertrophy of intrapancreatic nerve fibers. It is possible that this may be related to the difference in the activity of the NGF/TrkA-pathway between the two types of pancreatitis. Copyright © 2017 IAP and EPC. Published by Elsevier B.V. All rights reserved.

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

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

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.

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.

Effect of diet induced obesity or type 1 or type 2 diabetes on corneal nerves and peripheral neuropathy in C57Bl/6J mice

PubMed Central

Yorek, Matthew S.; Obrosov, Alexander; Shevalye, Hanna; Holmes, Amey; Harper, Matthew M.; Kardon, Randy H.; Yorek, Mark A.

2015-01-01

We determined the impact diet induced obesity (DIO) and types 1 and 2 diabetes has on peripheral neuropathy with emphasis on corneal nerve structural changes in C57Bl/6J mice. Endpoints examined included nerve conduction velocity, response to thermal and mechanical stimuli and innervation of the skin and cornea. DIO mice and to a greater extent type 2 diabetic mice were insulin resistant. DIO and both types 1 and 2 diabetic mice developed motor and sensory nerve conduction deficits. In the cornea of DIO and type 2 diabetic mice there was a decrease in sub-epithelial corneal nerves, innervation of the corneal epithelium and corneal sensitivity. Type 1 diabetic mice did not present with any significant changes in corneal nerve structure until after 20 weeks of hyperglycemia. DIO and type 2 diabetic mice developed corneal structural damage more rapidly than type 1 diabetic mice even though hemoglobin A1C values were significantly higher in type 1 diabetic mice. This suggests that DIO with or without hyperglycemia contributes to development and progression of peripheral neuropathy and nerve structural damage in the cornea. PMID:25858759

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

PubMed

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

2010-11-01

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

[Changes in facial nerve function, morphology and neurotrophic factor III expression following three types of facial nerve injury].

PubMed

Zhang, Lili; Wang, Haibo; Fan, Zhaomin; Han, Yuechen; Xu, Lei; Zhang, Haiyan

2011-01-01

To study the changes in facial nerve function, morphology and neurotrophic factor III (NT-3) expression following three types of facial nerve injury. Changes in facial nerve function (in terms of blink reflex (BF), vibrissae movement (VM) and position of nasal tip) were assessed in 45 rats in response to three types of facial nerve injury: partial section of the extratemporal segment (group one), partial section of the facial canal segment (group two) and complete transection of the facial canal segment lesion (group three). All facial nerves specimen were then cut into two parts at the site of the lesion after being taken from the lesion site on 1st, 7th, 21st post-surgery-days (PSD). Changes of morphology and NT-3 expression were evaluated using the improved trichrome stain and immunohistochemistry techniques ,respectively. Changes in facial nerve function: In group 1, all animals had no blink reflex (BF) and weak vibrissae movement (VM) at the 1st PSD; The blink reflex in 80% of the rats recovered partly and the vibrissae movement in 40% of the rats returned to normal at the 7th PSD; The facial nerve function in 600 of the rats was almost normal at the 21st PSD. In group 2, all left facial nerve paralyzed at the 1st PSD; The blink reflex partly recovered in 40% of the rats and the vibrissae movement was weak in 80% of the rats at the 7th PSD; 8000 of the rats'BF were almost normal and 40% of the rats' VM completely recovered at the 21st PSD. In group 3, The recovery couldn't happen at anytime. Changes in morphology: In group 1, the size of nerve fiber differed in facial canal segment and some of myelin sheath and axons degenerated at the 7th PSD; The fibres' degeneration turned into regeneration at the 21st PSD; In group 2, the morphologic changes in this group were familiar with the group 1 while the degenerated fibers were more and dispersed in transection at the 7th PSD; Regeneration of nerve fibers happened at the 21st PSD. In group 3, most of the fibers

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.

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

Granulocyte colony-stimulating factor (G-CSF) positive effects on muscle fiber degeneration and gait recovery after nerve lesion in MDX mice

PubMed Central

Simões, Gustavo F; Benitez, Suzana U; Oliveira, Alexandre L R

2014-01-01

Background G-CSF has been shown to decrease inflammatory processes and to act positively on the process of peripheral nerve regeneration during the course of muscular dystrophy. Aims The aims of this study were to investigate the effects of treatment of G-CSF during sciatic nerve regeneration and histological analysis in the soleus muscle in MDX mice. Methods Six-week-old male MDX mice underwent left sciatic nerve crush and were G-CSF treated at 7 days prior to and 21 days after crush. Ten and twenty-one days after surgery, the mice were euthanized, and the sciatic nerves were processed for immunohistochemistry (anti-p75NTR and anti-neurofilament) and transmission electron microscopy. The soleus muscles were dissected out and processed for H&E staining and subsequent morphologic analysis. Motor function analyses were performed at 7 days prior to and 21 days after sciatic crush using the CatWalk system and the sciatic nerve index. Results Both groups treated with G-CSF showed increased p75NTR and neurofilament expression after sciatic crush. G-CSF treatment decreased the number of degenerated and regenerated muscle fibers, thereby increasing the number of normal muscle fibers. Conclusions The reduction in p75NTR and neurofilament indicates a decreased regenerative capacity in MDX mice following a lesion to a peripheral nerve. The reduction in motor function in the crushed group compared with the control groups may reflect the cycles of muscle degeneration/regeneration that occur postnatally. Thus, G-CSF treatment increases motor function in MDX mice. Nevertheless, the decrease in baseline motor function in these mice is not reversed completely by G-CSF. PMID:25328849

Ultrasound assessment of peripheral nerve pathology in neurofibromatosis type 1 and 2.

PubMed

Winter, Natalie; Rattay, Tim W; Axer, Hubertus; Schäffer, Eva; Décard, Bernhard F; Gugel, Isabel; Schuhmann, Martin; Grimm, Alexander

2017-05-01

The neurofibromatoses (NF) type 1 and 2 are hereditary tumor predisposition syndromes caused by germline mutations in the NF1 and NF2 tumor suppressor genes. In NF1 and 2, peripheral nerve tumors occur regularly. For further characterizing nerve ultrasound was performed in patients with NF1 and 2. Patients with established diagnosis of NF1 (n=27) and NF2 (n=10) were included. Ultrasound of peripheral nerves and cervical roots was performed during routine follow-up visits. Healthy volunteers were studied for comparison. In patients with NF1, median cross-sectional area (CSA) of most nerves was significantly increased compared to controls and to NF2 due to generalized plexiform tumors, which arose out of multiple fascicles in 23 of 27 patients (85%). These were often accompanied by cutaneous or subcutaneous neurofibromas. In NF2, the overall aspect of peripheral nerves consisted of localized schwannomas (80%) and, apart from that, normal nerve segments. Nerve ultrasound is able to visualize different nerve pathologies in NF1 and NF2. It is a precise and inexpensive screening method for peripheral nerve manifestation in neurofibromatosis and should be considered as the first choice screening imaging modality for all peripheral nerves within reach of non-invasive ultrasound techniques. Ultrasound patterns of peripheral nerve pathologies are described for the first time in a large cohort of patients with NF1 and NF2. It is a suitable screening tool and enables targeted MRI analysis. Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

The role of the oximes HI-6 and HS-6 inside human acetylcholinesterase inhibited with nerve agents: a computational study.

PubMed

Cuya, Teobaldo; Gonçalves, Arlan da Silva; da Silva, Jorge Alberto Valle; Ramalho, Teodorico C; Kuca, Kamil; C C França, Tanos

2017-10-27

The oximes 4-carbamoyl-1-[({2-[(E)-(hydroxyimino) methyl] pyridinium-1-yl} methoxy) methyl] pyridinium (known as HI-6) and 3-carbamoyl-1-[({2-[(E)-(hydroxyimino) methyl] pyridinium-1-yl} methoxy) methyl] pyridinium (known as HS-6) are isomers differing from each other only by the position of the carbamoyl group on the pyridine ring. However, this slight difference was verified to be responsible for big differences in the percentual of reactivation of acetylcholinesterase (AChE) inhibited by the nerve agents tabun, sarin, cyclosarin, and VX. In order to try to find out the reason for this, a computational study involving molecular docking, molecular dynamics, and binding energies calculations, was performed on the binding modes of HI-6 and HS-6 on human AChE (HssAChE) inhibited by those nerve agents.

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.

Motor unit and muscle fiber type grouping after peripheral nerve injury in the rat.

PubMed

Gordon, Tessa; de Zepetnek, Joanne E Totosy

2016-11-01

Muscle unit (MU) fibers innervated by one motoneuron and corresponding muscle fiber types are normally distributed in a mosaic. We asked whether, 4-8months after common peroneal nerve transection and random surgical alignment of nerve stumps in rat tibialis anterior muscles 1) reinnervated MU muscle and muscle fiber type clumping is invariant and 2) slow and fast motoneurons regenerate their nerve fibers within original endoneurial pathways. MU contractile forces were recorded in vivo, the MUs classified into types according to their contractile speed and fatigability, and one MU subjected to alternate exhaustive stimulation-recovery cycles to deplete glycogen for histochemical MU fiber recognition and enumeration, and muscle fiber typing. MU muscle fibers occupied defined territories whose size increased with MU force and muscle fiber numbers in normal and reinnervated muscles. The reinnervated MU muscle fiber territories were significantly smaller, the fibers clumped within 1-3 groups in 90% of the MUs, and each fiber lying adjacent to another significantly more frequently. Most reinnervated slow muscle fibers were normally located in the deep muscle compartment but substantial numbers were located abnormally in the superficial compartment. Our findings that well reinnervated muscle fibers clump in small muscles contrast with our earlier findings of clumping in large muscles only when reinnervated MU numbers were significantly reduced. We conclude that fiber type clumping is predictive of muscle reinnervation in small but not large muscles. In the latter muscles, clumping is more indicative of sprouting after partial nerve injuries than of muscle reinnervation after complete nerve injuries. Copyright © 2016 Elsevier Inc. All rights reserved.

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

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

Use of nerve conduits for peripheral nerve injury repair: A Web of Science-based literature analysis.

PubMed

Nan, Jinniang; Hu, Xuguang; Li, Hongxiu; Zhang, Xiaonong; Piao, Renjing

2012-12-15

To identify global research trends in the use of nerve conduits for peripheral nerve injury repair. Numerous basic and clinical studies on nerve conduits for peripheral nerve injury repair were performed between 2002-2011. We performed a bibliometric analysis of the institutions, authors, and hot topics in the field, from the Web of Science, using the key words peripheral nerve and conduit or tube. peer-reviewed published articles on nerve conduits for peripheral nerve injury repair, indexed in the Web of Science; original research articles, reviews, meeting abstracts, proceedings papers, book chapters, editorial material, and news items. articles requiring manual searching or telephone access; documents not published in the public domain; and several corrected papers. (a) Annual publication output; (b) publication type; (c) publication by research field; (d) publication by journal; (e) publication by funding agency; (f) publication by author; (g) publication by country and institution; (h) publications by institution in China; (i) most-cited papers. A total of 793 publications on the use of nerve conduits for peripheral nerve injury repair were retrieved from the Web of Science between 2002-2011. The number of publications gradually increased over the 10-year study period. Articles constituted the main type of publication. The most prolific journals were Biomaterials, Microsurgery, and Journal of Biomedical Materials Research Part A. The National Natural Science Foundation of China supported 27 papers, more than any other funding agency. Of the 793 publications, almost half came from American and Chinese authors and institutions. Nerve conduits have been studied extensively for peripheral nerve regeneration; however, many problems remain in this field, which are difficult for researchers to reach a consensus.

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

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

Early Corneal Cellular and Nerve Fiber Pathology in Young Patients With Type 1 Diabetes Mellitus Identified Using Corneal Confocal Microscopy.

PubMed

Szalai, Eszter; Deák, Eszter; Módis, László; Németh, Gábor; Berta, András; Nagy, Annamária; Felszeghy, Eniko; Káposzta, Rita; Malik, Rayaz A; Csutak, Adrienne

2016-03-01

The aim of this study was to quantify epithelial, stromal, and endothelial cell density, and subbasal nerve morphology in young patients with type 1 diabetes mellitus with and without diabetic retinopathy. A total of 28 young patients (mean age, 22.86 ± 9.05 years) with type 1 diabetes, with (n = 18) and without (n = 10) retinopathy, and 17 age-matched healthy control subjects (mean age, 26.53 ± 2.43 years) underwent corneal confocal microscopy (CCM). We found significantly lower epithelial (P < 0.0001) and endothelial (P = 0.001) cell densities and higher keratocyte cell density (P = 0.024) in patients with type 1 diabetes compared to controls. Significantly lower corneal nerve fiber density (P = 0.004), nerve branch density (P = 0.004), total nerve branch density (P = 0.04), and nerve fiber length (P = 0.001), and greater nerve fiber width (P = 0.04) were observed in patients with type 1 diabetes compared to control subjects. Significantly lower epithelial (P < 0.001) and endothelial (P = 0.02) cell densities, nerve branch density (P = 0.02), and nerve fiber length (P = 0.04), and significantly higher keratocyte cell density (P = 0.02) were found in patients with type 1 diabetes without retinopathy compared to control subjects. Corneal confocal microscopy identifies corneal cellular and small nerve fiber pathology in young patients with type 1 diabetes without retinopathy, which increases in severity in those with retinopathy. Corneal confocal microscopy appears to have considerable use as an imaging biomarker for early subclinical pathology in young patients with type 1 diabetes mellitus.

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

Extralaryngeal division of the recurrent laryngeal nerve: a new description for the inferior laryngeal nerve.

PubMed

Yalcin, Bulent; Tunali, Selcuk; Ozan, Hasan

2008-05-01

Extralaryngeal division of the recurrent laryngeal nerve was contradictory in the literature. We aimed to investigate extralaryngeal division of the nerve, and also propose a new description for the inferior laryngeal nerve. Sixty specimens (120 sides) were examined for this project, including 41 men and 19 women cadavers between the ages of 40 and 89 years at death. In one right side, terminal segment of the nerve gave off many small branches surrounding the inferior thyroid artery then reaching the larynx, trachea, thyroid gland and esophagus. In eight sides, terminal segment of the nerve had no extralaryngeal division and entered the larynx as a single trunk. In 110 sides, the nerve had extralaryngeal division. One hundred and three nerves had two laryngeal and one to three extralaryngeal branches. Two types were described in this group. In type I (66 nerves), both branches arose from the same level of nerve. Type I had two subtypes: type Ia, the origin of the branches was just below the inferior constrictor muscle; type Ib, the origin of the branches was 15-35 mm below the muscle. In type II (37 nerves), the laryngeal branches arose just 3-5 mm above the extralaryngeal branches. We observed that the laryngeal and extralaryngeal branches arose generally from the same point of the recurrent laryngeal nerve. The inferior laryngeal nerve is thus very short, or even nonexistent. Therefore, we suggest that if the term "superior laryngeal nerve" is a given, standard, and accepted term, then the term "inferior laryngeal nerve" should also be accepted instead of the term "recurrent laryngeal nerve."

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

PubMed

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

2006-05-01

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

Peripheral nerve blocks in patients with Ehlers-Danlos syndrome, hypermobility type: a report of 2 cases.

PubMed

Patzkowski, Michael S

2016-03-01

Ehlers-Danlos syndrome is an inherited disorder of collagen production that results in multiorgan dysfunction. Patients with hypermobility type display skin hyperextensibility and joint laxity, which can result in chronic joint instability, dislocation, peripheral neuropathy, and severe musculoskeletal pain. A bleeding diathesis can be found in all subtypes of varying severity despite a normal coagulation profile. There have also been reports of resistance to local anesthetics in these patients. Several sources advise against the use of regional anesthesia in these patients citing the 2 previous features. There have been reports of successful neuraxial anesthesia, but few concerning peripheral nerve blocks, none of which describe nerves of the lower extremity. This report describes 2 cases of successful peripheral regional anesthesia in the lower extremity. In case 1, a 16-year-old adolescent girl with hypermobility type presented for osteochondral grafting of tibiotalar joint lesions. She underwent a popliteal sciatic (with continuous catheter) and femoral nerve block under ultrasound guidance. She proceeded to surgery and tolerated the procedure under regional block and intravenous sedation. She did not require any analgesics for the following 15 hours. In case 2, an 18-year-old woman with hypermobility type presented for medial patellofemoral ligament reconstruction for chronic patella instability. She underwent a saphenous nerve block above the knee with analgesia in the distribution of the saphenous nerve lasting for approximately 18 hours. There were no complications in either case. Prohibitions against peripheral nerve blocks in patients with Ehlers-Danlos syndrome, hypermobility type, appear unwarranted. Published by Elsevier Inc.

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.

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

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.

Complex regional pain syndrome type I (RSD): pathology of skeletal muscle and peripheral nerve.

PubMed

van der Laan, L; ter Laak, H J; Gabreëls-Festen, A; Gabreëls, F; Goris, R J

1998-07-01

Reflex sympathetic dystrophy (RSD) (recently reclassified as complex regional pain syndrome type I) is a syndrome occurring in extremities and, when chronic, results in severe disability and untractable pain. RSD may be accompanied by neurologic symptoms even when there is no previous neurologic lesion. There is no consensus as to the pathogenic mechanism involved in RSD. To gain insight into the pathophysiology of RSD, we studied histopathology of skeletal muscle and peripheral nerve from patients with chronic RSD in a lower extremity. In eight patients with chronic RSD, an above-the-knee amputation was performed because of a nonfunctional limb. Specimens of sural nerves, tibial nerves, common peroneal nerves, gastrocnemius muscles, and soleus muscles were obtained from the amputated legs and analyzed by light and electron microscopy. In all patients, the affected leg showed similar neurologic symptoms such as spontaneous pain, hyperpathy, allodynia, paresis, and anesthesia dolorosa. The nerves showed no consistent abnormalities of myelinated fibers. In four patients, the C-fibers showed electron microscopic pathology. In all patients, the gastrocnemius and soleus muscle specimens showed a decrease of type I fibers, an increase of lipofuscin pigment, atrophic fibers, and severely thickened basal membrane layers of the capillaries. In chronic RSD, efferent nerve fibers were histologically unaffected; from afferent fibers, only C-fibers showed histopathologic abnormalities. Skeletal muscle showed a variety of histopathologic findings, which are similar to the histologic abnormalities found in muscles of patients with diabetes.

The relationship between the fistula tract and the facial nerve in type II first branchial cleft anomalies.

PubMed

Ertas, Burak; Gunaydin, Rıza Onder; Unal, Omer Faruk

2015-04-01

To share our experience involving seven patients with type II first branchial cleft anomalies (hereafter, type II anomalies), to determine whether the location of the external fistula openings of the anomalies are associated with the location of the facial nerve tract, and elucidate the relationship between the location of the fistula opening and the facial nerve. The medical records of seven patients who underwent surgery from 2005 to 2013 for type II anomalies were retrospectively examined. The relationship between the fistula opening and the facial nerve was evaluated in each patient with respect to whether the fistula opening was superior or inferior to the mandibular angle. All patients underwent partial parotidectomy, facial nerve exposure, and total excision of the mass together with connection of a small cuff of the external auditory canal skin to the fistula tract. The fistula tracts were located medially to the facial nerve in two patients, and both fistulae had openings inferior to the mandibular angle. The fistula tracts were located laterally to the facial nerve in the remaining five patients: one patient had no external opening, one had an opening inferior to the mandibular angle, and the remaining three had openings superior to the mandibular angle. Because type II anomalies are rare, their diagnosis is difficult. Surgery of such lesions is challenging and associated with a high risk due to their proximity to the facial nerve. We believe that the location of the fistula opening may help to identify the relationship between the anomalous lesion and facial nerve. Studies involving larger series of cases are needed to confirm our hypothesis; however, because of the rarity of this specific anomaly, it will not be easy to compile a large number of cases. We believe that our study will encourage further investigation on this subject. Copyright © 2014. Published by Elsevier Ireland Ltd.

Identification of V-type nerve agents in vapor samples using a field-portable capillary gas chromatography/membrane-interfaced electron ionization quadrupole mass spectrometry instrument with Tri-Bed concentrator and fluoridating conversion tube.

PubMed

Ohrui, Y; Nagoya, T; Kurimata, N; Sodeyama, M; Seto, Y

2017-07-01

A field-portable gas chromatography-mass spectrometry (GC-MS) system (Hapsite ER) was evaluated for the detection of nonvolatile V-type nerve agents (VX and Russian VX (RVX)) in the vapor phase. The Hapsite ER system consists of a Tri-Bed concentrator gas sampler, a nonpolar low thermal-mass capillary GC column and a hydrophobic membrane-interfaced electron ionization quadrupole mass spectrometer evacuated by a non-evaporative getter pump. The GC-MS system was attached to a VX-G fluoridating conversion tube containing silver nitrate and potassium fluoride. Sample vapors of VX and RVX were converted into O-ethyl methylphosphonofluoridate (EtGB) and O-isobutyl methylphosphonofluoridate (iBuGB), respectively. These fluoridated derivatives were detected within 10 min. No compounds were detected when the VX and RVX samples were analyzed without the conversion tube. A vapor sample of tabun (GA) was analyzed, in which GA and O-ethyl N,N-dimethylphosphoramidofluoridate were detected. The molar recovery percentages of EtGB and iBuGB from VX and RVX vapors varied from 0.3 to 17%, which was attributed to variations in the vaporization efficiency of the glass vapor container. The conversion efficiencies of the VX-G conversion tube for VX and RVX to their phosphonate derivatives were estimated to be 40%. VX and RVX vapors were detected at concentrations as low as 0.3 mg m -3 . Gasoline vapor was found to interfere with the analyses of VX and RVX. In the presence of 160 mg m -3 gasoline, the detection limits of VX and RVX vapor were increased to 20 mg m -3 . Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Peripheral nerve block in patients with Ehlers-Danlos syndrome, hypermobility type: a case series.

PubMed

Neice, Andrew E; Stubblefield, Eryn E; Woodworth, Glenn E; Aziz, Michael F

2016-09-01

Ehlers-Danlos syndrome (EDS) is an inherited disease characterized by defects in various collagens or their post translational modification, with an incidence estimated at 1 in 5000. Performance of peripheral nerve block in patients with EDS is controversial, due to easy bruising and hematoma formation after injections as well as reports of reduced block efficacy. The objective of this study was to review the charts of EDS patients who had received peripheral nerve block for any evidence of complications or reduced efficacy. Case series, chart review. Academic medical center. Patients with a confirmed or probable diagnosis of EDS who had received a peripheral nerve block in the last 3 years were identified by searching our institutions electronic medical record system. The patients were classified by their subtype of EDS. Patients with no diagnosed subtype were given a probable subtype based on a chart review of the patient's symptoms. Patient charts were reviewed for any evidence of complications or reduced block efficacy. A total of 21 regional anesthetics, on 16 unique patients were identified, 10 of which had a EDS subtype diagnosis. The majority of these patients had a diagnosis of hypermobility-type EDS. No block complications were noted in any patients. Two block failures requiring repeat block were noted, and four patients reported uncontrolled pain on postoperative day one despite successful placement of a peripheral nerve catheter. Additionally, blocks were performed without incident in patients with classical-type and vascular-type EDS although the number was so small that no conclusions can be drawn about relative safety of regional anesthesia in these groups. This series fails to show an increased risk of complications of peripheral nerve blockade in patients with hypermobility-type EDS. Copyright © 2016 Elsevier Inc. All rights reserved.

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.

Hydrogel derived from porcine decellularized nerve tissue as a promising biomaterial for repairing peripheral nerve defects.

PubMed

Lin, Tao; Liu, Sheng; Chen, Shihao; Qiu, Shuai; Rao, Zilong; Liu, Jianghui; Zhu, Shuang; Yan, Liwei; Mao, Haiquan; Zhu, Qingtang; Quan, Daping; Liu, Xiaolin

2018-06-01

Decellularized matrix hydrogels derived from tissues or organs have been used for tissue repair due to their biocompatibility, tunability, and tissue-specific extracellular matrix (ECM) components. However, the preparation of decellularized peripheral nerve matrix hydrogels and their use to repair nerve defects have not been reported. Here, we developed a hydrogel from porcine decellularized nerve matrix (pDNM-G), which was confirmed to have minimal DNA content and retain collagen and glycosaminoglycans content, thereby allowing gelatinization. The pDNM-G exhibited a nanofibrous structure similar to that of natural ECM, and a ∼280-Pa storage modulus at 10 mg/mL similar to that of native neural tissues. Western blot and liquid chromatography tandem mass spectrometry analysis revealed that the pDNM-G consisted mostly of ECM proteins and contained primary ECM-related proteins, including fibronectin and collagen I and IV). In vitro experiments showed that pDNM-G supported Schwann cell proliferation and preserved cell morphology. Additionally, in a 15-mm rat sciatic nerve defect model, pDNM-G was combined with electrospun poly(lactic-acid)-co-poly(trimethylene-carbonate)conduits to bridge the defect, which did not elicit an adverse immune response and promoted the activation of M2 macrophages associated with a constructive remodeling response. Morphological analyses and electrophysiological and functional examinations revealed that the regenerative outcomes achieved by pDNM-G were superior to those by empty conduits and closed to those using rat decellularized nerve matrix allograft scaffolds. These findings indicated that pDNM-G, with its preserved ECM composition and nanofibrous structure, represents a promising biomaterial for peripheral nerve regeneration. Decellularized nerve allografts have been widely used to treat peripheral nerve injury. However, given their limited availability and lack of bioactive factors, efforts have been made to improve the efficacy

TGFbeta type II receptor signaling controls Schwann cell death and proliferation in developing nerves.

PubMed

D'Antonio, Maurizio; Droggiti, Anna; Feltri, M Laura; Roes, Jürgen; Wrabetz, Lawrence; Mirsky, Rhona; Jessen, Kristján R

2006-08-16

During development, Schwann cell numbers are precisely adjusted to match the number of axons. It is essentially unknown which growth factors or receptors carry out this important control in vivo. Here, we tested whether the type II transforming growth factor (TGF) beta receptor has a role in this process. We generated a conditional knock-out mouse in which the type II TGFbeta receptor is specifically ablated only in Schwann cells. Inactivation of the receptor, evident at least from embryonic day 18, resulted in suppressed Schwann cell death in normally developing and injured nerves. Notably, the mutants also showed a strong reduction in Schwann cell proliferation. Consequently, Schwann cell numbers in wild-type and mutant nerves remained similar. Lack of TGFbeta signaling did not appear to affect other processes in which TGFbeta had been implicated previously, including myelination and response of adult nerves to injury. This is the first in vivo evidence for a growth factor receptor involved in promoting Schwann cell division during development and the first genetic evidence for a receptor that controls normal developmental Schwann cell death.

Optic Nerve Disorders

MedlinePlus

The optic nerve is a bundle of more than 1 million nerve fibers that carry visual messages. You have one connecting ... retina) to your brain. Damage to an optic nerve can cause vision loss. The type of vision ...

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

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

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.

Cannabinoid Type 1 Receptors Transiently Silence Glutamatergic Nerve Terminals of Cultured Cerebellar Granule Cells

PubMed Central

Ramírez-Franco, Jorge; Bartolomé-Martín, David; Alonso, Beatris; Torres, Magdalena; Sánchez-Prieto, José

2014-01-01

Cannabinoid receptors are the most abundant G protein-coupled receptors in the brain and they mediate retrograde short-term inhibition of neurotransmitter release, as well as long-term depression of synaptic transmission at many excitatory synapses. The induction of presynaptically silent synapses is a means of modulating synaptic strength, which is important for synaptic plasticity. Persistent activation of cannabinoid type 1 receptors (CB1Rs) mutes GABAergic terminals, although it is unclear if CB1Rs can also induce silencing at glutamatergic synapses. Cerebellar granule cells were transfected with VGLUT1-pHluorin to visualise the exo-endocytotic cycle. We found that prolonged stimulation (10 min) of cannabinoid receptors with the agonist HU-210 induces the silencing of previously active synapses. However, the presynaptic silencing induced by HU-210 is transient as it reverses after 20 min. cAMP with forskolin prevented CB1R-induced synaptic silencing, via activation of the Exchange Protein directly Activated by cAMP (Epac). Furthermore, Epac activation accelerated awakening of already silent boutons. Electron microscopy revealed that silencing was associated with synaptic vesicle (SV) redistribution within the nerve terminal, which diminished the number of vesicles close to the active zone of the plasma membrane. Finally, by combining functional and immunocytochemical approaches, we observed a strong correlation between the release capacity of the nerve terminals and RIM1α protein content, but not that of Munc13-1 protein. These results suggest that prolonged stimulation of cannabinoid receptors can transiently silence glutamatergic nerve terminals. PMID:24533119

Low Peripheral Nerve Conduction Velocities and Amplitudes Are Strongly Related to Diabetic Microvascular Complications in Type 1 Diabetes

PubMed Central

Charles, Morten; Soedamah-Muthu, Sabita S.; Tesfaye, Solomon; Fuller, John H.; Arezzo, Joseph C.; Chaturvedi, Nishi; Witte, Daniel R.

2010-01-01

OBJECTIVE Slow nerve conduction velocity and reduction in response amplitude are objective hallmarks of diabetic sensorimotor polyneuropathy. Because subjective or clinical indicators of neuropathy do not always match well with the presence of abnormal nerve physiology tests, we evaluated associations to nerve conduction in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS Nerve conduction studies were performed in the distal sural and ulnar sensory nerves and the peroneal motor nerve in 456 individuals with type 1 diabetes who participated in the follow-up visit of the EURODIAB Prospective Complications Study (EPCS). We used multivariate regression models to describe associations to decreased nerve conduction measures. RESULTS In addition to an effect of duration of diabetes and A1C, which were both associated with low nerve conduction velocity and response amplitude, we found that the presence of nephropathy, retinopathy, or a clinical diagnosis of neuropathy was associated with low nerve conduction velocity and amplitude. In the case of nonproliferative retinopathy, the odds ratio (OR) for being in lowest tertile was 2.30 (95% CI 1.13–4.67) for nerve conduction velocity. A similar OR was found for each 2% difference in A1C (2.39 [1.68–3.41]). CONCLUSIONS We show that the presence of other microvascular diabetes complications, together with diabetes duration and A1C, are associated with low nerve conduction velocity and amplitude response and that cardiovascular disease or risk factors do not seem to be associated with these measures. PMID:20823346

Routine exposure of recurrent laryngeal nerve in thyroid surgery can prevent nerve injury.

PubMed

Shen, Chenling; Xiang, Mingliang; Wu, Hao; Ma, Yan; Chen, Li; Cheng, Lan

2013-06-15

To determine the value of dissecting the recurrent laryngeal nerve during thyroid surgery with respect to preventing recurrent laryngeal nerve injury, we retrospectively analyzed clinical data from 5 344 patients undergoing thyroidectomy. Among these cases, 548 underwent dissection of the recurrent laryngeal nerve, while 4 796 did not. There were 12 cases of recurrent laryngeal nerve injury following recurrent laryngeal nerve dissection (injury rate of 2.2%) and 512 cases of recurrent laryngeal nerve injury in those not undergoing nerve dissection (injury rate of 10.7%). This difference remained statistically significant between the two groups in terms of type of thyroid disease, type of surgery, and number of surgeries. Among the 548 cases undergoing recurrent laryngeal nerve dissection, 128 developed anatomical variations of the recurrent laryngeal nerve (incidence rate of 23.4%), but no recurrent laryngeal nerve injury was found. In addition, the incidence of recurrent laryngeal nerve injury was significantly lower in patients with the inferior parathyroid gland and middle thyroid veins used as landmarks for locating the recurrent laryngeal nerve compared with those with the entry of the recurrent laryngeal nerve into the larynx as a landmark. These findings indicate that anatomical variations of the recurrent laryngeal nerve are common, and that dissecting the recurrent laryngeal nerve during thyroid surgery is an effective means of preventing nerve injury.

Routine exposure of recurrent laryngeal nerve in thyroid surgery can prevent nerve injury★

PubMed Central

Shen, Chenling; Xiang, Mingliang; Wu, Hao; Ma, Yan; Chen, Li; Cheng, Lan

2013-01-01

To determine the value of dissecting the recurrent laryngeal nerve during thyroid surgery with respect to preventing recurrent laryngeal nerve injury, we retrospectively analyzed clinical data from 5 344 patients undergoing thyroidectomy. Among these cases, 548 underwent dissection of the recurrent laryngeal nerve, while 4 796 did not. There were 12 cases of recurrent laryngeal nerve injury following recurrent laryngeal nerve dissection (injury rate of 2.2%) and 512 cases of recurrent laryngeal nerve injury in those not undergoing nerve dissection (injury rate of 10.7%). This difference remained statistically significant between the two groups in terms of type of thyroid disease, type of surgery, and number of surgeries. Among the 548 cases undergoing recurrent laryngeal nerve dissection, 128 developed anatomical variations of the recurrent laryngeal nerve (incidence rate of 23.4%), but no recurrent laryngeal nerve injury was found. In addition, the incidence of recurrent laryngeal nerve injury was significantly lower in patients with the inferior parathyroid gland and middle thyroid veins used as landmarks for locating the recurrent laryngeal nerve compared with those with the entry of the recurrent laryngeal nerve into the larynx as a landmark. These findings indicate that anatomical variations of the recurrent laryngeal nerve are common, and that dissecting the recurrent laryngeal nerve during thyroid surgery is an effective means of preventing nerve injury. PMID:25206452

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

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

[The role of 2,3-DPG in nerve conduction of children with type 1 diabetes].

PubMed

Pańkowska, Ewa; Szypowska, Agnieszka; Wysocka, Marta; Lipka, Maria

2005-01-01

Neuropathy is one of the chronic complications of diabetes, and it is uncommon in children and adolescents. It can be recognized in a short period after the onset of diabetes and not always is connected with poor metabolic control. Hypoxia is considered as one from greatest factors diabetic neuropathy and oxygen transport to tissue partially depends on the diphosphoglycerate (2,3 DPG) concentration. As showed recent clinical studies, its concentration in children with diabetes can be abnormal. To assess the role of 2,3 DPG in nerve conduction velocity, as well as qualification of risk factors. To study were included randomly selected 37 patients with diabetes type 1, average age 15.5+/-2.25 years, with a duration of diabetes of more than 5 years (av 9.64+/-1.95 years), treated with intensive insulin therapy (MDI and CSII), without metabolic acidosis pH - 7.35. The nerve conduction velocity was measured in the sensor and motor nerves. HbA1c and 2,3 DPG were assessed additionally. Changes in motor nerve conduction velocity were observed at 22 patients. Average value of HbA1c in the studied group was 8.22+/-1.2%, Average concentration of 2,3 DPG was 6.15+/-1.67 mmol/l (3.84-11 mmol/l), in group with nerve dysfunction was lower - 5.86+/-1.69 mmol/l vs. 6.38+/-1.67, but this difference was not statistically significant. The lower value of 2,3 DPG significantly correlated with abnormal results of electroneurography test, especially with motor and sensor nerve latency (r=-0.34, p=0.038; r=-0.4, p=0.013) but not correlated with HbA1c (r= -0,19;p= 0,25), age of patients (r=0.008; p=0.96) and diabetes duration (r=-0.16; p=0.31). Nerve dysfunction is common in children with type 1 diabetes despite metabolic control and duration of diabetes. 2,3 DPG can be an independent factor of diabetes neuropathy correlated with abnormal value of the nerve conduction test.

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.

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.

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

The Expanded Bead Size of Corneal C-Nerve Fibers Visualized by Corneal Confocal Microscopy Is Associated with Slow Conduction Velocity of the Peripheral Nerves in Patients with Type 2 Diabetes Mellitus.

PubMed

Ishibashi, Fukashi; Kojima, Rie; Taniguchi, Miki; Kosaka, Aiko; Uetake, Harumi; Tavakoli, Mitra

2016-01-01

This study aims to establish the corneal nerve fiber (CNF) morphological alterations in a large cohort of type 2 diabetic patients and to investigate the association between the bead size, a novel parameter representing composite of accumulated mitochondria, glycogen particles, and vesicles in CNF, and the neurophysiological dysfunctions of the peripheral nerves. 162 type 2 diabetic patients and 45 healthy control subjects were studied in detail with a battery of clinical and neurological examinations and corneal confocal microscopy. Compared with controls, patients had abnormal CNF parameters. In particular the patients had reduced density and length of CNF and beading frequency and increased bead size. Alterations in CNF parameters were significant even in patients without neuropathy. The HbA1c levels were tightly associated with the bead size, which was inversely related to the motor and sensory nerve conduction velocity (NCV) and to the distal latency period of the median nerve positively. The CNF density and length positively correlated with the NCV and amplitude. The hyperglycemia-induced expansion of beads in CNF might be a predictor of slow NCV in peripheral nerves in type 2 diabetic patients.

Prevention and Treatment of Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors

DTIC Science & Technology

2015-04-01

AWARD NUMBER: W81XWH-14-1-0073 TITLE: Prevention and Treatment of Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath...Annual 3. DATES COVERED 1 Apr 2014 - 31 Mar 2015 4. TITLE AND SUBTITLE Prevention and Treatment of Neurofibromatosis Type 1- 5a. CONTRACT NUMBER...Public Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT The most common cause of death in Neurofibromatosis Type 1 (NF1) patients is

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.

Effect of Platelet-Rich Fibrin on Peripheral Nerve Regeneration.

PubMed

Şenses, Fatma; Önder, Mustafa E; Koçyiğit, Ismail D; Kul, Oğuz; Aydin, Gülümser; Inal, Elem; Atil, Fethi; Tekin, Umut

2016-10-01

This study aimed to evaluate the effect of platelet-rich fibrin (PRF) on peripheral nerve regeneration on the sciatic nerve of rats by using functional, histopathologic, and electrophysiologic analyses. Thirty female Wistar rats were divided randomly into 3 experimental groups. In group 1 (G1), which was the control group, the sciatic nerve was transected and sutured (n = 10). In group 2 (G2), the sciatic nerve was transected, sutured, and then covered with PRF as a membrane (n = 10). In group 3 (G3), the sciatic nerve was transected, sutured by leaving a 5-mm gap, and then covered by PRF as a nerve guide (n = 10). Functional, histopathologic, and electrophysiologic analyses were performed. The total histopathologic semiquantitative score was significantly higher in G1 compared to G2 and G3 (P < 0.05). Myelin thickness and capillaries were significantly lower in G3 compared to G1 (P < 0.05). There was no statistically significant difference between the groups with regard to the functional and electrophysiologic results. The study results suggest that PRF decreases functional recovery in sciatic nerve injury. Further studies are required to determine the efficacy of PRF on peripheral nerve regeneration.

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.

Structural parameters of collagen nerve grafts influence peripheral nerve regeneration.

PubMed

Stang, Felix; Fansa, Hisham; Wolf, Gerald; Reppin, Michael; Keilhoff, Gerburg

2005-06-01

Large nerve defects require nerve grafts to allow regeneration. To avoid donor nerve problems the concept of tissue engineering was introduced into nerve surgery. However, non-neuronal grafts support axonal regeneration only to a certain extent. They lack viable Schwann cells which provide neurotrophic and neurotopic factors and guide the sprouting nerve. This experimental study used the rat sciatic nerve to bridge 2 cm nerve gaps with collagen (type I/III) tubes. The tubes were different in their physical structure (hollow versus inner collagen skeleton, different inner diameters). To improve regeneration Schwann cells were implanted. After 8 weeks the regeneration process was monitored clinically, histologically and morphometrically. Autologous nerve grafts and collagen tubes without Schwann cells served as control. In all parameters autologous nerve grafts showed best regeneration. Nerve regeneration in a noteworthy quality was also seen with hollow collagen tubes and tubes with reduced lumen, both filled with Schwann cells. The inner skeleton, however, impaired nerve regeneration independent of whether Schwann cells were added or not. This indicates that not only viable Schwann cells are an imperative prerequisite but also structural parameters determine peripheral nerve regeneration.

Prevention and Treatment of Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors

DTIC Science & Technology

2016-04-01

Page 1 AWARD NUMBER: W81XWH-14-1-0073 TITLE: Prevention and Treatment of Neurofibromatosis Type 1-Associated Malignant Peripheral...COVERED 04/01/2015 to 03/31/2016 4. TITLE AND SUBTITLE Prevention and Treatment of Neurofibromatosis Type 1- 5a. CONTRACT NUMBER W81XWH-14-1-0073...ABSTRACT The most common cause of death in Neurofibromatosis Type 1 (NF1) patients is malignant peripheral nerve sheath tumor (MPNST). MPNSTs are

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

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

Magnetic Resonance Neurography Visualizes Abnormalities in Sciatic and Tibial Nerves in Patients With Type 1 Diabetes and Neuropathy.

PubMed

Vaeggemose, Michael; Pham, Mirko; Ringgaard, Steffen; Tankisi, Hatice; Ejskjaer, Niels; Heiland, Sabine; Poulsen, Per L; Andersen, Henning

2017-07-01

This study evaluates whether diffusion tensor imaging magnetic resonance neurography (DTI-MRN), T2 relaxation time, and proton spin density can detect and grade neuropathic abnormalities in patients with type 1 diabetes. Patients with type 1 diabetes ( n = 49) were included-11 with severe polyneuropathy (sDPN), 13 with mild polyneuropathy (mDPN), and 25 without polyneuropathy (nDPN)-along with 30 healthy control subjects (HCs). Clinical examinations, nerve conduction studies, and vibratory perception thresholds determined the presence and severity of DPN. DTI-MRN covered proximal (sciatic nerve) and distal (tibial nerve) nerve segments of the lower extremity. Fractional anisotropy (FA) and the apparent diffusion coefficient (ADC) were calculated, as were T2 relaxation time and proton spin density obtained from DTI-MRN. All magnetic resonance findings were related to the presence and severity of neuropathy. FA of the sciatic and tibial nerves was lowest in the sDPN group. Corresponding with this, proximal and distal ADCs were highest in patients with sDPN compared with patients with mDPN and nDPN, as well as the HCs. DTI-MRN correlated closely with the severity of neuropathy, demonstrating strong associations with sciatic and tibial nerve findings. Quantitative group differences in proton spin density were also significant, but less pronounced than those for DTI-MRN. In conclusion, DTI-MRN enables detection in peripheral nerves of abnormalities related to DPN, more so than proton spin density or T2 relaxation time. These abnormalities are likely to reflect pathology in sciatic and tibial nerve fibers. © 2017 by the American Diabetes Association.

Distinct Immunoglobulin Class and Immunoglobulin G Subclass Patterns against Ganglioside GQ1b in Miller Fisher Syndrome following Different Types of Infection

PubMed Central

Schwerer, Beatrix; Neisser, Andrea; Bernheimer, Hanno

1999-01-01

We studied serum antibodies against gangliosides GQ1b and GM1 in 13 patients with Miller Fisher syndrome (MFS) and in 18 patients with Guillain-Barré syndrome (GBS) with cranial nerve involvement. Anti-GQ1b titers were elevated in all patients with MFS cases (immunoglobulin G [IgG] > IgA, IgM), and in 8 of the 18 with GBS. Lower frequencies of increased anti-GM1 titers were observed in MFS patients (3 of 13), as well as in GBS patients (5 of 18). During the course of MFS, anti-GQ1b titers of all Ig classes decreased within 3 weeks after onset. By contrast, anti-GM1 titers (mainly IgM) transiently increased during the course of MFS in five of six patients, suggesting a nonspecific secondary immune response. In patients with MFS following respiratory infections, IgG was the major anti-GQ1b Ig class (six of six patients) and IgG3 was the major subclass (five of six). In contrast, four of five patients with MFS following gastrointestinal infections showed predominance of anti-GQ1b IgA or IgM over IgG and predominance of the IgG2 subclass; anti-GQ1b IgG (IgG3) prevailed in one patient only. These distinct Ig patterns strongly suggest that different infections may trigger different mechanisms of anti-GQ1b production, such as via T-cell-dependent as opposed to T-cell-independent pathways. Thus, the origin of antibodies against GQ1b in MFS may be determined by the type of infectious agent that precipitates the disease. PMID:10225903

Preservation of Facial Nerve Function Repaired by Using Fibrin Glue-Coated Collagen Fleece for a Totally Transected Facial Nerve during Vestibular Schwannoma Surgery

PubMed Central

Choi, Kyung-Sik; Kim, Min-Su; Jang, Sung-Ho

2014-01-01

Recently, the increasing rates of facial nerve preservation after vestibular schwannoma (VS) surgery have been achieved. However, the management of a partially or completely damaged facial nerve remains an important issue. The authors report a patient who was had a good recovery after a facial nerve reconstruction using fibrin glue-coated collagen fleece for a totally transected facial nerve during VS surgery. And, we verifed the anatomical preservation and functional outcome of the facial nerve with postoperative diffusion tensor (DT) imaging facial nerve tractography, electroneurography (ENoG) and House-Brackmann (HB) grade. DT imaging tractography at the 3rd postoperative day revealed preservation of facial nerve. And facial nerve degeneration ratio was 94.1% at 7th postoperative day ENoG. At postoperative 3 months and 1 year follow-up examination with DT imaging facial nerve tractography and ENoG, good results for facial nerve function were observed. PMID:25024825

Cross sectional study to evaluate the effect of duration of type 2 diabetes mellitus on the nerve conduction velocity in diabetic peripheral neuropathy.

PubMed

Hussain, Gauhar; Rizvi, S Aijaz Abbas; Singhal, Sangeeta; Zubair, Mohammad; Ahmad, Jamal

2014-01-01

To study the nerve conduction velocity in clinically undetectable and detectable peripheral neuropathy in type 2 diabetes mellitus with variable duration. This cross sectional study was conducted in diagnosed type 2 diabetes mellitus patients. They were divided in groups: Group I (n=37) with clinically detectable diabetic peripheral neuropathy of shorter duration and Group II (n=27) with clinically detectable diabetic peripheral neuropathy of longer duration. They were compared with T2DM patients (n=22) without clinical neuropathy. Clinical diagnosis was based on neuropathy symptom score (NSS) and neuropathy disability score (NDS) for signs. Nerve conduction velocity was measured in both upper and lower limbs. Median, ulnar, common peroneal and posterior tibial nerves were selected for motor nerve conduction study and median and sural nerves were selected for sensory nerve conduction study. The comparisons were done between nerve conduction velocities of motor and sensory nerves in patients of clinically detectable neuropathy and patients without neuropathy in type 2 diabetes mellitus population. This study showed significant electrophysiological changes with duration of disease. Nerve conduction velocities in lower limbs were significantly reduced even in patients of shorter duration with normal upper limb nerve conduction velocities. Diabetic neuropathy symptom score (NSS) and neuropathy disability score (NDS) can help in evaluation of diabetic sensorimotor polyneuropathy though nerve conduction study is more powerful test and can help in diagnosing cases of neuropathy. Copyright © 2013 Diabetes India. Published by Elsevier Ltd. All rights reserved.

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

DTIC Science & Technology

2013-01-01

5]. It has been identified as a candidate enzyme for developing 0009-2797/$ - see front matter Published by Elsevier Ireland Ltd. http://dx.doi.org...toluidine salt (BCIP) and nitro-blue tetrazo- lium chloride (NBT) reagent (Sigma), identifying AP activity. Western blots were scanned with an EPSON...was a 20 m 0.25 mm internal diameter Astec G-TA Chiraldex c-cyclo- dextrin trifluoroacetyl column, 0.12 lm film thickness (Supelco, Bellefont, PA

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.

Early changes in muscle atrophy and muscle fiber type conversion after spinal cord transection and peripheral nerve transection in rats.

PubMed

Higashino, Kosaku; Matsuura, Tetsuya; Suganuma, Katsuyoshi; Yukata, Kiminori; Nishisho, Toshihiko; Yasui, Natsuo

2013-05-20

Spinal cord transection and peripheral nerve transection cause muscle atrophy and muscle fiber type conversion. It is still unknown how spinal cord transection and peripheral nerve transection each affect the differentiation of muscle fiber type conversion mechanism and muscle atrophy. The aim of our study was to evaluate the difference of muscle weight change, muscle fiber type conversion, and Peroxisome proliferator-activated receptor-γ coactivatior-1α (PGC-1α) expression brought about by spinal cord transection and by peripheral nerve transection. Twenty-four Wistar rats underwent surgery, the control rats underwent a laminectomy; the spinal cord injury group underwent a spinal cord transection; the denervation group underwent a sciatic nerve transection. The rats were harvested of the soleus muscle and the TA muscle at 0 week, 1 week and 2 weeks after surgery. Histological examination was assessed using hematoxylin and eosin (H&E) staining and immunofluorescent staing. Western blot was performed with 3 groups. Both sciatic nerve transection and spinal cord transection caused muscle atrophy with the effect being more severe after sciatic nerve transection. Spinal cord transection caused a reduction in the expression of both sMHC protein and PGC-1α protein in the soleus muscle. On the other hand, sciatic nerve transection produced an increase in expression of sMHC protein and PGC-1α protein in the soleus muscle. The results of the expression of PGC-1α were expected in other words muscle atrophy after sciatic nerve transection is less than after spinal cord transection, however muscle atrophy after sciatic nerve transection was more severe than after spinal cord transection. In the conclusion, spinal cord transection diminished the expression of sMHC protein and PGC-1α protein in the soleus muscle. On the other hand, sciatic nerve transection enhanced the expression of sMHC protein and PGC-1α protein in the soleus muscle.

Chiral Separation of G-type Chemical Warfare Nerve Agents via Analytical Seupercritical Fluid Chromatography

DTIC Science & Technology

2014-01-01

UNCLASSIFIED b . ABSTRACT UNCLASSIFIED c. THIS PAGE UNCLASSIFIED UNLIMITED 8 19b. TELEPHONE NUMBER (include area code) 410-436-4412 Standard Form 298...plates (N), retention fac- tor ( k ), separation factor (α), and resolution (RS). 16 Parameters were used to verify both the enantioselectivity and the...time, tR, was determined by averaging the time to peak max- ima from subsequent injections. Calculation of k was carried out using the following

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

Motor nerve transplantation.

PubMed

Gray, W P; Keohane, C; Kirwan, W O

1997-10-01

The motor nerve transplantation (MNT) technique is used to transfer an intact nerve into a denervated muscle by harvesting a neurovascular pedicle of muscle containing motor endplates from the motor endplate zone of a donor muscle and implanting it into a denervated muscle. Thirty-six adult New Zealand White rabbits underwent reinnervation of the left long peroneal (LP) muscle (fast twitch) with a motor nerve graft from the soleus muscle (slow twitch). The right LP muscle served as a control. Reinnervation was assessed using microstimulatory single-fiber electromyography (SFEMG), alterations in muscle fiber typing and grouping, and isometric response curves. Neurofilament antibody was used for axon staining. The neurofilament studies provided direct evidence of nerve growth from the motor nerve graft into the adjacent denervated muscle. Median motor endplate jitter was 13 microsec preoperatively, and 26 microsec at 2 months, 29.5 microsec at 4 months, and 14 microsec at 6 months postoperatively (p < 0.001). Isometric tetanic tension studies showed a progressive functional recovery in the reinnervated muscle over 6 months. There was no histological evidence of aberrant reinnervation from any source outside the nerve pedicle. Isometric twitch responses and adenosine triphosphatase studies confirmed the conversion of the reinnervated LP muscle to a slow-type muscle. Acetylcholinesterase studies confirmed the presence of functioning motor endplates beneath the insertion of the motor nerve graft. It is concluded that the MNT technique achieves motor reinnervation by growth of new nerve fibers across the pedicle graft into the recipient muscle.

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

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.

The Association Between the Levels of Thyroid Hormones and Peripheral Nerve Conduction in Patients with Type 2 Diabetes Mellitus.

PubMed

Zhu, Fan-Fan; Yang, Li-Zhen

2018-06-26

Type 2 diabetes has an underlying pathology with thyroid dysfunction. However, few studies have investigated the association between thyroid hormones and diabetic peripheral neuropathy. Our aim was to evaluate the relationship between thyroid hormones and electrophysiological properties of peripheral nerves in type 2 diabetes. The medical records of 308 patients with type 2 diabetes were enrolled in this study. Subjects stratified by sex were divided into subgroups based on the diagnosis of nerve conduction study. The nerve conduction parameters were separately described with the spectrum of thyroid hormones. Multivariate regression models to analyze the potential links between thyroid hormones and nerve conduction parameters. The serum free triiodine thyronine levels between normal and abnormal nerve conduction groups were statistically different in total (4.55±0.65 vs 4.37±0.63, P<0.05) and female diabetic patients (4.46±0.50 vs 4.14±0.57, P<0.01). Moreover, the summed amplitude and velocity Z score of female and male increased with free triiodine thyronine levels (P<0.05). Sex-specific binary logistic regression models showed that free triiodine thyronine levels were associated with decreased odds of abnormal nerve conduction diagnosis (odds ratio [95%CI]=0.151[0.047-0.186]) and low tertile of summed amplitude Z score (odds ratio [95%CI]=0.283[0.099-0.809]) in female. In total patients, free triiodine thyronine level was negatively associated with odds of abnormal nerve conduction (odds ratio [95%CI]=0.436 [0.226-0.842]), low tertile of summed velocity (odds ratio [95%CI]=0.44[0.226-0.858]) and amplitude (odds ratio [95%CI]=0.436[0.227-0.838) Z score. Serum free triiodine thyronine level is associated with nerve conduction in diabetes. Low free triiodine thyronine may be a potential risk for diabetic peripheral neuropathy. © Georg Thieme Verlag KG Stuttgart · New York.

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

Fate of combat nerve injury.

PubMed

Beltran, Michael J; Burns, Travis C; Eckel, Tobin T; Potter, Benjamin K; Wenke, Joseph C; Hsu, Joseph R

2012-11-01

Assess a cohort of combat-related type III open tibia fractures with peripheral nerve injury to determine the injury mechanism and likelihood for recovery or improvement in nerve function. Retrospective study. Three military medical centers. Out of a study cohort of 213 type III open tibia fractures, 32 fractures (in 32 patients) with a total of 43 peripheral nerve injuries (peroneal or tibial) distal to the popliteal fossa met inclusion criteria and were available for follow-up at an average of 20 months (range, 2-48 months). Clinical assessment of motor and sensory nerve improvement. There was a 22% incidence of peripheral nerve injury in the study cohort. At an average follow-up of 20 months (range, 2-48 months), 89% of injured motor nerves were functional, whereas the injured sensory nerves had function in 93%. Fifty percent and 27% of motor and sensory injuries demonstrated improvement, respectively (P = 0.043). With the numbers available, there was no difference in motor or sensory improvement based on mechanism of injury, fracture severity or location, soft tissue injury, or specific nerve injured. In the subset of patients with an initially impaired sensory examination, full improvement was related to fracture location (P = 0.0164). Type III open tibia fractures sustained in combat are associated with a 22% incidence of peripheral nerve injury, and the majority are due to multiple projectile penetrating injury. Despite the severe nature of these injuries, the vast majority of patients had a functional nerve status by an average of 2-year follow-up. Based on these findings, discussions regarding limb salvage and amputation should not be overly influenced by the patient's peripheral nerve status. Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

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.

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.

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

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.

Peripheral nerve conduits: technology update

PubMed Central

Arslantunali, D; Dursun, T; Yucel, D; Hasirci, N; Hasirci, V

2014-01-01

Peripheral nerve injury is a worldwide clinical problem which could lead to loss of neuronal communication along sensory and motor nerves between the central nervous system (CNS) and the peripheral organs and impairs the quality of life of a patient. The primary requirement for the treatment of complete lesions is a tension-free, end-to-end repair. When end-to-end repair is not possible, peripheral nerve grafts or nerve conduits are used. The limited availability of autografts, and drawbacks of the allografts and xenografts like immunological reactions, forced the researchers to investigate and develop alternative approaches, mainly nerve conduits. In this review, recent information on the various types of conduit materials (made of biological and synthetic polymers) and designs (tubular, fibrous, and matrix type) are being presented. PMID:25489251

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.

Pathological confirmation of nerve-sparing types performed during robot-assisted radical prostatectomy (RARP).

PubMed

Ko, Woo Jin; Hruby, Gregory W; Turk, Andrew T; Landman, Jaime; Badani, Ketan K

2013-03-01

WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Incremental nerve-sparing techniques (NSTs) improve postoperative erectile function after robot-assisted radical prostatectomy (RARP). However, there are no studies to date that histologically confirm the surgeon intended NST. Thus, in the present study, we histologically confirmed that the surgeon performed the nerve preservation as his intended NSTs during RARP. Also, we found that there was more variability in fascia width outcome on the left side compared with the right. Therefore, when performing nerve preservation on the surgeon's non-dominant side, we need to pay more close attention. To confirm that the surgeon achieved true intended histological nerve sparing during robot-assisted radical prostatectomy (RARP) by studying RP specimens. To aid the novice robotic surgeon to develop the skills of RARP. Between June 2008 and May 2009, 122 consecutive patients underwent RARP by a single surgeon (K.K.B.). The degree of nerve sparing (wide resection [WR], interfascial nerve sparing [ITE-NS], intrafascial nerve sparing [ITR-NS]) on both sides was recorded. The posterior sectors of RP specimens from distal, mid, and proximal parts were evaluated. Fascia width (FW) of each position in RP specimens were compared across nerve-sparing types (NSTs). FW was recorded at 15 ° intervals (3-9 o'clock position), measured as the distance between the outermost prostate gland and surgical margin. The slides were reviewed by an experienced uropathologist who was 'blinded' to the NST. In all, 93 men were included. The overall mean (sd) FW was the greatest in the order of WR, ITE-NS, and ITR-NS, at 2.42 (1.62), 1.71 (1.40) and 1.16 (1.08) mm, respectively (P < 0.001). FW was statistically significantly correlated with the surgical technique used. When the surgeon intended to perform various levels of nerve sparing, these were reflected in the FW. Interestingly, the left-side FW showed more variability than the

Facial nerve palsy after reactivation of herpes simplex virus type 1 in diabetic mice.

PubMed

Esaki, Shinichi; Yamano, Koji; Katsumi, Sachiyo; Minakata, Toshiya; Murakami, Shingo

2015-04-01

Bell's palsy is highly associated with diabetes mellitus (DM). Either the reactivation of herpes simplex virus type 1 (HSV-1) or diabetic mononeuropathy has been proposed to cause the facial paralysis observed in DM patients. However, distinguishing whether the facial palsy is caused by herpetic neuritis or diabetic mononeuropathy is difficult. We previously reported that facial paralysis was aggravated in DM mice after HSV-1 inoculation of the murine auricle. In the current study, we induced HSV-1 reactivation by an auricular scratch following DM induction with streptozotocin (STZ). Controlled animal study. Diabetes mellitus was induced with streptozotocin injection in only mice that developed transient facial nerve paralysis with HSV-1. Recurrent facial palsy was induced after HSV-1 reactivation by auricular scratch. After DM induction, the number of cluster of differentiation 3 (CD3)(+) T cells decreased by 70% in the DM mice, and facial nerve palsy recurred in 13% of the DM mice. Herpes simplex virus type 1 deoxyribonucleic acid (DNA) was detected in the facial nerve of all of the DM mice with palsy, and HSV-1 capsids were found in the geniculate ganglion using electron microscopy. Herpes simplex virus type 1 DNA was also found in some of the DM mice without palsy, which suggested the subclinical reactivation of HSV-1. These results suggested that HSV-1 reactivation in the geniculate ganglion may be the main causative factor of the increased incidence of facial paralysis in DM patients. © 2014 The American Laryngological, Rhinological and Otological Society, Inc.

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.

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.

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.

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.

Reduced epidermal thickness, nerve degeneration and increased pain-related behavior in rats with diabetes type 1 and 2.

PubMed

Boric, Matija; Skopljanac, Ivan; Ferhatovic, Lejla; Jelicic Kadic, Antonia; Banozic, Adriana; Puljak, Livia

2013-11-01

To examine the mechanisms contributing to pain genesis in diabetic neuropathy, we investigated epidermal thickness and number of intraepidermal nerve fibers in rat foot pad of the animal model of diabetes type 1 and type 2 in relation to pain-related behavior. Male Sprague-Dawley rats were used. Diabetes type 1 was induced with intraperitoneal injection of streptozotocin (STZ) and diabetes type 2 was induced with a combination of STZ and high-fat diet. Control group for diabetes type 1 was fed with regular laboratory chow, while control group for diabetes type 2 received high-fat diet. Body weights and blood glucose levels were monitored to confirm induction of diabetes. Pain-related behavior was analyzed using thermal (hot, cold) and mechanical stimuli (von Frey fibers, number of hyperalgesic responses). Two months after induction of diabetes, glabrous skin samples from plantar surface of the both hind paws were collected. Epidermal thickness was evaluated with hematoxylin and eosin staining. Intraepidermal nerve fibers quantification was performed after staining skin with polyclonal antiserum against protein gene product 9.5. We found that induction of diabetes type 1 and type 2 causes significant epidermal thinning and loss of intraepidermal nerve fibers in a rat model, and both changes were more pronounced in diabetes type 1 model. Significant increase of pain-related behavior two months after induction of diabetes was observed only in a model of diabetes type 1. In conclusion, animal models of diabetes type 1 and diabetes type 2 could be used in pharmacological studies, where cutaneous changes could be used as outcome measures for predegenerative markers of neuropathies. Copyright © 2013 Elsevier B.V. All rights reserved.

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.

Expressed sequence tag analysis of adult human optic nerve for NEIBank: Identification of cell type and tissue markers

PubMed Central

Bernstein, Steven L; Guo, Yan; Peterson, Katherine; Wistow, Graeme

2009-01-01

Background The optic nerve is a pure white matter central nervous system (CNS) tract with an isolated blood supply, and is widely used in physiological studies of white matter response to various insults. We examined the gene expression profile of human optic nerve (ON) and, through the NEIBANK online resource, to provide a resource of sequenced verified cDNA clones. An un-normalized cDNA library was constructed from pooled human ON tissues and was used in expressed sequence tag (EST) analysis. Location of an abundant oligodendrocyte marker was examined by immunofluorescence. Quantitative real time polymerase chain reaction (qRT-PCR) and Western analysis were used to compare levels of expression for key calcium channel protein genes and protein product in primate and rodent ON. Results Our analyses revealed a profile similar in many respects to other white matter related tissues, but significantly different from previously available ON cDNA libraries. The previous libraries were found to include specific markers for other eye tissues, suggesting contamination. Immune/inflammatory markers were abundant in the new ON library. The oligodendrocyte marker QKI was abundant at the EST level. Immunofluorescence revealed that this protein is a useful oligodendrocyte cell-type marker in rodent and primate ONs. L-type calcium channel EST abundance was found to be particularly low. A qRT-PCR-based comparative mammalian species analysis reveals that L-type calcium channel expression levels are significantly lower in primate than in rodent ON, which may help account for the class-specific difference in responsiveness to calcium channel blocking agents. Several known eye disease genes are abundantly expressed in ON. Many genes associated with normal axonal function, mRNAs associated with axonal transport, inflammation and neuroprotection are observed. Conclusion We conclude that the new cDNA library is a faithful representation of human ON and EST data provide an initial overview

Characterization of nerve and microvessel damage and recovery in type 1 diabetic mice after permanent femoral artery ligation.

PubMed

Lozeron, Pierre; Mantsounga, Chris S; Broqueres-You, Dong; Dohan, Anthony; Polivka, Marc; Deroide, Nicolas; Silvestre, Jean-Sébastien; Kubis, Nathalie; Lévy, Bernard I

2015-09-01

Neuropathy is the most common complication of the peripheral nervous system during the progression of diabetes. The pathophysiology is unclear but may involve microangiopathy, reduced endoneurial blood flow, and tissue ischemia. We used a mouse model of type 1 diabetes to study parallel alterations of nerves and microvessels following tissue ischemia. We designed an easily reproducible model of ischemic neuropathy induced by irreversible ligation of the femoral artery. We studied the evolution of behavioral function, epineurial and endoneurial vessel impairment, and large nerve myelinated fiber as well as small cutaneous unmyelinated fiber impairment for 1 month following the onset of ischemia. We observed a more severe hindlimb dysfunction and delayed recovery in diabetic animals. This was associated with reduced density of large arteries in the hindlimb and reduced sciatic nerve epineurial blood flow. A reduction in sciatic nerve endoneurial capillary density was also observed, associated with a reduction in small unmyelinated epidermal fiber number and large myelinated sciatic nerve fiber dysfunction. Moreover, vascular recovery was delayed, and nerve dysfunction was still present in diabetic animals at day 28. This easily reproducible model provides clear insight into the evolution over time of the impact of ischemia on nerve and microvessel homeostasis in the setting of diabetes. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

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.

Comparative study of phrenic nerve transfers with and without nerve graft for elbow flexion after global brachial plexus injury.

PubMed

Liu, Yuzhou; Lao, Jie; Gao, Kaiming; Gu, Yudong; Zhao, Xin

2014-01-01

Nerve transfer is a valuable surgical technique in peripheral nerve reconstruction, especially in brachial plexus injuries. Phrenic nerve transfer for elbow flexion was proved to be one of the optimal procedures in the treatment of brachial plexus injuries in the study of Gu et al. The aim of this study was to compare phrenic nerve transfers with and without nerve graft for elbow flexion after brachial plexus injury. A retrospective review of 33 patients treated with phrenic nerve transfer for elbow flexion in posttraumatic global root avulsion brachial plexus injury was carried out. All the 33 patients were confirmed to have global root avulsion brachial plexus injury by preoperative and intraoperative electromyography (EMG), physical examination and especially by intraoperative exploration. There were two types of phrenic nerve transfers: type1 - the phrenic nerve to anterolateral bundle of anterior division of upper trunk (14 patients); type 2 - the phrenic nerve via nerve graft to anterolateral bundle of musculocutaneous nerve (19 patients). Motor function and EMG evaluation were performed at least 3 years after surgery. The efficiency of motor function in type 1 was 86%, while it was 84% in type 2. The two groups were not statistically different in terms of Medical Research Council (MRC) grade (p=1.000) and EMG results (p=1.000). There were seven patients with more than 4 month's delay of surgery, among whom only three patients regained biceps power to M3 strength or above (43%). A total of 26 patients had reconstruction done within 4 months, among whom 25 patients recovered to M3 strength or above (96%). There was a statistically significant difference of motor function between the delay of surgery within 4 months and more than 4 months (p=0.008). Phrenic nerve transfers with and without nerve graft for elbow flexion after brachial plexus injury had no significant difference for biceps reinnervation according to MRC grading and EMG. A delay of the surgery

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

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

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

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

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.

Scaffolds for peripheral nerve repair and reconstruction.

PubMed

Yi, Sheng; Xu, Lai; Gu, Xiaosong

2018-06-02

Trauma-associated peripheral nerve defect is a widespread clinical problem. Autologous nerve grafting, the current gold standard technique for the treatment of peripheral nerve injury, has many internal disadvantages. Emerging studies showed that tissue engineered nerve graft is an effective substitute to autologous nerves. Tissue engineered nerve graft is generally composed of neural scaffolds and incorporating cells and molecules. A variety of biomaterials have been used to construct neural scaffolds, the main component of tissue engineered nerve graft. Synthetic polymers (e.g. silicone, polyglycolic acid, and poly(lactic-co-glycolic acid)) and natural materials (e.g. chitosan, silk fibroin, and extracellular matrix components) are commonly used along or together to build neural scaffolds. Many other materials, including the extracellular matrix, glass fabrics, ceramics, and metallic materials, have also been used to construct neural scaffolds. These biomaterials are fabricated to create specific structures and surface features. Seeding supporting cells and/or incorporating neurotrophic factors to neural scaffolds further improve restoration effects. Preliminary studies demonstrate that clinical applications of these neural scaffolds achieve satisfactory functional recovery. Therefore, tissue engineered nerve graft provides a good alternative to autologous nerve graft and represents a promising frontier in neural tissue engineering. Copyright © 2018 Elsevier Inc. All rights reserved.

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

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

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.

The effect of methylprednisolone on facial nerve paralysis with different etiologies.

PubMed

Yildirim, Mehmet Akif; Karlidag, Turgut; Akpolat, Nusret; Kaygusuz, Irfan; Keles, Erol; Yalcin, Sinasi; Akyigit, Abdulvahap

2015-05-01

The objective of this study was to evaluate the effectiveness of methylprednisolone (MP) in models of facial nerve paralysis obtained by nerve section, compression, or inoculation with herpes simplex virus (HSV). Experimental controlled animal study. Tertiary referral center. A total of 30 female New Zealand rabbits weighing 1200-3000 g were used for the study. They were randomly assigned to one of 6 groups of 5 animals each. A nerve section injury was realized in Groups 1a (section and MP) and 1b (section, control) rabbits. A compression-type injury was inflicted to rabbits in Groups 2a (compression and MP) and 2b (compression, control). As for animals in Groups 3a (Type 1 HSV and MP) and 3b (Type 1 HSV, controls), facial nerve paralysis resulting from viral infection was obtained. Animals in the 3 treatment groups, designated with the letter "a", were administered MP, 1 mg/kg/d, whereas those in control groups "b" received 1 mL normal saline, both during 3 weeks. All subjects were followed up for 2 months. At the end of this period, all animals had the buccal branch of the facial nerve excised on the operated side. Semi-thin sections of these specimens were evaluated under light microscopy for the following: perineural fibrosis, increase in collagen fibers, myelin degeneration, axonal degeneration, Schwann cell proliferation, and edema. No significant difference was observed (P > 0.05) between the MP treatment group and the control group with regard to perineural fibrosis, increase in collagen fibers, myelin degeneration, axonal degeneration, edema, or Schwann cell proliferation. In the group with a compressive lesion (Group 2), controls were no different from MP-treated animals as to perineural fibrosis, increase in collagen fibers, or Schwann cell proliferation, whereas axonal degeneration, myelin degeneration, and edema were significantly higher (P < 0.05) in the control group. When comparing the treatment and control groups among the animals inoculated with

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

Effects of laser therapy in peripheral nerve regeneration

PubMed Central

Sene, Giovana Almeida Leitão; Sousa, Fausto Fernandes de Almeida; Fazan, Valéria Sassoli; Barbieri, Cláudio Henrique

2013-01-01

OBJECTIVE: The influence of dose of low power lasertherapy (AsGaAl, 830 nm) on the regeneration of the fibular nerve of rats after a crush injury was evaluated by means of the functional gait analysis and histomorphometric parameters. METHODS: Controlled crush injury of the right common fibular nerve, immediately followed by increasing doses (G1: no irradiation; G2: simulated; G3: 5 J/cm2; G4: 10 J/cm2; G5: 20 J/cm2) laser irradiation directly on the lesion site for 21 consecutive days. Functional gait analysis was carried out at weekly intervals by measuring the peroneal/fibular functional index (PFI). The animals were killed on the 21st postoperative day for removal of the fibular nerve, which was prepared for the histomorphometric analysis. RESULTS: The PFI progressively increased during the observation period in all groups, without significant differences between them (p>0.05). The transverse nerve area was significantly wider in group 2 than in groups 3 and 4, while fiber density was significantly greater in group 4 than in all remaining groups. CONCLUSION: The low power AsGaAl laser irradiation did not accelerate nerve recovery with any of the doses used. Level of Evidence I, Therapeutic Studies Investigating the Results of Treatment. PMID:24453680

A simple immunofluorescence technique for simultaneous visualization of mast cells and nerve fibers reveals selectivity and hair cycle--dependent changes in mast cell--nerve fiber contacts in murine skin.

PubMed

Botchkarev, V A; Eichmüller, S; Peters, E M; Pietsch, P; Johansson, O; Maurer, M; Paus, R

1997-04-01

Close contacts between mast cells (MC) and nerve fibers have previously been demonstrated in normal and inflamed skin by light and electron microscopy. A key step for any study in MC-nerve interactions in situ is to simultaneously visualize both communication partners, preferably with the option of double labelling the nerve fibers. For this purpose, we developed the following triple-staining technique. After paraformaldehyde-picric acid perfusion fixation, cryostat sections of back skin from C57BL/6 mice were incubated with a primary rat monoclonal antibody to substance P (SP), followed by incubation with a secondary goat-anti-rat TRITC-conjugated IgG. A rabbit antiserum to CGRP was then applied, followed by a secondary goat-anti-rabbit FITC-conjugated IgG. MCs were visualized by incubation with AMCA-labelled avidin, or (for a more convenient quantification of close MC-nerve fiber contacts) with a mixture of TRITC- and FITC-labelled avidins. Using this simple, novel covisualization method, we were able to show that MC-nerve associations in mouse skin are, contrary to previous suggestions, highly selective for nerve fiber types, and that these interactions are regulated in a hair cycle-dependent manner: in telogen and early anagen skin, MCs preferentially contacted CGRP-immunoreactive (IR) or SP/CGRP-IR double-labelled nerve fibers. Compared with telogen values, there was a significant increase in the number of close contacts between MCs and tyrosine hydroxylase-IR fibers during late anagen, and between MCs and peptide histidine-methionine-IR and choline acetyl transferase-IR fibers during catagen.

Mechanical properties of a bioabsorbable nerve guide tube for long nerve defects.

PubMed

Ichihara, S; Facca, S; Liverneaux, P; Inada, Y; Takigawa, T; Kaneko, K; Nakamura, T

2015-09-01

The mechanical properties of nerve guide tubes must be taken into consideration when they are being developed. We previously reported the feasibility of using 50:50 tubes in a canine 40mm peroneal nerve defect model, where 50:50 represents the proportion of poly(L-lactic) acid (PLLA) and polyglycolic acid (PGA). The aim of the current study was to show that 50:50 tubes have suitable mechanical properties for repairing long nerve defects. Four types of nerve guide tubes made with PLLA to PGA fiber ratios of 100:0 (i.e. 100% PLLA) (100:0 tube), 50:50 (50:50 tube), 10:90 (10:90 tube), and 0:100 (0:100 tube) were designed and created using a tubular braiding machine. Their mechanical properties were examined in vitro (up to 16 weeks). In compression testing, 50:50 tubes had the highest normalized force value, followed in order by the 100:0, 10:90, and 0:100 tubes up to 8 weeks after immersion. From the point of view of biomechanics and bioresorbability, out of the 4 tube types tested, 50:50 tubes appeared to have the optimal mechanical properties for longer nerve defects. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Exacerbation of Charcot-Marie-Tooth type 2E neuropathy following traumatic nerve injury

PubMed Central

Villalon, Eric; Dale, Jeffrey M.; Jones, Maria; Shen, Hailian; Garcia, Michael L.

2018-01-01

Charcot-Marie-Tooth disease (CMT) is the most commonly inherited peripheral neuropathy. CMT disease signs include distal limb neuropathy, abnormal gait, sensory defects, and deafness. We generated a novel line of CMT2E mice expressing hNF-LE397K, which displayed muscle atrophy of the lower limbs without denervation, proximal reduction in large caliber axons, and decreased nerve conduction velocity. In this study, we challenged wild type, hNF-L, and hNF-LE397K mice with crush injury to the sciatic nerve. We analyzed functional recovery by measuring toe spread and analyzed gaitusing the Catwalk system. hNF-LE397K mice demonstrated reduced recovery from nerve injury consistent with increased susceptibility to neuropathy observed in CMT patients. In addition, hNF-LE397K developed a permanent reduction in their ability to weight bear, increased mechanical allodynia, and premature gait shift in the injured limb, which led to increasingly disrupted interlimb coordination in hNF-LE397K. Exacerbation of neuropathy after injury and identification of gait alterations in combination with previously described pathology suggests that hNF-LE397K mice recapitulate many of clinical signs associated with CMT2. Therefore, hNF-LE397K mice provide a model for determining the efficacy of novel therapies. PMID:26423936

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

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

Miller, Steven L., E-mail: stevenmiller17@gmail.com; Program in Neuroscience, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814; Aroniadou-Anderjaska, Vassiliki, E-mail: vanderjaska@usuhs.edu

Inhibition of acetylcholinesterase (AChE) after nerve agent exposure induces status epilepticus (SE), which causes brain damage or death. The development of countermeasures appropriate for the pediatric population requires testing of anticonvulsant treatments in immature animals. In the present study, exposure of 21-day-old (P21) rats to different doses of soman, followed by probit analysis, produced an LD{sub 50} of 62 μg/kg. The onset of behaviorally-observed SE was accompanied by a dramatic decrease in brain AChE activity; rats who did not develop SE had significantly less reduction of AChE activity in the basolateral amygdala than rats who developed SE. Atropine sulfate (ATS)more » at 2 mg/kg, administered 20 min after soman exposure (1.2 × LD{sub 50}), terminated seizures. ATS at 0.5 mg/kg, given along with an oxime within 1 min after exposure, allowed testing of anticonvulsants at delayed time-points. The AMPA/GluK1 receptor antagonist LY293558, or the specific GluK1 antagonist UBP302, administered 1 h post-exposure, terminated SE. There were no degenerating neurons in soman-exposed P21 rats, but both the amygdala and the hippocampus were smaller than in control rats at 30 and 90 days post-exposure; this pathology was not present in rats treated with LY293558. Behavioral deficits present at 30 days post-exposure, were also prevented by LY293558 treatment. Thus, in immature animals, a single injection of atropine is sufficient to halt nerve agent-induced seizures, if administered timely. Testing anticonvulsants at delayed time-points requires early administration of ATS at a low dose, sufficient to counteract only peripheral toxicity. LY293558 administered 1 h post-exposure, prevents brain pathology and behavioral deficits. - Highlights: • The LD{sub 50} of soman was determined in postnatal-day-21 rats. • Rats with no seizures after 1.2XLD{sub 50} soman had less reduction of AChE in the amygdala. • Atropine sulfate (ATS) at 2 mg/kg, given at 20 min

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.

Influence of insulin-like growth factor-I (IGF-I) on nerve autografts and tissue-engineered nerve grafts.

PubMed

Fansa, Hisham; Schneider, Wolfgang; Wolf, Gerald; Keilhoff, Gerburg

2002-07-01

To overcome the problems of limited donor nerves for nerve reconstruction, we established nerve grafts made from cultured Schwann cells and basal lamina from acellular muscle and used them to bridge a 2-cm defect of the rat sciatic nerve. Due to their basal lamina and to viable Schwann cells, these grafts allow regeneration that is comparable to autologous nerve grafts. In order to enhance regeneration, insulin-like growth factor (IGF-I) was locally applied via osmotic pumps. Autologous nerve grafts with and without IGF-I served as controls. Muscle weight ratio was significantly increased in the autograft group treated with IGF-I compared to the group with no treatment; no effect was evident in the tissue-engineered grafts. Autografts with IGF-I application revealed a significantly increased axon count and an improved g-ratio as indicator for "maturity" of axons compared to autografts without IGF-I. IGF-I application to the engineered grafts resulted in a decreased axon count compared to grafts without IGF-I. The g-ratio, however, revealed no significant difference between the groups. Local administration of IGF-I improves axonal regeneration in regular nerve grafts, but not in tissue-engineered grafts. Seemingly, in these grafts the interactive feedback mechanisms of neuron, glial cell, and extracellular matrix are not established, and IGF-I cannot exert its action as a pleiotrophic signal. Copyright 2002 Wiley Periodicals, Inc.

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

Synovial sarcoma of nerve.

PubMed

Scheithauer, Bernd W; Amrami, Kimberly K; Folpe, Andrew L; Silva, Ana I; Edgar, Mark A; Woodruff, James M; Levi, Allan D; Spinner, Robert J

2011-04-01

Tumors of peripheral nerve are largely neuroectodermal in nature and derived from 2 elements of nerve, Schwann or perineurial cells. In contrast, mesenchymal tumors affecting peripheral nerve are rare and are derived mainly from epineurial connective tissue. The spectrum of the latter is broad and includes lipoma, vascular neoplasms, hematopoietic tumors, and even meningioma. Of malignant peripheral nerve neoplasms, the vast majority are primary peripheral nerve sheath tumors. Malignancies of mesenchymal type are much less common. To date, only 12 cases of synovial sarcoma of nerve have been described. Whereas in the past, parallels were drawn between synovial sarcoma and malignant glandular schwannoma, an uncommon form of malignant peripheral nerve sheath tumor, molecular genetics have since clarified the distinction. Herein, we report 10 additional examples of molecularly confirmed synovial sarcoma, all arising within minor or major nerves. Affecting 7 female and 3 male patients, 4 tumors occurred in pediatric patients. Clinically and radiologically, most lesions were initially thought to be benign nerve sheath tumors. On reinterpretation of imaging, they were considered indeterminate in nature with some features suspicious for malignancy. Synovial sarcoma of nerve, albeit rare, seems to behave in a manner similar to its more common, soft tissue counterpart. Those affecting nerve have a variable prognosis. Definitive recommendations regarding surgery and adjuvant therapies await additional reports and long-term follow-up. The literature is reviewed and a meta-analysis is performed with respect to clinicopathologic features versus outcome. Copyright © 2011. Published by Elsevier Inc.

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.

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

Deficiency in Monocarboxylate Transporter 1 (MCT1) in Mice Delays Regeneration of Peripheral Nerves following Sciatic Nerve Crush

PubMed Central

Morrison, Brett M.; Tsingalia, Akivaga; Vidensky, Svetlana; Lee, Youngjin; Jin, Lin; Farah, Mohamed H.; Lengacher, Sylvain; Magistretti, Pierre J.; Pellerin, Luc; Rothstein, Jeffrey D.

2014-01-01

Peripheral nerve regeneration following injury occurs spontaneously, but many of the processes require metabolic energy. The mechanism of energy supply to axons has not previously been determined. In the central nervous system, monocarboxylate transporter 1 (MCT1), expressed in oligodendroglia, is critical for supplying lactate or other energy metabolites to axons. In the current study, MCT1 is shown to localize within the peripheral nervous system to perineurial cells, dorsal root ganglion neurons, and Schwann cells by MCT1 immunofluorescence and MCT1 tdTomato BAC reporter mice. To investigate whether MCT1 is necessary for peripheral nerve regeneration, sciatic nerves in MCT1 heterozygous null mice are crushed and peripheral nerve regeneration quantified electrophysiologically and anatomically. Compound muscle action potential (CMAP) recovery is delayed from a median of 21 days in wild-type mice to greater than 38 days in MCT1 heterozygote null mice. In fact, half of the MCT1 heterozygote null mice have no recovery of CMAP at 42 days, while all of the wild-type mice recovered. In addition, muscle fibers remain 40% more atrophic and neuromuscular junctions 40% more denervated at 42 days post-crush in the MCT1 heterozygote null mice than wild-type mice. The delay in nerve regeneration is not only in motor axons, as the number of regenerated axons in the sural sensory nerve of MCT1 heterozygote null mice at 4 weeks and tibial mixed sensory and motor nerve at 3 weeks is also significantly reduced compared to wild-type mice. This delay in regeneration may be partly through failed Schwann cell function, as there is reduced early phagocytosis of myelin debris and remyelination of axon segments. These data for the first time demonstrate that MCT1 is critical for regeneration of both sensory and motor axons in mice following sciatic nerve crush. PMID:25447940

Deficiency in monocarboxylate transporter 1 (MCT1) in mice delays regeneration of peripheral nerves following sciatic nerve crush.

PubMed

Morrison, Brett M; Tsingalia, Akivaga; Vidensky, Svetlana; Lee, Youngjin; Jin, Lin; Farah, Mohamed H; Lengacher, Sylvain; Magistretti, Pierre J; Pellerin, Luc; Rothstein, Jeffrey D

2015-01-01

Peripheral nerve regeneration following injury occurs spontaneously, but many of the processes require metabolic energy. The mechanism of energy supply to axons has not previously been determined. In the central nervous system, monocarboxylate transporter 1 (MCT1), expressed in oligodendroglia, is critical for supplying lactate or other energy metabolites to axons. In the current study, MCT1 is shown to localize within the peripheral nervous system to perineurial cells, dorsal root ganglion neurons, and Schwann cells by MCT1 immunofluorescence in wild-type mice and tdTomato fluorescence in MCT1 BAC reporter mice. To investigate whether MCT1 is necessary for peripheral nerve regeneration, sciatic nerves of MCT1 heterozygous null mice are crushed and peripheral nerve regeneration was quantified electrophysiologically and anatomically. Compound muscle action potential (CMAP) recovery is delayed from a median of 21 days in wild-type mice to greater than 38 days in MCT1 heterozygote null mice. In fact, half of the MCT1 heterozygote null mice have no recovery of CMAP at 42 days, while all of the wild-type mice recovered. In addition, muscle fibers remain 40% more atrophic and neuromuscular junctions 40% more denervated at 42 days post-crush in the MCT1 heterozygote null mice than wild-type mice. The delay in nerve regeneration is not only in motor axons, as the number of regenerated axons in the sural sensory nerve of MCT1 heterozygote null mice at 4 weeks and tibial mixed sensory and motor nerve at 3 weeks is also significantly reduced compared to wild-type mice. This delay in regeneration may be partly due to failed Schwann cell function, as there is reduced early phagocytosis of myelin debris and remyelination of axon segments. These data for the first time demonstrate that MCT1 is critical for regeneration of both sensory and motor axons in mice following sciatic nerve crush. Copyright © 2014 Elsevier Inc. All rights reserved.

Exacerbation of Charcot-Marie-Tooth type 2E neuropathy following traumatic nerve injury.

PubMed

Villalón, Eric; Dale, Jeffrey M; Jones, Maria; Shen, Hailian; Garcia, Michael L

2015-11-19

Charcot-Marie-Tooth disease (CMT) is the most commonly inherited peripheral neuropathy. CMT disease signs include distal limb neuropathy, abnormal gait, sensory defects, and deafness. We generated a novel line of CMT2E mice expressing hNF-L(E397K), which displayed muscle atrophy of the lower limbs without denervation, proximal reduction in large caliber axons, and decreased nerve conduction velocity. In this study, we challenged wild type, hNF-L and hNF-L(E397K) mice with crush injury to the sciatic nerve. We analyzed functional recovery by measuring toe spread and analyzed gait using the Catwalk system. hNF-L(E397K) mice demonstrated reduced recovery from nerve injury consistent with increased susceptibility to neuropathy observed in CMT patients. In addition, hNF-L(E397K) developed a permanent reduction in their ability to weight bear, increased mechanical allodynia, and premature gait shift in the injured limb, which led to increasingly disrupted interlimb coordination in hNF-L(E397K). Exacerbation of neuropathy after injury and identification of gait alterations in combination with previously described pathology suggests that hNF-L(E397K) mice recapitulate many of clinical signs associated with CMT2. Therefore, hNF-L(E397K) mice provide a model for determining the efficacy of novel therapies. Copyright © 2015 Elsevier B.V. All rights reserved.

Handheld Delivery System for Modified Boron-Type Fire Extinguishment Agent

DTIC Science & Technology

1993-11-01

was to develop and test a handheld portable delivery system for use with the modified boron-type fire extinguishing agent for metal fires . B...BACKGROUND A need exists for an extinguishing agent and accompanying delivery system that are effective against complex geometry metal fires . A modified...agent and its delivery system have proven effective against complex geometry metal fires containing up to 200 pounds of magnesium metal. Further

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.

Chronic nerve compression alters Schwann cell myelin architecture in a murine model

PubMed Central

Gupta, Ranjan; Nassiri, Nima; Hazel, Antony; Bathen, Mary; Mozaffar, Tahseen

2011-01-01

Introduction Myelinating Schwann cells compartmentalize their outermost layer to form actin-rich channels known as Cajal bands. Here, we investigate changes in Schwann cell architecture and cytoplasmic morphology in a novel mouse model of carpal tunnel syndrome. Methods Chronic nerve compression (CNC) injury was created in wild-type and slow-Wallerian degeneration (WldS) mice. Over 12 weeks, nerves were electrodiagnostically assessed, and Schwann cell morphology was thoroughly evaluated. Results A decline in nerve conduction velocity and increase in g-ratio is observed without early axonal damage. Schwann cells display shortened internodal lengths and severely disrupted Cajal bands. Quite surprisingly, the latter is reconstituted without improvements to nerve conduction velocity. Discussion Chronic entrapment injuries like carpal tunnel syndrome are primarily mediated by the Schwann cell response, wherein decreases in internodal length and myelin thickness disrupt the efficiency of impulse propagation. Restitution of Cajal bands is not sufficient for remyelination post-CNC injury. PMID:22246880

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

NASA Astrophysics Data System (ADS)

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

2015-05-01

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

Laser-activated protein solder for peripheral nerve repair

NASA Astrophysics Data System (ADS)

Trickett, Rodney I.; Lauto, Antonio; Dawes, Judith M.; Owen, Earl R.

1995-05-01

A 100 micrometers core optical fiber-coupled 75 mW diode laser operating at a wavelength of 800 nm has been used in conjunction with a protein solder to stripe weld severed rat tibial nerves, reducing the long operating time required for microsurgical nerve repair. Welding is produced by selective laser denaturation of the albumin based solder which contains the dye indocyanine green. Operating time for laser soldering was 10 +/- 5 min. (n equals 20) compared to 23 +/- 9 min. (n equals 10) for microsuturing. The laser solder technique resulted in patent welds with a tensile strength of 15 +/- 5 g, while microsutured nerves had a tensile strength of 40 +/- 10 g. Histopathology of the laser soldered nerves, conducted immediately after surgery, displayed solder adhesion to the outer membrane with minimal damage to the inner axons of the nerves. An in vivo study is under way comparing laser solder repaired tibial nerves to conventional microsuture repair. At the time of submission 15 laser soldered nerves and 7 sutured nerves were characterized at 3 months and showed successful regeneration with compound muscle action potentials of 27 +/- 8 mV and 29 +/- 8 mW respectively. A faster, less damaging and long lasting laser based anastomotic technique is presented.

What is the role of biosimilar G-CSF agents in hematopoietic stem cell mobilization at present?

PubMed

Korkmaz, Serdal; Altuntas, Fevzi

2017-12-01

Mobilization of hematopoietic stem cells, which has largely replaced bone marrow harvesting as a source of hematopoietic stem cells, using recombinant agents such as filgrastim or lenograstim has become a standard procedure in both patients and healthy donors prior to peripheral blood stem cell collection for autologous and allogeneic stem cell transplantation. Published literature data suggest that mobilization with recombinant granulocyte-colony stimulating factor (G-CSF) is safe and mobilization outcomes are satisfactory. In recent years, besides G-CSF originators, biosimilar G-CSF agents have been approved by the regulatory agencies for the same indications. Current data showed that by using the biosimilar G-CSF, similar results regarding safety and efficacy of hematopoietic stem cell mobilization may be achieved compared to the originator G-CSF. Although the issues such as the similarity to a licenced biological medicine, differences in manufacturing processes, the potential to cause immunogenicity, extrapolation and interchangeability of these biosimilar products are still being discussed by the scientific area, however, more experience with these agents now exists in approved endications and there seems to be no reason to expect significant differences between biosimilar G-CSF and originator G-CSF regarding their efficacy and safety in both patients and healthy donors. Also, the significant cost savings of biosimilars in real life setting may enhance the use of these agents in the future. Nonetheless, the collection of long-term follow-up data is mandatory for both patients and healthy donors, and multicentre randomized clinical trials that directly compare biosimilar G-CSF with the originator G-CSF are needed in order to allow the transplant community to make informed decisions regarding the choice of G-CSF. Copyright © 2017 Elsevier Ltd. All rights reserved.

Malignant nerve sheath tumor involving glossopharyngeal, vagus and spinal nerve with intracranial-extracranial extension and systemic metastases in a patient with type 1 neurofibromatosis: A case report.

PubMed

Guerra-Mora, José Raúl; Del Castillo-Calcáneo, Juan D; Córdoba-Mosqueda, María Elena; Yáñez-Castro, Jorge; García-González, Ulises; Soriano-Navarro, Eduardo; Llamas-Ceras, Leticia; Vicuña-González, Rosa María

2016-01-01

Intracranial malignant peripheral nerve sheath tumors are an extremely rare pathology with a high morbidity and mortality. Epidemiological, clinical and prognostic data are scarce and with little certainty in the literature. The aim of this paper is to report for first time in English literature, the case of a patient with type 1 neurofibromatosis, who presented a malignant peripheral nerve sheath tumor that involved the left glossopharyngeal, vagus and spinal nerves with intracranial and extracranial extension through jugular foramen and systemic metastases. A 37 years-old female patient with malnutrition and Villaret́s syndrome. It was confirmed by brain magnetic resonance imaging and PET-CT the presence of a neoplasic lesion which was radiologically compatible with malignant peripheral nerve sheath tumor with systemic metastases. Partial surgical resection was performed; the patient postoperative course was without significant clinical improvement but with added peripheral facial palsy. The patient did not accept adjuvant management because of personal reasons. Behavior therapy is unclear due to the low frequency of the disease and the lack of case series, representing a challenge for the physician in its approach and a poor prognosis for the patient. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

[Relationship between Work Ⅱ type of congenital first branchial cleft anomaly and facial nerve and surgical strategies].

PubMed

Zhang, B; Chen, L S; Huang, S L; Liang, L; Gong, X X; Wu, P N; Zhang, S Y; Luo, X N; Zhan, J D; Sheng, X L; Lu, Z M

2017-10-07

Objective: To investigate the relationship between Work Ⅱ type of congenital first branchial cleft anomaly (CFBCA) and facial nerve and discuss surgical strategies. Methods: Retrospective analysis of 37 patients with CFBCA who were treated from May 2005 to September 2016. Among 37 cases with CFBCA, 12 males and 25 females; 24 in the left and 13 in the right; the age at diagnosis was from 1 to 76 ( years, with a median age of 20, 24 cases with age of 18 years or less and 13 with age more than 18 years; duration of disease ranged from 1 to 10 years (median of 6 years); 4 cases were recurren after fistula resection. According to the classification of Olsen, all 37 cases were non-cyst (sinus or fistula). External fistula located over the mandibular angle in 28 (75.7%) cases and below the angle in 9 (24.3%) cases. Results: Surgeries were performed successfully in all the 37 cases. It was found that lesions located at anterior of the facial nerve in 13 (35.1%) cases, coursed between the branches in 3 cases (8.1%), and lied in the deep of the facial nerve in 21 (56.8%) cases. CFBCA in female with external fistula below mandibular angle and membranous band was more likely to lie deep of the facial nerve than in male with external fistula over the mandibular angle but without myringeal web. Conclusions: CFBCA in female patients with a external fistula located below the mandibular angle, non-cyst of Olsen or a myringeal web is more likely to lie deep of the facial nerve. Surgeons should particularly take care of the protection of facial nerve in these patients, if necessary, facial nerve monitoring technology can be used during surgery to complete resection of lesions.

An update-tissue engineered nerve grafts for the repair of peripheral nerve injuries.

PubMed

Patel, Nitesh P; Lyon, Kristopher A; Huang, Jason H

2018-05-01

Peripheral nerve injuries (PNI) are caused by a range of etiologies and result in a broad spectrum of disability. While nerve autografts are the current gold standard for the reconstruction of extensive nerve damage, the limited supply of autologous nerve and complications associated with harvesting nerve from a second surgical site has driven groups from multiple disciplines, including biomedical engineering, neurosurgery, plastic surgery, and orthopedic surgery, to develop a suitable or superior alternative to autografting. Over the last couple of decades, various types of scaffolds, such as acellular nerve grafts (ANGs), nerve guidance conduits, and non-nervous tissues, have been filled with Schwann cells, stem cells, and/or neurotrophic factors to develop tissue engineered nerve grafts (TENGs). Although these have shown promising effects on peripheral nerve regeneration in experimental models, the autograft has remained the gold standard for large nerve gaps. This review provides a discussion of recent advances in the development of TENGs and their efficacy in experimental models. Specifically, TENGs have been enhanced via incorporation of genetically engineered cells, methods to improve stem cell survival and differentiation, optimized delivery of neurotrophic factors via drug delivery systems (DDS), co-administration of platelet-rich plasma (PRP), and pretreatment with chondroitinase ABC (Ch-ABC). Other notable advancements include conduits that have been bioengineered to mimic native nerve structure via cell-derived extracellular matrix (ECM) deposition, and the development of transplantable living nervous tissue constructs from rat and human dorsal root ganglia (DRG) neurons. Grafts composed of non-nervous tissues, such as vein, artery, and muscle, will be briefly discussed.

Comparing in vitro and in vivo virulence phenotypes of Burkholderia pseudomallei type G strains.

PubMed

Lewis, Eric R G; Kilgore, Paul B; Mott, Tiffany M; Pradenas, Gonzalo A; Torres, Alfredo G

2017-01-01

Burkholderia pseudomallei (Bpm) is a saprophytic rod-shaped gram-negative bacterium and the causative agent of melioidosis. This disease has previously been described as endemic in areas such as northern Australia and Southeast Asia, but, more recently, a better understanding of the epidemiology of melioidosis indicated that the disease is distributed worldwide, including regions of the Americas and Africa. A 16S-23S rDNA internal transcribed spacer (ITS) typing system has been developed for Bpm and has revealed that ITS types C, E, and hybrid CE are mainly associated with Australia and Southeast Asia while type G strains are more associated with cases of melioidosis in the Western Hemisphere. The purpose of the current study was to determine the in vitro and in vivo virulence profiles of the understudied Bpm type G strains Ca2009, Ca2013a, Mx2013, and 724644 and compared such phenotypes to the commonly studied Bpm type C strain K96243. We evaluated virulence by measuring invasion/uptake and survival of these Bpm strains in murine respiratory epithelial LA-4 cells and alveolar macrophage MH-S cells using different multiplicity of infections (MOIs of 1 and 10). We also calculated the lethal dose 50 values (LD50) in BALB/c mice that were inoculated intranasally with either Ca2009, Ca2013a, or Mx2013. Overall, the virulence and lethality phenotypes of Bpm type G strains were similar to the Bpm type C strain K96243. Additional comparative analyses between the Bpm ITS types may lead to a better understanding of the contribution of the ITS type to the epidemiology and ecology of Bpm strains.

Comparing in vitro and in vivo virulence phenotypes of Burkholderia pseudomallei type G strains

PubMed Central

Mott, Tiffany M.; Pradenas, Gonzalo A.

2017-01-01

Burkholderia pseudomallei (Bpm) is a saprophytic rod-shaped gram-negative bacterium and the causative agent of melioidosis. This disease has previously been described as endemic in areas such as northern Australia and Southeast Asia, but, more recently, a better understanding of the epidemiology of melioidosis indicated that the disease is distributed worldwide, including regions of the Americas and Africa. A 16S-23S rDNA internal transcribed spacer (ITS) typing system has been developed for Bpm and has revealed that ITS types C, E, and hybrid CE are mainly associated with Australia and Southeast Asia while type G strains are more associated with cases of melioidosis in the Western Hemisphere. The purpose of the current study was to determine the in vitro and in vivo virulence profiles of the understudied Bpm type G strains Ca2009, Ca2013a, Mx2013, and 724644 and compared such phenotypes to the commonly studied Bpm type C strain K96243. We evaluated virulence by measuring invasion/uptake and survival of these Bpm strains in murine respiratory epithelial LA-4 cells and alveolar macrophage MH-S cells using different multiplicity of infections (MOIs of 1 and 10). We also calculated the lethal dose 50 values (LD50) in BALB/c mice that were inoculated intranasally with either Ca2009, Ca2013a, or Mx2013. Overall, the virulence and lethality phenotypes of Bpm type G strains were similar to the Bpm type C strain K96243. Additional comparative analyses between the Bpm ITS types may lead to a better understanding of the contribution of the ITS type to the epidemiology and ecology of Bpm strains. PMID:28414823

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

Nerve stripper-assisted sural nerve harvest.

PubMed

Hassanpour, Esmail; Yavari, Masoud; Karbalaeikhani, Ali; Saremi, Hossein

2014-03-01

Sural nerve has the favorite length and size for nerve graft interposition. Here two techniques, that is, "stocking seam" and "stair-step" or "stepladder," have been used for harvesting sural nerve. The first technique results in an unsightly scar at the posterior calf, and the latter one takes a long time to perform and exert undue traction to the graft during harvesting. The purpose of this article is to describe our experience in harvesting the sural nerve by a nerve stripper. A nerve stripper was used for harvesting sural nerve in 35 adult patients (in 6 patients, sural harvesting was done bilaterally), 27 men and 8 women. Thirty-one sural nerve harvests were done by closed technique (i.e., harvesting of sural nerve only by two incisions, one in the posterior of the lateral malleolus and the other in popliteal fossa), in 8 others by limited open technique, and in 2 cases, there was early laceration of the sural nerve at the beginning of the study. The contralateral sural nerve was harvested in one patient and medial antebrachial nerve in another by open technique. The mean length of the retrieved sural nerve was 34.5 cm in the closed technique group and 35 cm in the limited open technique group. We detected advancing Tinel's sign in all nerve stripper-assisted sural nerve harvested group members in both the closed and limited open groups. Sural nerve harvesting by the nerve stripper is a reliable and simple technique, and it is applicable as a routine technique. Applying controlled rotatory movements of the nerve stripper instead of pushing can result in satisfactory harvesting of the sural nerve without early laceration. Georg Thieme Verlag KG Stuttgart · New York.

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

NASA Astrophysics Data System (ADS)

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

2016-05-01

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

Increased expression of CaV3.2 T-type calcium channels in damaged DRG neurons contributes to neuropathic pain in rats with spared nerve injury.

PubMed

Kang, Xue-Jing; Chi, Ye-Nan; Chen, Wen; Liu, Feng-Yu; Cui, Shuang; Liao, Fei-Fei; Cai, Jie; Wan, You

2018-01-01

Ion channels are very important in the peripheral sensitization in neuropathic pain. Our present study aims to investigate the possible contribution of Ca V 3.2 T-type calcium channels in damaged dorsal root ganglion neurons in neuropathic pain. We established a neuropathic pain model of rats with spared nerve injury. In these model rats, it was easy to distinguish damaged dorsal root ganglion neurons (of tibial nerve and common peroneal nerve) from intact dorsal root ganglion neurons (of sural nerves). Our results showed that Ca V 3.2 protein expression increased in medium-sized neurons from the damaged dorsal root ganglions but not in the intact ones. With whole cell patch clamp recording technique, it was found that after-depolarizing amplitudes of the damaged medium-sized dorsal root ganglion neurons increased significantly at membrane potentials of -85 mV and -95 mV. These results indicate a functional up-regulation of Ca V 3.2 T-type calcium channels in the damaged medium-sized neurons after spared nerve injury. Behaviorally, blockade of Ca V 3.2 with antisense oligodeoxynucleotides could significantly reverse mechanical allodynia. These results suggest that Ca V 3.2 T-type calcium channels in damaged medium-sized dorsal root ganglion neurons might contribute to neuropathic pain after peripheral nerve injury.

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

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

Trends in the design of nerve guidance channels in peripheral nerve tissue engineering.

PubMed

Chiono, Valeria; Tonda-Turo, Chiara

2015-08-01

The current trend of peripheral nerve tissue engineering is the design of advanced nerve guidance channels (NGCs) acting as physical guidance for regeneration of nerves across lesions. NGCs should present multifunctional properties aiming to direct the sprouting of axons from the proximal nerve end, to concentrate growth factors secreted by the injured nerve ends, and to reduce the ingrowth of scar tissue into the injury site. A critical aspect in the design of NGCs is conferring them the ability to provide topographic, chemotactic and haptotactic cues that lead to functional nerve regeneration thus increasing the axon growth rate and avoiding or minimizing end-organ (e.g. muscle) atrophy. The present work reviews the recent state of the art in NGCs engineering and defines the external guide and internal fillers structural and compositional requirements that should be satisfied to improve nerve regeneration, especially in the case of large gaps (>2 cm). Techniques for NGCs fabrication were described highlighting the innovative approaches direct to enhance the regeneration of axon stumps compared to current clinical treatments. Furthermore, the possibility to apply stem cells as internal cues to the NGCs was discussed focusing on scaffold properties necessary to ensure cell survival. Finally, the optimized features for NGCs design were summarized showing as multifunctional cues are needed to produce NGCs having improved results in clinics. Copyright © 2015 Elsevier Ltd. All rights reserved.

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.

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.

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

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.

Neonatal hyperthyroidism impairs epinephrine-provoked secretion of nerve growth factor and epidermal growth factor in mouse saliva.

PubMed

Lakshmanan, J; Landel, C P

1986-07-01

We examined long-term effects of neonatal hyperthyroidism on salivary secretions of nerve growth factor and epidermal growth factor in male and female mice at the age of 31 days. Hyperthyroidism was induced by thyroxine (T4) injections (0.4 microgram/g body weight/day) during days 0-6. Littermate control mice were treated with vehicle. T4 treatment did not alter the amounts of protein secreted into saliva but hormone administration induced alteration in the types of protein secreted. T4 treatment decreased the contents of both nerve growth factor and epidermal growth factor secreted into the saliva. A Sephadex G-200 column chromatographic profile revealed the presence of two distinct nerve growth factor immunoreactive peaks, while epidermal growth factor immunoreactivity predominantly eluted as a single low molecular weight form. T4 treatment did not alter the molecular nature of their secretion, but the treatment decreased their contents. These results indicate an impairment in salivary secretion of nerve growth factor and epidermal growth factor long after T4 treatment has been discontinued.

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

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.

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.

Engineering a multimodal nerve conduit for repair of injured peripheral nerve

NASA Astrophysics Data System (ADS)

Quigley, A. F.; Bulluss, K. J.; Kyratzis, I. L. B.; Gilmore, K.; Mysore, T.; Schirmer, K. S. U.; Kennedy, E. L.; O'Shea, M.; Truong, Y. B.; Edwards, S. L.; Peeters, G.; Herwig, P.; Razal, J. M.; Campbell, T. E.; Lowes, K. N.; Higgins, M. J.; Moulton, S. E.; Murphy, M. A.; Cook, M. J.; Clark, G. M.; Wallace, G. G.; Kapsa, R. M. I.

2013-02-01

Injury to nerve tissue in the peripheral nervous system (PNS) results in long-term impairment of limb function, dysaesthesia and pain, often with associated psychological effects. Whilst minor injuries can be left to regenerate without intervention and short gaps up to 2 cm can be sutured, larger or more severe injuries commonly require autogenous nerve grafts harvested from elsewhere in the body (usually sensory nerves). Functional recovery is often suboptimal and associated with loss of sensation from the tissue innervated by the harvested nerve. The challenges that persist with nerve repair have resulted in development of nerve guides or conduits from non-neural biological tissues and various polymers to improve the prognosis for the repair of damaged nerves in the PNS. This study describes the design and fabrication of a multimodal controlled pore size nerve regeneration conduit using polylactic acid (PLA) and (PLA):poly(lactic-co-glycolic) acid (PLGA) fibers within a neurotrophin-enriched alginate hydrogel. The nerve repair conduit design consists of two types of PLGA fibers selected specifically for promotion of axonal outgrowth and Schwann cell growth (75:25 for axons; 85:15 for Schwann cells). These aligned fibers are contained within the lumen of a knitted PLA sheath coated with electrospun PLA nanofibers to control pore size. The PLGA guidance fibers within the nerve repair conduit lumen are supported within an alginate hydrogel impregnated with neurotrophic factors (NT-3 or BDNF with LIF, SMDF and MGF-1) to provide neuroprotection, stimulation of axonal growth and Schwann cell migration. The conduit was used to promote repair of transected sciatic nerve in rats over a period of 4 weeks. Over this period, it was observed that over-grooming and self-mutilation (autotomy) of the limb implanted with the conduit was significantly reduced in rats implanted with the full-configuration conduit compared to rats implanted with conduits containing only an alginate

Laser-activated protein bands for peripheral nerve repair

NASA Astrophysics Data System (ADS)

Lauto, Antonio; Trickett, Rodney I.; Malik, Richard; Dawes, Judith M.; Owen, Earl R.

1996-01-01

A 100 micrometer core optical fiber-coupled 75 mW diode laser operating at a wavelength of 800 nm has been used in conjunction with a protein solder to stripe weld severed rat tibial nerves, reducing the long operating time required for microsurgical nerve repair. Welding is produced by selective laser denaturation of the protein based solder which contains the dye indocyanine green. Operating time for laser soldering was 10 plus or minus 5 min. (n equals 24) compared to 23 plus or minus 9 min (n equals 13) for microsuturing. The laser solder technique resulted in patent welds with a tensile strength of 15 plus or minus 5 g, while microsutured nerves had a tensile strength of 40 plus or minus 10 g. Histopathology of the laser soldered nerves, conducted immediately after surgery, displayed solder adhesion to the outer membrane with minimal damage to the inner axons of the nerves. An in vivo study, with a total of fifty-seven adult male wistar rats, compared laser solder repaired tibial nerves to conventional microsuture repair. Twenty-four laser soldered nerves and thirteen sutured nerves were characterized at three months and showed successful regeneration with average compound muscle action potentials (CMAP) of 2.4 plus or minus 0.7 mV and 2.7 plus or minus 0.8 mV respectively. Histopathology of the in vivo study, confirmed the comparable regeneration of axons in laser and suture operated nerves. A faster, less damaging and long lasting laser based anastomotic technique is presented.

[Sural nerve removal using a nerve stripper].

PubMed

Assmus, H

1983-03-01

In 19 patients the sural nerve was removed for nerve grafting by a specially designed nerve stripper. This technique provides a safe and time-saving removal of the nerve in length up to 34 cm (depending on the length of the stripper used). From a single short incision at the level of the lateral malleolus the nerve is stripped proximally tearing some small branches of the distal nerve. The relatively blunt tip avoids inadvertent transection of the nerve at a lower level or dissection of the nerve at a point where branching occurs. Finally the nerve is cut by the divided cylinder at the tip of the stripper.

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

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

End-to-side neurorrhaphy repairs peripheral nerve injury: sensory nerve induces motor nerve regeneration.

PubMed

Yu, Qing; Zhang, She-Hong; Wang, Tao; Peng, Feng; Han, Dong; Gu, Yu-Dong

2017-10-01

End-to-side neurorrhaphy is an option in the treatment of the long segment defects of a nerve. It involves suturing the distal stump of the disconnected nerve (recipient nerve) to the side of the intimate adjacent nerve (donor nerve). However, the motor-sensory specificity after end-to-side neurorrhaphy remains unclear. This study sought to evaluate whether cutaneous sensory nerve regeneration induces motor nerves after end-to-side neurorrhaphy. Thirty rats were randomized into three groups: (1) end-to-side neurorrhaphy using the ulnar nerve (mixed sensory and motor) as the donor nerve and the cutaneous antebrachii medialis nerve as the recipient nerve; (2) the sham group: ulnar nerve and cutaneous antebrachii medialis nerve were just exposed; and (3) the transected nerve group: cutaneous antebrachii medialis nerve was transected and the stumps were turned over and tied. At 5 months, acetylcholinesterase staining results showed that 34% ± 16% of the myelinated axons were stained in the end-to-side group, and none of the myelinated axons were stained in either the sham or transected nerve groups. Retrograde fluorescent tracing of spinal motor neurons and dorsal root ganglion showed the proportion of motor neurons from the cutaneous antebrachii medialis nerve of the end-to-side group was 21% ± 5%. In contrast, no motor neurons from the cutaneous antebrachii medialis nerve of the sham group and transected nerve group were found in the spinal cord segment. These results confirmed that motor neuron regeneration occurred after cutaneous nerve end-to-side neurorrhaphy.

End-to-side neurorrhaphy repairs peripheral nerve injury: sensory nerve induces motor nerve regeneration

PubMed Central

Yu, Qing; Zhang, She-hong; Wang, Tao; Peng, Feng; Han, Dong; Gu, Yu-dong

2017-01-01

End-to-side neurorrhaphy is an option in the treatment of the long segment defects of a nerve. It involves suturing the distal stump of the disconnected nerve (recipient nerve) to the side of the intimate adjacent nerve (donor nerve). However, the motor-sensory specificity after end-to-side neurorrhaphy remains unclear. This study sought to evaluate whether cutaneous sensory nerve regeneration induces motor nerves after end-to-side neurorrhaphy. Thirty rats were randomized into three groups: (1) end-to-side neurorrhaphy using the ulnar nerve (mixed sensory and motor) as the donor nerve and the cutaneous antebrachii medialis nerve as the recipient nerve; (2) the sham group: ulnar nerve and cutaneous antebrachii medialis nerve were just exposed; and (3) the transected nerve group: cutaneous antebrachii medialis nerve was transected and the stumps were turned over and tied. At 5 months, acetylcholinesterase staining results showed that 34% ± 16% of the myelinated axons were stained in the end-to-side group, and none of the myelinated axons were stained in either the sham or transected nerve groups. Retrograde fluorescent tracing of spinal motor neurons and dorsal root ganglion showed the proportion of motor neurons from the cutaneous antebrachii medialis nerve of the end-to-side group was 21% ± 5%. In contrast, no motor neurons from the cutaneous antebrachii medialis nerve of the sham group and transected nerve group were found in the spinal cord segment. These results confirmed that motor neuron regeneration occurred after cutaneous nerve end-to-side neurorrhaphy. PMID:29171436

Occipital peripheral nerve stimulation in the management of chronic intractable occipital neuralgia in a patient with neurofibromatosis type 1: a case report.

PubMed

Skaribas, Ioannis; Calvillo, Octavio; Delikanaki-Skaribas, Evangelia

2011-05-10

Occipital peripheral nerve stimulation is an interventional pain management therapy that provides beneficial results in the treatment of refractory chronic occipital neuralgia. Herein we present a first-of-its-kind case study of a patient with neurofibromatosis type 1 and bilateral occipital neuralgia treated with occipital peripheral nerve stimulation. A 42-year-old Caucasian woman presented with bilateral occipital neuralgia refractory to various conventional treatments, and she was referred for possible treatment with occipital peripheral nerve stimulation. She was found to be a suitable candidate for the procedure, and she underwent implantation of two octapolar stimulating leads and a rechargeable, programmable, implantable generator. The intensity, severity, and frequency of her symptoms resolved by more than 80%, but an infection developed at the implantation site two months after the procedure that required explantation and reimplantation of new stimulating leads three months later. To date she continues to experience symptom resolution of more than 60%. These results demonstrate the significance of peripheral nerve stimulation in the management of refractory occipital neuralgias in patients with neurofibromatosis type 1 and the possible role of neurofibromata in the development of occipital neuralgia in these patients.

Occipital peripheral nerve stimulation in the management of chronic intractable occipital neuralgia in a patient with neurofibromatosis type 1: a case report

PubMed Central

2011-01-01

Introduction Occipital peripheral nerve stimulation is an interventional pain management therapy that provides beneficial results in the treatment of refractory chronic occipital neuralgia. Herein we present a first-of-its-kind case study of a patient with neurofibromatosis type 1 and bilateral occipital neuralgia treated with occipital peripheral nerve stimulation. Case presentation A 42-year-old Caucasian woman presented with bilateral occipital neuralgia refractory to various conventional treatments, and she was referred for possible treatment with occipital peripheral nerve stimulation. She was found to be a suitable candidate for the procedure, and she underwent implantation of two octapolar stimulating leads and a rechargeable, programmable, implantable generator. The intensity, severity, and frequency of her symptoms resolved by more than 80%, but an infection developed at the implantation site two months after the procedure that required explantation and reimplantation of new stimulating leads three months later. To date she continues to experience symptom resolution of more than 60%. Conclusion These results demonstrate the significance of peripheral nerve stimulation in the management of refractory occipital neuralgias in patients with neurofibromatosis type 1 and the possible role of neurofibromata in the development of occipital neuralgia in these patients. PMID:21569290

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

Association of vagus nerve severance and decreased risk of subsequent type 2 diabetes in peptic ulcer patients

PubMed Central

Wu, Shih-Chi; Chen, William Tzu-Liang; Fang, Chu-Wen; Muo, Chih-Hsin; Sung, Fung-Chang; Hsu, Chung Y.

2016-01-01

Abstract Vagus nerve may play a role in serum glucose modulation. The complicated peptic ulcer patients (with perforation or/and bleeding) who received surgical procedures with or without vagotomy provided 2 patient populations for studying the impact of vagus nerve integrity. We assessed the risk of developing type 2 diabetes in peptic ulcer patients without and with complications by surgical treatment received in a retrospective population study using the National Health Insurance database in Taiwan. A cohort of 163,385 patients with peptic ulcer and without Helicobacter pylori infection in 2000 to 2003 was established. A randomly selected cohort of 163,385 persons without peptic ulcer matched by age, sex, hypertension, hyperlipidemia, Charlson comorbidity index score, and index year was utilized for comparison. The risks of developing diabetes in both cohorts and in the complicated peptic ulcer patients who received truncal vagotomy or simple suture/hemostasis (SSH) were assessed at the end of 2011. The overall diabetes incidence was higher in patients with peptic ulcer than those without peptic ulcer (15.87 vs 12.60 per 1000 person-years) by an adjusted hazard ratio (aHR) of 1.43 (95% confidence interval [CI] = 1.40–1.47) based on the multivariable Cox proportional hazards regression analysis (competing risk). Comparing ulcer patients with truncal vagotomy and SSH or those without surgical treatment, the aHR was the lowest in the vagotomy group (0.48, 95% CI = 0.41–0.56). Peptic ulcer patients have an elevated risk of developing type 2 diabetes. Moreover, there were associations of vagus nerve severance and decreased risk of subsequent type 2 diabetes in complicated peptic ulcer patients. PMID:27930533

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

Rotavirus A genotype G1P[8]: a novel method to distinguish wild-type strains from the Rotarix vaccine strain.

PubMed

Rose, Tatiana L; Miagostovich, Marize P; Leite, José Paulo G

2010-12-01

Rotaviruses are important enteric pathogens for humans and animals. Group A rotaviruses (RV-A) are the most common agents of severe gastroenteritis in infants and young children and vaccination is the most effective method to reduce RV-A-associated diseases. G1P[8], the most prevalent RV-A genotype worldwide, is included in the RV-A vaccine Rotarix®. The discrimination between wild-type G1P[8] and vaccine G1P[8] strains is an important topic in the study of RV-A epidemiology to manage outbreaks and to define control measures for vaccinated children. In this study, we developed a novel method to segregate the wild-type and vaccine strains using restriction endonucleases. The dsRNA from the Rotarix® vaccine was sequenced and the NSP3 gene was selected as the target gene. The vaccine strain has a restriction pattern that is different than that of wild-type RV-A G1P[8] isolates after digestion with the restriction endonuclease BspHI. This pattern could be used as a marker for the differentiation of wild-type G1P[8] strains from the vaccine strain.

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.

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.

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

PubMed

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

2008-09-01

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

Myricetin arrests human telomeric G-quadruplex structure: a new mechanistic approach as an anticancer agent.

PubMed

Mondal, Soma; Jana, Jagannath; Sengupta, Pallabi; Jana, Samarjit; Chatterjee, Subhrangsu

2016-07-19

The use of small molecules to arrest G-quadruplex structure has become a potential strategy for the development and design of a new class of anticancer therapeutics. We have studied the interaction of myricetin, a plant flavonoid and a putative anticancer agent, with human telomeric G-quadruplex TTAGGG(TTAGGG)3 DNA. Reverse transcription PCR data revealed significant repression in hTERT expression in MCF-7 breast cancer cells upon increasing the concentration of myricetin. Further, we conducted a telomeric repeat amplification protocol assay to confirm the inhibition of telomerase by myricetin. Optical spectroscopic techniques like circular dichroism, UV spectroscopy and fluorescence spectroscopy revealed the formation of a stable myricetin-G-quadruplex complex. The thermodynamic parameters of myricetin-G-quadruplex complex formation, presented through isothermal titration calorimetry studies, indicate the binding process to be thermodynamically favorable. In addition, high resolution NMR spectroscopy in conjunction with molecular dynamics simulation is employed to provide detailed mechanistic insights into the binding in the myricetin-G-quadruplex complex at the atomic level. Our results thus propose a new mode of action of myricetin as an anticancer agent via arresting telomeric G-quadruplex structure.

Oral Transmission of L-Type Bovine Spongiform Encephalopathy Agent among Cattle.

PubMed

Okada, Hiroyuki; Iwamaru, Yoshifumi; Imamura, Morikazu; Miyazawa, Kohtaro; Matsuura, Yuichi; Masujin, Kentaro; Murayama, Yuichi; Yokoyama, Takashi

2017-02-01

To determine oral transmissibility of the L-type bovine spongiform encephalopathy (BSE) prion, we orally inoculated 16 calves with brain homogenates of the agent. Only 1 animal, given a high dose, showed signs and died at 88 months. These results suggest low risk for oral transmission of the L-BSE agent among cattle.

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

Optimization of four types of antimicrobial agents to increase the inhibitory ability of marine Arthrobacter oxydans KQ11 dextranase mouthwash

NASA Astrophysics Data System (ADS)

Ren, Wei; Wang, Shujun; Lü, Mingsheng; Wang, Xiaobei; Fang, Yaowei; Jiao, Yuliang; Hu, Jianen

2016-03-01

We adopted the response surface methodology using single factor and orthogonal experiments to optimize four types of antimicrobial agents that could inhibit biofilm formation by Streptococcus mutans, which is commonly found in the human oral cavity and causes tooth decay. The objective was to improve the function of marine Arthrobacter oxydans KQ11 dextranase mouthwash (designed and developed by our laboratory). The experiment was conducted in a three-level, four-variable central composite design to determine the best combination of ZnSO4, lysozyme, citric acid and chitosan. The optimized antibacterial agents were 2.16 g/L ZnSO4, 14 g/L lysozyme, 4.5 g/L citric acid and 5 g/L chitosan. The biofilm formation inhibition reached 84.49%. In addition, microscopic observation of the biofilm was performed using scanning electron microscopy and confocal laser scanning microscopy. The optimized formula was tested in marine dextranase Arthrobacter oxydans KQ11 mouthwash and enhanced the inhibition of S. mutans. This work may be promoted for the design and development of future marine dextranase oral care products.

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

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

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

Liu, Guodong; Lin, Yuehe

2005-09-15

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

High-resolution measurement of electrically-evoked vagus nerve activity in the anesthetized dog

NASA Astrophysics Data System (ADS)

Yoo, Paul B.; Lubock, Nathan B.; Hincapie, Juan G.; Ruble, Stephen B.; Hamann, Jason J.; Grill, Warren M.

2013-04-01

Objective. Not fully understanding the type of axons activated during vagus nerve stimulation (VNS) is one of several factors that limit the clinical efficacy of VNS therapies. The main goal of this study was to characterize the electrical recruitment of both myelinated and unmyelinated fibers within the cervical vagus nerve. Approach. In anesthetized dogs, recording nerve cuff electrodes were implanted on the vagus nerve following surgical excision of the epineurium. Both the vagal electroneurogram (ENG) and laryngeal muscle activity were recorded in response to stimulation of the right vagus nerve. Main results. Desheathing the nerve significantly increased the signal-to-noise ratio of the ENG by 1.2 to 9.9 dB, depending on the nerve fiber type. Repeated VNS following nerve transection or neuromuscular block (1) enabled the characterization of A-fibers, two sub-types of B-fibers, and unmyelinated C-fibers, (2) confirmed the absence of stimulation-evoked reflex compound nerve action potentials in both the ipsilateral and contralateral vagus nerves, and (3) provided evidence of stimulus spillover into muscle tissue surrounding the stimulating electrode. Significance. Given the anatomical similarities between the canine and human vagus nerves, the results of this study provide a template for better understanding the nerve fiber recruitment patterns associated with VNS therapies.

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

Facial nerve paralysis associated with temporal bone masses.

PubMed

Nishijima, Hironobu; Kondo, Kenji; Kagoya, Ryoji; Iwamura, Hitoshi; Yasuhara, Kazuo; Yamasoba, Tatsuya

2017-10-01

To investigate the clinical and electrophysiological features of facial nerve paralysis (FNP) due to benign temporal bone masses (TBMs) and elucidate its differences as compared with Bell's palsy. FNP assessed by the House-Brackmann (HB) grading system and by electroneurography (ENoG) were compared retrospectively. We reviewed 914 patient records and identified 31 patients with FNP due to benign TBMs. Moderate FNP (HB Grades II-IV) was dominant for facial nerve schwannoma (FNS) (n=15), whereas severe FNP (Grades V and VI) was dominant for cholesteatomas (n=8) and hemangiomas (n=3). The average ENoG value was 19.8% for FNS, 15.6% for cholesteatoma, and 0% for hemangioma. Analysis of the correlation between HB grade and ENoG value for FNP due to TBMs and Bell's palsy revealed that given the same ENoG value, the corresponding HB grade was better for FNS, followed by cholesteatoma, and worst in Bell's palsy. Facial nerve damage caused by benign TBMs could depend on the underlying pathology. Facial movement and ENoG values did not correlate when comparing TBMs and Bell's palsy. When the HB grade is found to be unexpectedly better than the ENoG value, TBMs should be included in the differential diagnosis. Copyright © 2017 Elsevier B.V. All rights reserved.

Multiple schwannomas of the digital nerves and superficial radial nerve: two unusual cases of segmental schwannomatosis.

PubMed

Gosk, Jerzy; Gutkowska, Olga; Kuliński, Sebastian; Urban, Maciej; Hałoń, Agnieszka

2015-01-01

Two cases of segmental sporadic schwannomatosis characterized by unusual location of multiple schwannomas in digital nerves (case 1) and the superficial radial nerve (case 2) are described in this paper. In the first of the described cases, 6 tumours located at the base of the middle finger and in its distal portion were excised from both digital nerves. In the second case, 3 tumours located in the proximal 1/3 and halfway down the forearm were removed from the superficial radial nerve. In both cases, symptoms such as palpable tumour mass, pain, paraesthesias, and positive Tinel-Hoffman sign resolved after operative treatment. Final diagnoses were made based on histopathological examination results. In the second of the described cases, the largest of the excised lesions had features enabling diagnosis of a rare tumour type - ancient schwannoma.

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.

Patterning of sympathetic nerve activity in response to vestibular stimulation

NASA Technical Reports Server (NTRS)

Kerman, I. A.; McAllen, R. M.; Yates, B. J.

2000-01-01

Growing evidence suggests a role for the vestibular system in regulation of autonomic outflow during postural adjustments. In the present paper we review evidence for the patterning of sympathetic nerve activity elicited by vestibular stimulation. In response to electrical activation of vestibular afferents, firing of sympathetic nerves located throughout the body is altered. However, activity of the renal nerve is most sensitive to vestibular inputs. In contrast, high-intensity simultaneous activation of cutaneous and muscle inputs elicits equivalent changes in firing of the renal, superior mesenteric and lumbar colonic nerves. Responses of muscle vasoconstrictor (MVC) efferents to vestibular stimulation are either inhibitory (Type I) or are comprised of a combination of excitation and inhibition (Type II). Interestingly, single MVC units located in the hindlimb exhibited predominantly Type I responses while those located in the forelimb and face exhibited Type II responses. Furthermore, brachial and femoral arterial blood flows were dissociated in response to vestibular stimulation, such that brachial vascular resistance increased while femoral resistance decreased. These studies demonstrate that vestibulosympathetic reflexes are patterned according to both the anatomical location and innervation target of a particular sympathetic nerve, and can lead to distinct changes in local blood flow.

Diabetic Foot Syndrome and Corneal Subbasal Nerve Plexus Changes in Congolese Patients with Type 2 Diabetes

PubMed Central

Schober, Hans-Christof; Stachs, Oliver; Baltrusch, Simone; Bambi, Marie Therese; Kilangalanga, Janvier; Winter, Karsten; Kundt, Guenther; Guthoff, Rudolf F.

2015-01-01

Background To study the severity of diabetic neuropathy, diabetic retinopathy and grades of diabetic foot syndrome for correlations with corneal subbasal nerve plexus (SBP) changes in Congolese patients with type 2 diabetes. Methodology/Principal Findings Twenty-eight type 2 diabetes patients with diabetes-related foot ulceration were recruited in a diabetic care unit in Kinshasa, Democratic Republic of Congo. Corneal SBP was investigated by confocal laser-scanning microscopy to analyse nerve fibre density (NFD) [µm/ µm²], number of branches [n] and number of connectivity points [n]. Foot ulceration was graded using the Wagner ulcer classification. Corneal sensitivity (Cochet-Bonnet), Neuropathy Symptom Score (NSS), Neuropathy Disability Score (NDS), ankle-brachial index (ABI) and ophthalmological status were evaluated. Foot ulceration was ranked as mild (Wagner 0-1: 13 patients/46.4%), moderate (Wagner 2-3: 10 patients/35.7%) and severe (Wagner 4-5: 5 patients/17.9%). The correlation between Wagner Score and NFD (p=0.017, r = - 0,454), NDS and NFD (p=0,039, r = - 0.400) as well as Wagner Score and HbA1c (p=0,007, r = - 0.477) was stated. Significant differences in confocal SBP parameters were observed between Wagner 0-1 and Wagner 4 5 (number of branches (p=0.012), number of connectivity points (p=0.001), nerve fibre density (p=0.033)) and ABI (p=0.030), and between Wagner 2-3 and Wagner 4-5 (number of branches (p=0.003), number of connectivity points (p=0.005) and nerve fibre density (p=0.014)). Differences in NDS (p=0.001) and corneal sensation (p=0.032) were significant between Wagner 0-1 and Wagner 2-3. Patients with diabetic retinopathy had significantly longer diabetes duration (p=0.03) and higher NDS (p=0.01), but showed no differences in SBP morphology or corneal sensation. Conclusions/Significance While confirming the diabetic aetiology of foot ulceration due to medial arterial calcification, this study indicates that the grade of diabetic foot

Effects of nerve cells and adhesion molecules on nerve conduit for peripheral nerve regeneration

PubMed Central

Fiorellini, Joseph P.

2017-01-01

Background For peripheral nerve regeneration, recent attentions have been paid to the nerve conduits made by tissue-engineering technique. Three major elements of tissue-engineering are cells, molecules, and scaffolds. Methods In this study, the attachments of nerve cells, including Schwann cells, on the nerve conduit and the effects of both growth factor and adhesion molecule on these attachments were investigated. Results The attachment of rapidly-proliferating cells, C6 cells and HS683 cells, on nerve conduit was better than that of slowly-proliferating cells, PC12 cells and Schwann cells, however, the treatment of nerve growth factor improved the attachment of slowly-proliferating cells. In addition, the attachment of Schwann cells on nerve conduit coated with fibronectin was as good as that of Schwann cells treated with glial cell line-derived neurotrophic factor (GDNF). Conclusions Growth factor changes nerve cell morphology and affects cell cycle time. And nerve growth factor or fibronectin treatment is indispensable for Schwann cell to be used for implantation in artificial nerve conduits. PMID:29090249

Ionotropic and metabotropic receptor mediated airway sensory nerve activation.

PubMed

Lee, Min-Goo; Kollarik, Marian; Chuaychoo, Benjamas; Undem, Bradley J

2004-01-01

There are several receptors capable of inducing activating generator potentials in cough-associated afferent terminals in the airways. The chemical receptors leading to generator potentials can be subclassified into ionotropic and metabotropic types. An ionotropic receptor has an agonist-binding domain, and also serves directly as an ion channel that is opened upon binding of the agonist. Examples of ionotropic receptors found in airway sensory nerve terminals include receptors for serotonin (5-HT3 receptors), ATP (P2X receptors), acetylcholine (nicotinic receptors), receptors for capsaicin and related vanilloids (TRPV1 receptors), and acid receptors (acid sensing ion channels). Afferent nerve terminals can also be depolarized via activation of metabotropic or G-protein coupled receptors (GPCRs). Among the GPCRs that can lead to activation of airway afferent fibers include bradykinin B2 and adenosine A1 receptors. The signaling events leading to GPCR-mediated membrane depolarization are more complex than that seen with ionotropic receptors. The GPCR-mediated effects are thought to occur through classical second messenger systems such as activation of phospholipase C. This may lead to membrane depolarization through interaction with specific ionotropic receptors (such as TRPV1) and/or various types of calcium activated channels.

IgG4-related cerebral pseudotumor with perineural spreading along branches of the trigeminal nerves causing compressive optic neuropathy: A case report.

PubMed

Wu, Po-Chang; Tien, Peng-Tai; Li, Ying-Hsuan; Chen, Rui-Yun; Cho, Der-Yang

2017-11-01

Immunoglobulin G4-related disease (IgG4-RD) is characterized by tumor-like lesions, a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis. IgG4-RD has been described in a variety of organ systems; however, it rarely involves the central nervous system. A 17-year-old woman visited our clinic with a complaint of blurred vision for the past 5 months. She also reported a painless right submandibular mass that had been present for 1 year. Her best-corrected visual acuity (BCVA) was 2.0 LogMAR, with an almost total visual field defect in the right eye. Magnetic resonance imaging (MRI) revealed lobulated parasellar tumors with perineural spreading along branches of the trigeminal nerves causing right optic nerve compression. A craniotomy with tumor removal and submandibular gland biopsy was performed. Histopathological analysis of the tumor revealed stromal fibrosis with atypical lymphoid infiltrations. Histopathological and immunohistochemical analysis of the submandibular gland confirmed the diagnosis of IgG4-RD. The patient was administered 500mg/d of pulse methylprednisolone for 3 days, 500mg of intravenous rituximab every 2 weeks (for a total of 2 doses), and 500mg of intravenous pulse cyclophosphamide every month (for a total of 3 doses). Two months after the initiation of immunosuppressive therapy, the patient's BCVA returned to 0.1 LogMAR with visual field defect recovery. The follow-up MRI showed the almost complete disappearance of the previously contrast-enhanced lesions. Herein, we report a rare case of IgG4-RD presenting as a parasellar tumor and present a review of the related literature. Based on the case report, we propose that aggressive therapy with glucocorticoid, rituximab, and cyclophosphamide may potentially be useful for treating such cases. Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.

Patients with chronic tension-type headache demonstrate increased mechano-sensitivity of the supra-orbital nerve.

PubMed

Fernández-de-Las-Peñas, César; Coppieters, Michel W; Cuadrado, María Luz; Pareja, Juan A

2008-04-01

This study aimed to establish whether increased sensitivity to mechanical stimuli is present in neural tissues in chronic tension-type headache (CTTH). Muscle hyperalgesia is a common finding in CTTH. No previous studies have investigated the sensitivity of peripheral nerves in patients with CTTH. A blinded controlled study. Pressure pain thresholds (PPT) and pain intensity following palpation of the supra-orbital nerve (V1) were compared between 20 patients with CTTH and 20 healthy matched subjects. A pressure algometer and numerical pain rate scale were used to quantify PPT and pain to palpation. A headache diary was kept for 4 weeks to substantiate the diagnosis and record the pain history. The analysis of variance demonstrated significantly lower PPT for patients (0.86+/-0.13 kg/cm2) than controls (1.50+/-0.19 kg/cm2) (P<.001). Pain to palpation was also higher for patients (2.73+/-1.58) than controls (0.15+/-0.28) (P<.001). Within the CTTH group, intensity, frequency, and duration of the headaches were negatively correlated with PPT (rsor=0.72; P<.001). These findings reveal that mechanical hypersensitivity is not limited to muscles but also occurs in cranial nerves, and that the level of sensitization, either due to peripheral or central processes, is related to the severity of the primary headache.

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

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.

Raman spectroscopic detection of peripheral nerves towards nerve-sparing surgery

NASA Astrophysics Data System (ADS)

Minamikawa, Takeo; Harada, Yoshinori; Takamatsu, Tetsuro

2017-02-01

The peripheral nervous system plays an important role in motility, sensory, and autonomic functions of the human body. Preservation of peripheral nerves in surgery, namely nerve-sparing surgery, is now promising technique to avoid functional deficits of the limbs and organs following surgery as an aspect of the improvement of quality of life of patients. Detection of peripheral nerves including myelinated and unmyelinated nerves is required for the nerve-sparing surgery; however, conventional nerve identification scheme is sometimes difficult to identify peripheral nerves due to similarity of shape and color to non-nerve tissues or its limited application to only motor peripheral nerves. To overcome these issues, we proposed a label-free detection technique of peripheral nerves by means of Raman spectroscopy. We found several fingerprints of peripheral myelinated and unmyelinated nerves by employing a modified principal component analysis of typical spectra including myelinated nerve, unmyelinated nerve, and adjacent tissues. We finally realized the sensitivity of 94.2% and the selectivity of 92.0% for peripheral nerves including myelinated and unmyelinated nerves against adjacent tissues. Although further development of an intraoperative Raman spectroscopy system is required for clinical use, our proposed approach will serve as a unique and powerful tool for peripheral nerve detection for nerve-sparing surgery in the future.

Different types of spinal afferent nerve endings in stomach and esophagus identified by anterograde tracing from dorsal root ganglia.

PubMed

Spencer, Nick J; Kyloh, Melinda; Beckett, Elizabeth A; Brookes, Simon; Hibberd, Tim

2016-10-15

In visceral organs of mammals, most noxious (painful) stimuli as well as innocuous stimuli are detected by spinal afferent neurons, whose cell bodies lie in dorsal root ganglia (DRGs). One of the major unresolved questions is the location, morphology, and neurochemistry of the nerve endings of spinal afferents that actually detect these stimuli in the viscera. In the upper gastrointestinal (GI) tract, there have been many anterograde tracing studies of vagal afferent endings, but none on spinal afferent endings. Recently, we developed a technique that now provides selective labeling of only spinal afferents. We used this approach to identify spinal afferent nerve endings in the upper GI tract of mice. Animals were anesthetized, and injections of dextran-amine were made into thoracic DRGs (T8-T12). Seven days post surgery, mice were euthanized, and the stomach and esophagus were removed, fixed, and stained for calcitonin gene-related peptide (CGRP). Spinal afferent axons were identified that ramified extensively through many rows of myenteric ganglia and formed nerve endings in discrete anatomical layers. Most commonly, intraganglionic varicose endings (IGVEs) were identified in myenteric ganglia of the stomach and varicose simple-type endings in the circular muscle and mucosa. Less commonly, nerve endings were identified in internodal strands, blood vessels, submucosal ganglia, and longitudinal muscle. In the esophagus, only IGVEs were identified in myenteric ganglia. No intraganglionic lamellar endings (IGLEs) were identified in the stomach or esophagus. We present the first identification of spinal afferent endings in the upper GI tract. Eight distinct types of spinal afferent endings were identified in the stomach, and most of them were CGRP immunoreactive. J. Comp. Neurol. 524:3064-3083, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Optogenetic probing of nerve and muscle function after facial nerve lesion in the mouse whisker system

NASA Astrophysics Data System (ADS)

Bandi, Akhil; Vajtay, Thomas J.; Upadhyay, Aman; Yiantsos, S. Olga; Lee, Christian R.; Margolis, David J.

2018-02-01

Optogenetic modulation of neural circuits has opened new avenues into neuroscience research, allowing the control of cellular activity of genetically specified cell types. Optogenetics is still underdeveloped in the peripheral nervous system, yet there are many applications related to sensorimotor function, pain and nerve injury that would be of great benefit. We recently established a method for non-invasive, transdermal optogenetic stimulation of the facial muscles that control whisker movements in mice (Park et al., 2016, eLife, e14140)1. Here we present results comparing the effects of optogenetic stimulation of whisker movements in mice that express channelrhodopsin-2 (ChR2) selectively in either the facial motor nerve (ChAT-ChR2 mice) or muscle (Emx1-ChR2 or ACTA1-ChR2 mice). We tracked changes in nerve and muscle function before and up to 14 days after nerve transection. Optogenetic 460 nm transdermal stimulation of the distal cut nerve showed that nerve degeneration progresses rapidly over 24 hours. In contrast, the whisker movements evoked by optogenetic muscle stimulation were up-regulated after denervation, including increased maximum protraction amplitude, increased sensitivity to low-intensity stimuli, and more sustained muscle contractions (reduced adaptation). Our results indicate that peripheral optogenetic stimulation is a promising technique for probing the timecourse of functional changes of both nerve and muscle, and holds potential for restoring movement after paralysis induced by nerve damage or motoneuron degeneration.

Biological monitoring of exposure to nerve agents.

PubMed Central

Bajgar, J

1992-01-01

Changes in acetylcholinesterase activity in blood and some organs of rats after intoxication with sarin, soman, VX, and 2-dimethylaminoethyl-(dimethylamido)-phosphonofluoridate (GV), in doses of roughly 2 x LD50 given intramuscularly, were obtained from published data and by experiment. The time course of inhibition of acetylcholinesterase in blood, regions of brain, and diaphragm and the occurrence of signs and symptoms of poisoning (none, salivation, disturbed ventilation and fasciculations, convulsions, or death) were summarised and compared. When blood enzyme activities were 70-100% normal, no obvious signs were seen; at 60-70%, salivation occurred; at less than 30-55%, disturbed ventilation and fasciculations were seen, and at 15-30%, convulsions occurred. Less than 10% was fatal. In experiments with narcotised dogs, the blood acetylcholinesterase activity and the ability to reactivate it with trimedoxime were determined after intoxication by intramuscular administration of the four compounds. It is concluded that acetylcholinesterase activity in the blood corresponds to that in the target organs and can be considered as an appropriate parameter for biological monitoring of exposure to nerve gases. Moreover, determination of reactivation of blood acetylcholinesterase gives more information than simple determination of enzyme activity. PMID:1390271

[Biological agents].

PubMed

Amano, Koichi

2009-03-01

There are two types of biological agents for the treatment of rheumatoid arthritis (RA); monoclonal antibodies and recombinant proteins. Among the latter, etanercept, a recombinant fusion protein of soluble TNF receptor and IgG was approved in 2005 in Japan. The post-marketing surveillance of 13,894 RA patients revealed the efficacy and safety profiles of etanercept in the Japanese population, as well as overseas studies. Abatacept, a recombinant fusion protein of CTLA4 and IgG, is another biological agent for RA. Two clinical trials disclosed the efficacy of abatacept for difficult-to-treat patients: the AIM for MTX-resistant cases and the ATTAIN for patients who are resistant to anti-TNF. The ATTEST trial suggested abatacept might have more acceptable safety profile than infliximab. These biologics are also promising for the treatment of RA for not only relieving clinical symptoms and signs but retarding structural damage.

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

Repair of nerve injury by implanting prostheses obtained from isogenic acellular nerve segments.

PubMed

García-Medrano, B; Mesuro Domínguez, N; Simón Pérez, Cl; Garrosa García, M; Gayoso Del Villar, S; Mayo Íscar, A; Gayoso Rodríguez, M J; Martín Ferrero, M A

When a nerve section with a significant gap occurs, it is necessary to use a prosthesis to suture it. To date an autologous nerve segment graft appears to be the best treatment; but it has several important disadvantages. Our goal is to study the effectiveness of an isogenic acellular nerve prosthesis comparing a simple suture with tubulisation. Four groups of Wistar rats were used. The animals in Group 0 served as donors of nerve segments to graft. Group 1 received the implant with an end-to-end suture. In group 2, the implant was sutured inside an ɛ-caprolactone tube. Group 3 received it in a polylactic-co-glycolic acid tube. We evaluated the motor function (sciatic index and step test in motion), and the regeneration length by histological study of regeneration, after a maximum of 3 weeks. Regeneration was uneven in the three groups. In all groups, there were implants with regenerated nerve fibres at the maximum studied length (15mm) and others where regeneration was scarce. The mean regeneration length was greater in the direct end-to-end suture group (G1), although the regeneration speed was similar in the three groups. Group 1 showed the highest percentage of regeneration, but the variability of results prevents this difference reaching statistical significance. We found no significant differences between the two groups with polymer tubes. For the implantation of isogenic acellular nerve prosthesis, under our experimental conditions, the direct end-to-end suture was more effective than when it isprotected with biopolymer tubes. Copyright © 2017 SECOT. Publicado por Elsevier España, S.L.U. All rights reserved.

Acellular Nerve Allografts in Peripheral Nerve Regeneration: A Comparative Study

PubMed Central

Moore, Amy M.; MacEwan, Matthew; Santosa, Katherine B.; Chenard, Kristofer E.; Ray, Wilson Z.; Hunter, Daniel A.; Mackinnon, Susan E.; Johnson, Philip J.

2011-01-01

Background Processed nerve allografts offer a promising alternative to nerve autografts in the surgical management of peripheral nerve injuries where short deficits exist. Methods Three established models of acellular nerve allograft (cold-preserved, detergent-processed, and AxoGen® -processed nerve allografts) were compared to nerve isografts and silicone nerve guidance conduits in a 14 mm rat sciatic nerve defect. Results All acellular nerve grafts were superior to silicone nerve conduits in support of nerve regeneration. Detergent-processed allografts were similar to isografts at 6 weeks post-operatively, while AxoGen®-processed and cold-preserved allografts supported significantly fewer regenerating nerve fibers. Measurement of muscle force confirmed that detergent-processed allografts promoted isograft-equivalent levels of motor recovery 16 weeks post-operatively. All acellular allografts promoted greater amounts of motor recovery compared to silicone conduits. Conclusions These findings provide evidence that differential processing for removal of cellular constituents in preparing acellular nerve allografts affects recovery in vivo. PMID:21660979

A precision mechanical nerve stimulator

NASA Technical Reports Server (NTRS)

Tcheng, Ping; Supplee, Frank H., Jr.; Prass, Richard L.

1988-01-01

An electromechanical device, used to apply and monitor stimulating pulses to a mammalian motor nerve, has been successfully developed at NASA Langley Research Center. Two existing force transducers, a flight skin friction balance and a miniature skin friction balance which were designed for making aerodynamic drag measurements, were modified and incorporated to form this precision instrument. The nerve stimulator is a type one servomechanism capable of applying and monitoring stimulating pulses of 0 to 10 grams with a precision of better than +/- 0.05 grams. Additionally, the device can be independently used to apply stimulating pulses by displacing the nerve from 0 to 0.25 mm with a precision of better than +/- 0.001 mm while measuring the level of the load applied.

Nerve Transfer Versus Nerve Graft for Reconstruction of High Ulnar Nerve Injuries.

PubMed

Sallam, Asser A; El-Deeb, Mohamed S; Imam, Mohamed A

2017-04-01

To assess the efficacy of nerve transfer versus nerve grafting in restoring motor and sensory hand function in patients with complete, isolated high ulnar nerve injuries. A retrospective chart review was performed, at a minimum 2 years of follow-up, of 52 patients suffering complete, isolated high ulnar nerve injury between January 2006 and June 2013 in one specialized hand surgery unit. Twenty-four patients underwent motor and sensory nerve transfers (NT group). Twenty-eight patients underwent sural nerve grafting (NG group). Motor recovery, return of sensibility and complications were examined as outcome measures. The Medical Research Council scale was applied to evaluate sensory and motor recovery. Grip and pinch strengths of the hand were measured. Twenty of 24 patients (83.33%) in the NT group regained M3 grade or greater for the adductor pollicis, the abductor digiti minimi, and the medial 2 lumbricals and interossei, compared with only 16 of 28 patients (57.14%) in the NG group. Means for percentage recovery of grip strengths compared with the other healthy hand were significantly higher for the NT group than the NG group. Sensory recovery of S3 or greater was achieved in more than half of each group with no significant difference between groups. Nerve transfer is favored over nerve grafting in managing high ulnar nerve injuries because of better improvement of motor power and better restoration of grip functions of the hand. Therapeutic IV. Copyright © 2017 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.

Anomalous Bilateral Communication between the Inferior Alveolar Nerve and the Auriculotemporal Nerve: A Rare Variation

PubMed Central

BHARDWAJ, Nikha; SAHNI, Priya; SINGHVI, Abhishek; NAYAK, Meghanand; TIWARI, Vineeta

2014-01-01

Branches of the posterior division of the mandibular nerve show various anomalous communications in the infratemporal region. Understanding such communication has relevance in the management of neuropathies and surgical procedures in this region. This study was conducted to explore such communicating branches, anticipating that they might provide information of clinical significance. A total of 15 human cadavers (30 infratemporal regions) were studied to explore such communicating branches in infratemporal region. The branches of the posterior division of the mandibular nerve were carefully dissected, and these branches were studied and analysed for any abnormal course. In one case, a rare type of bilateral communication between the auriculotemporal nerve and the inferior alveolar nerve, forming a loop with no association with any structure, was observed. It is possible that such communicating branches may be associated with delayed regression of the first arch vessels. The clinical implications of these anomalous communications require further detailed study for improved management of neuropathies and surgical procedures. PMID:25977637

Photothermal therapy improves the efficacy of a MEK inhibitor in neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors

NASA Astrophysics Data System (ADS)

Sweeney, Elizabeth E.; Burga, Rachel A.; Li, Chaoyang; Zhu, Yuan; Fernandes, Rohan

2016-11-01

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive tumors with low survival rates and the leading cause of death in neurofibromatosis type 1 (NF1) patients under 40 years old. Surgical resection is the standard of care for MPNSTs, but is often incomplete and can generate loss of function, necessitating the development of novel treatment methods for this patient population. Here, we describe a novel combination therapy comprising MEK inhibition and nanoparticle-based photothermal therapy (PTT) for MPNSTs. MEK inhibitors block activity driven by Ras, an oncogene constitutively activated in NF1-associated MPNSTs, while PTT serves as a minimally invasive method to ablate cancer cells. Our rationale for combining these seemingly disparate techniques for MPNSTs is based on several reports demonstrating the efficacy of systemic chemotherapy with local PTT. We combine the MEK inhibitor, PD-0325901 (PD901), with Prussian blue nanoparticles (PBNPs) as PTT agents, to block MEK activity and simultaneously ablate MPNSTs. Our data demonstrate the synergistic effect of combining PD901 with PBNP-based PTT, which converge through the Ras pathway to generate apoptosis, necrosis, and decreased proliferation, thereby mitigating tumor growth and increasing survival of MPNST-bearing animals. Our results suggest the potential of this novel local-systemic combination “nanochemotherapy” for treating patients with MPNSTs.

Photothermal therapy improves the efficacy of a MEK inhibitor in neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors.

PubMed

Sweeney, Elizabeth E; Burga, Rachel A; Li, Chaoyang; Zhu, Yuan; Fernandes, Rohan

2016-11-11

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive tumors with low survival rates and the leading cause of death in neurofibromatosis type 1 (NF1) patients under 40 years old. Surgical resection is the standard of care for MPNSTs, but is often incomplete and can generate loss of function, necessitating the development of novel treatment methods for this patient population. Here, we describe a novel combination therapy comprising MEK inhibition and nanoparticle-based photothermal therapy (PTT) for MPNSTs. MEK inhibitors block activity driven by Ras, an oncogene constitutively activated in NF1-associated MPNSTs, while PTT serves as a minimally invasive method to ablate cancer cells. Our rationale for combining these seemingly disparate techniques for MPNSTs is based on several reports demonstrating the efficacy of systemic chemotherapy with local PTT. We combine the MEK inhibitor, PD-0325901 (PD901), with Prussian blue nanoparticles (PBNPs) as PTT agents, to block MEK activity and simultaneously ablate MPNSTs. Our data demonstrate the synergistic effect of combining PD901 with PBNP-based PTT, which converge through the Ras pathway to generate apoptosis, necrosis, and decreased proliferation, thereby mitigating tumor growth and increasing survival of MPNST-bearing animals. Our results suggest the potential of this novel local-systemic combination "nanochemotherapy" for treating patients with MPNSTs.

Diet composition exacerbates or attenuates soman toxicity in rats: implied metabolic control of nerve agent toxicity.

PubMed

Myers, Todd M; Langston, Jeffrey L

2011-06-01

To evaluate the role of diet composition on nerve agent toxicity, rats were fed four distinct diets ad libitum for 28 d prior to challenge with 110 μg/kg (1.0 LD(50), sc) soman. The four diets used were a standard rodent diet, a choline-enriched diet, a glucose-enriched diet, and a ketogenic diet. Body weight was recorded throughout the study. Toxic signs and survival were evaluated at key times for up to 72 h following soman exposure. Additionally, acquisition of discriminated shuttlebox avoidance performance was characterized beginning 24h after soman challenge and across the next 8 d (six behavioral sessions). Prior to exposure, body weight was highest in the standard diet group and lowest in the ketogenic diet group. Upon exposure, differences in soman toxicity as a function of diet became apparent within the first hour, with mortality in the glucose-enriched diet group reaching 80% and exceeding all other groups (in which mortality ranged from 0 to 6%). At 72 h after exposure, mortality was 100% in the glucose-enriched diet group, and survival approximated 50% in the standard and choline-enriched diet groups, but equaled 87% in the ketogenic diet group. Body weight loss was significantly reduced in the ketogenic and choline-enriched diet groups, relative to the standard diet group. At 1 and 4h after exposure, rats in the ketogenic diet group had significantly lower toxic sign scores than all other groups. The ketogenic diet group performed significantly better than the standard diet group on two measures of active avoidance performance. The exacerbated soman toxicity observed in the glucose-enriched diet group coupled with the attenuated soman toxicity observed in the ketogenic diet group implicates glucose availability in the toxic effects of soman. This increased glucose availability may enhance acetylcholine synthesis and/or utilization, thereby exacerbating peripheral and central soman toxicity. Published by Elsevier B.V.

Non-Recurrent Laryngeal Nerve.

PubMed

Buła, Grzegorz; Mucha, Ryszard; Paliga, Michał; Koziołek, Henryk; Niedzielski, Zbigniew; Gawrychowski, Jacek

2015-07-01

The aim of the study was to assess the frequency of non-recurrent laryngeal nerves (Non-RLN). A total of 6110 patients were operated in our hospital between 1 January 2005 and 31 December 2013 for various goiters (5429) and various types of hyperparathyroidism (618). Laryngeal nerve was exposed during operation in 1700 patients from superior aperture of the chest to superior aperture of the larynx. Identification process of RLN was started with dissecting inferior thyroid artery (ITA) and its junction with the nerve. Then main trunk of the nerve was exposed backwards till the region of superior aperture of the chest together with the end portion till the nerve outlet to the larynx. In the group of 1700 patients, RLN was exposed bilaterally in 1400 (82.4%) and unilaterally in 300 (17.6%). In the group of 3100 dissected RLNs the course of RLN was observed on the right side in 1710 patients and on the left in 1390. Irreversible nature RLN was shown in four cases (0.1%) - four women (02%) aged 42-55 (mean 49.3) - three operated for non-toxic nodular goiter and one for primary hyperparathyroidism. Each time the Non-RLN was seen on the right side. The other patients manifested recurrent character RLN. Moreover, interstitial course of RLN was found on the left side in one man. Non recurrent laryngeal nerve is a rare anatomical variation, occurring more frequently on the right side. Surgeon during surgery of the thyroid and parathyroid glands should be aware of its existence to avoid damage.

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

PubMed

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

2015-01-01

To gain insights into the toxicity induced by the nerve agent VX, an MS-based phosphoproteomic analysis was carried out on the piriform cortex region of brains from VX-treated rats. Using isobaric tag based TMT labeling followed by titanium dioxide enrichment strategy, we identified 9975 unique phosphosites derived from 3287 phosphoproteins. Temporal changes in the phosphorylation status of peptides were observed over a time period of 24 h in rats exposed to a 1× LD50, intravenous (i.v.) dose with the most notable changes occurring at the 1 h postexposure time point. Five major functional classes of proteins exhibited changes in their phosphorylation status: (i) ion channels/transporters, including ATPases, (ii) kinases/phosphatases, (iii) GTPases, (iv) structural proteins, and (v) transcriptional regulatory proteins. This study is the first quantitative phosphoproteomic analysis of VX toxicity in the brain. Understanding the toxicity and compensatory signaling mechanisms will improve the understanding of the complex toxicity of VX in the brain and aid in the elucidation of novel molecular targets that would be important for development of improved countermeasures. All MS data have been deposited in the ProteomeXchange with identifier PXD001184 (http://proteomecentral.proteomexchange.org/dataset/PXD001184). © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Development of small bisquaternary cholinesterase inhibitors as drugs for pre-treatment of nerve agent poisonings

PubMed Central

Kuca, Kamil; Karasova, Jana Zdarova; Soukup, Ondrej; Kassa, Jiri; Novotna, Eva; Sepsova, Vendula; Horova, Anna; Pejchal, Jaroslav; Hrabinova, Martina; Vodakova, Eva; Jun, Daniel; Nepovimova, Eugenie; Valis, Martin; Musilek, Kamil

2018-01-01

Background Intoxication by nerve agents could be prevented by using small acetylcholinesterase inhibitors (eg, pyridostigmine) for potentially exposed personnel. However, the serious side effects of currently used drugs led to research of novel potent molecules for prophylaxis of organophosphorus intoxication. Methods The molecular design, molecular docking, chemical synthesis, in vitro methods (enzyme inhibition, cytotoxicity, and nicotinic receptors modulation), and in vivo methods (acute toxicity and prophylactic effect) were used to study bispyridinium, bisquinolinium, bisisoquinolinium, and pyridinium-quinolinium/isoquinolinium molecules presented in this study. Results The studied molecules showed non-competitive inhibitory ability towards human acetylcholinesterase in vitro that was further confirmed by molecular modelling studies. Several compounds were selected for further studies. First, their cytotoxicity, nicotinic receptors modulation, and acute toxicity (lethal dose for 50% of laboratory animals [LD50]; mice and rats) were tested to evaluate their safety with promising results. Furthermore, their blood levels were measured to select the appropriate time for prophylactic administration. Finally, the protective ratio of selected compounds against soman-induced toxicity was determined when selected compounds were found similarly potent or only slightly better to standard pyridostigmine. Conclusion The presented small bisquaternary molecules did not show overall benefit in prophylaxis of soman-induced in vivo toxicity. PMID:29563775

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

Changing epidemiology of rotavirus G-types circulating in Hong Kong, China.

PubMed

Lo, Janice Yee Chi; Szeto, Kai Cheung; Tsang, Dominic Ngai Chong; Leung, Kwok Hung; Lim, Wilina Wei Ling

2005-01-01

Group A rotaviruses are the most common cause of severe diarrhoeal disease in young children worldwide. The development of a vaccine is advocated by the World Health Organization. Obtaining local baseline information regarding rotavirus strain variation is important to ensure matching of circulating and vaccine strains. The current study was undertaken to determine the epidemiology of rotavirus G-types in Hong Kong in anticipation of a vaccination program. From 2001 to 2002 over a period of one year, diarrhoeal stool specimens known to be positive for rotavirus were subjected to G-typing by reverse transcriptase-polymerase chain reaction using nested type-specific primers. Rotavirus G-type distribution was correlated with patient demographics. Among 747 rotavirus positive stool specimens, 723 strains could be G-typed as G1 (302, 40.4%), G2 (128, 17.1%), G3 (231, 30.9%), G4 (24, 3.2%), and G9 (38, 5.1%). G1 strains were found predominantly in those 5 years old or younger (P < 0.0001), while G2 strains were more prevalent among those over 5 years of age (P < 0.001). When compared with similar studies in 1983 to 1984 and 1999 to 2000, there were significant changes in the prevalence of various G-types, with consistent detection of G9 strains in the current study. It is concluded that rotavirus G-type distribution in Hong Kong has varied with time. Continuous monitoring of the epidemiology of rotavirus is important, especially in anticipation of the introduction of a vaccine, in order to document its impact and to ensure its continued effectiveness. Copyright 2005 Wiley-Liss, Inc.

Nerve lesioning with direct current

NASA Astrophysics Data System (ADS)

Ravid, E. Natalie; Shi Gan, Liu; Todd, Kathryn; Prochazka, Arthur

2011-02-01

Spastic hypertonus (muscle over-activity due to exaggerated stretch reflexes) often develops in people with stroke, cerebral palsy, multiple sclerosis and spinal cord injury. Lesioning of nerves, e.g. with phenol or botulinum toxin is widely performed to reduce spastic hypertonus. We have explored the use of direct electrical current (DC) to lesion peripheral nerves. In a series of animal experiments, DC reduced muscle force by controlled amounts and the reduction could last several months. We conclude that in some cases controlled DC lesioning may provide an effective alternative to the less controllable molecular treatments available today.

Hand-held analyser based on microchip electrophoresis with contactless conductivity detection for measurement of chemical warfare agent degradation products

NASA Astrophysics Data System (ADS)

Duran, Karolina-Petkovic; Zhu, Yonggang; Chen, Chuanpin; Swallow, Anthony; Stewart, Robert; Hoobin, Pam; Leech, Patrick; Ovenden, Simon

2008-12-01

This paper reports on the development of a hand-held device for on-site detection of organophosphonate nerve agent degradation products. This field-deployable analyzer relies on efficient microchip electrophoresis separation of alkyl methylphosphonic acids and their sensitive contactless conductivity detection. Miniaturized, low-powered design is coupled with promising analytical performance for separating the breakdown products of chemical warfare agents such as Soman, Sarin and VX . The detector has a detection limit of about 10 μg/mL and has a good linear response in the range 10-300 μg/mL concentration range. Applicability to environmental samples is demonstrated .The new hand-held analyzer offers great promise for converting conventional ion chromatography or capillary electrophoresis sophisticated systems into a portable forensic laboratory for faster, simpler and more reliable on-site screening.

Preparation of O/I1-type Emulsions and S/I1-type Dispersions Encapsulating UV-Absorbing Agents.

PubMed

Aramaki, Kenji; Kimura, Minami; Masuda, Kazuki

2015-01-01

Oil-in-cubic phase (O/I1) emulsions encapsulating the cosmetic UV absorbing agents 2-ethylhexyl 4-methoxycinnamate (EHMC), 2-ethylhexyl 2-cyano-3,3-diphenylacrylate (octocrylene, OCR) and 1-(4-tertbutylphenyl)-3-(4-methoxyphenyl)-1,3-propanedione (Avobenzone, TBMP) were prepared by vortex mixing accompanied by a heating-cooling process. A ternary phase diagram in a water/C12EO25/EHMC system at 25°C was constructed and the two-phase equilibrium of an oil phase and an I1 phase, which is necessary to prepare the O/I1-type emulsions, was confirmed. Also, the melting of the I1 phase into a fluid micellar solution phase was confirmed, allowing emulsification by a heating-cooling process. The O/I1-type emulsions were formulated in the ternary system as well as a quaternary system. The four-component system contained an additional cosolvent, isopropyl myristate (IPM). The use of the cosolvent allows the use of reduced amounts of EHMC, which is desirable because EHMC can cause temporary skin irritation. Formulation of the O/I1-type emulsions with other UV absorbing agents (OCR and TBMP) was also possible using the same emulsification method. When IPM was changed to tripalmitin, which has a melting point greater than room temperature, a solid-oil dispersion in I1 phase was formed. We have termed this a "solidin-cubic phase (S/I1) type dispersion". These novel emulsions have not been reported previously. The UV absorbability of the O/I1-type emulsions and S/I1-type dispersions that encapsulate the UV absorbing agents was confirmed by measurement of UV absorption spectra.

Nerve Cross-Bridging to Enhance Nerve Regeneration in a Rat Model of Delayed Nerve Repair

PubMed Central

2015-01-01

There are currently no available options to promote nerve regeneration through chronically denervated distal nerve stumps. Here we used a rat model of delayed nerve repair asking of prior insertion of side-to-side cross-bridges between a donor tibial (TIB) nerve and a recipient denervated common peroneal (CP) nerve stump ameliorates poor nerve regeneration. First, numbers of retrogradely-labelled TIB neurons that grew axons into the nerve stump within three months, increased with the size of the perineurial windows opened in the TIB and CP nerves. Equal numbers of donor TIB axons regenerated into CP stumps either side of the cross-bridges, not being affected by target neurotrophic effects, or by removing the perineurium to insert 5-9 cross-bridges. Second, CP nerve stumps were coapted three months after inserting 0-9 cross-bridges and the number of 1) CP neurons that regenerated their axons within three months or 2) CP motor nerves that reinnervated the extensor digitorum longus (EDL) muscle within five months was determined by counting and motor unit number estimation (MUNE), respectively. We found that three but not more cross-bridges promoted the regeneration of axons and reinnervation of EDL muscle by all the CP motoneurons as compared to only 33% regenerating their axons when no cross-bridges were inserted. The same 3-fold increase in sensory nerve regeneration was found. In conclusion, side-to-side cross-bridges ameliorate poor regeneration after delayed nerve repair possibly by sustaining the growth-permissive state of denervated nerve stumps. Such autografts may be used in human repair surgery to improve outcomes after unavoidable delays. PMID:26016986

26 CFR 31.3402(g)-3 - Wages paid through an agent, fiduciary, or other person on behalf of two or more employers.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 26 Internal Revenue 15 2014-04-01 2014-04-01 false Wages paid through an agent, fiduciary, or other person on behalf of two or more employers. 31.3402(g)-3 Section 31.3402(g)-3 Internal Revenue... Source § 31.3402(g)-3 Wages paid through an agent, fiduciary, or other person on behalf of two or more...

26 CFR 31.3402(g)-3 - Wages paid through an agent, fiduciary, or other person on behalf of two or more employers.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Wages paid through an agent, fiduciary, or other person on behalf of two or more employers. 31.3402(g)-3 Section 31.3402(g)-3 Internal Revenue... Source § 31.3402(g)-3 Wages paid through an agent, fiduciary, or other person on behalf of two or more...

26 CFR 31.3402(g)-3 - Wages paid through an agent, fiduciary, or other person on behalf of two or more employers.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 26 Internal Revenue 15 2011-04-01 2011-04-01 false Wages paid through an agent, fiduciary, or other person on behalf of two or more employers. 31.3402(g)-3 Section 31.3402(g)-3 Internal Revenue... Source § 31.3402(g)-3 Wages paid through an agent, fiduciary, or other person on behalf of two or more...

26 CFR 31.3402(g)-3 - Wages paid through an agent, fiduciary, or other person on behalf of two or more employers.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 26 Internal Revenue 15 2012-04-01 2012-04-01 false Wages paid through an agent, fiduciary, or other person on behalf of two or more employers. 31.3402(g)-3 Section 31.3402(g)-3 Internal Revenue... Source § 31.3402(g)-3 Wages paid through an agent, fiduciary, or other person on behalf of two or more...

26 CFR 31.3402(g)-3 - Wages paid through an agent, fiduciary, or other person on behalf of two or more employers.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 26 Internal Revenue 15 2013-04-01 2013-04-01 false Wages paid through an agent, fiduciary, or other person on behalf of two or more employers. 31.3402(g)-3 Section 31.3402(g)-3 Internal Revenue... Source § 31.3402(g)-3 Wages paid through an agent, fiduciary, or other person on behalf of two or more...

Ultrastructural and cytochemical evidence for single impulse initiation zones in vestibular macular nerve fibers of rat

NASA Technical Reports Server (NTRS)

Ross, Muriel D.; Chee, Oliver; Black, Samuel; Cutler, Lynn

1991-01-01

Cupric ion-ferricyanide labeling methods and related ferrocyanide-stained tissues were used to locate the characterize, at the ultrastructural level, presumptive impulse initiation zones in the three types of vestibular macular nerve fibers. Large-diameter, M-type vestibular nerve fibers terminate in a calyx at the heminode, and labeling is coextensive with the base of the calyx. Intermediate, M/U-type nerve fibers have short, unmyelinated preterminal segments that sometimes bifurcate intamacularly, and small-diameter, U-type nerve fibers have long, unmyelinated preterminal axons and up to three branches. Preterminals of these nerve fibers display ultrastructural heterogeneity that is correlated with labeling patterns for sodium channels and/or associated polyanionic sites. They have a nodelike ultrastructure and label heavily from near the heminode to the base of the macula. Their intramacular branches, less organized ultrastructurally, label only slightly. Results indicate that vestibular nerve fibers have one impulse initiation zone, located near the heminode, that varies in length according to nerve fiber type. Structural heterogeneity may favor impulse conduction in the central direction, and length of the impulse initiation zone could influence nerve discharge patterns.

Distributions of nerve and muscle fibre types in locust jumping muscle.

PubMed

Hoyle, G

1978-04-01

Muscle fibres of the locust extensor tibiae (jumping muscle) were examined by interference microscopy and by electron microscopy. The electrical responses of single fibres and the mechanical responses of bundles or selected regions to the nerve fibres were examined. Four axons innervate the muscle: fast (FETi), slow (SETi), common inhibitor (CI) and dorsal unpaired median (DUMETi). Their distributions were examined by combined electrophysiological tracing and EM sectioning. The mean diameter of muscle fibres in different regions varies from 40 to 140 micrometer and is related to the local leg thickness rather than muscle fibre type. The fine structure of a fibre is related to its innervation. Fibres innervated by FETi but not SETi are of fast type ultrastructurally. Fibres innervated by SETi but not by FETi are of slow type ultrastructurally. Fibres innervated by both axons are generally intermediate between the extremes though more nearly of fast type than slow. Distal slow muscle fibres have much slower relaxation rates than do proximal ones. The most proximal bundles are of mixed muscle fibre type. There is an abrupt transition from a mixed population to homogeneous fast type, in the muscle units immediately distal to the most proximal bundles. This transition is associated with the presence of DUMETi terminals on some of the fibres distal to the transition point. There are no SETi endings on these same fibres. Fibres innervated by both SETi and FETi are scattered throughout the leg, but are commonest in the dorsal bundles. The percentage of these increases progressively passing distally. The most distal muscle fibres are innervated by SETi but not by FETi. It is concluded that different regions of the muscle will play different roles functionally since they are differentially sensitive to the pattern of SETi discharge.

Prognostic factors in sensory recovery after digital nerve repair.

PubMed

Bulut, Tuğrul; Akgün, Ulaş; Çıtlak, Atilla; Aslan, Cihan; Şener, Ufuk; Şener, Muhittin

2016-01-01

The prognostic factors that affect sensory nerve recovery after digital nerve repair are variable because of nonhomogeneous data, subjective tests, and different assessment/scoring methods. The aim of this study was to evaluate the success of sensory nerve recovery after digital nerve repair and to investigate the prognostic factors in sensorial healing. Ninety-six digital nerve repairs of 63 patients were retrospectively evaluated. All nerves were repaired with end-to-end neurorraphy. The static two-point discrimination (s2PD) and Semmes Weinstein monofilament (SWM) tests were performed to evaluate sensory recovery. The association between prognostic factors such as gender, age, involved digit, time from injury to repair, length of follow-up, smoking, concomitant injuries, type of injury, and sensory recovery results were assessed. The s2PD test demonstrated excellent results in 26 nerves (27%), good results in 61 nerves (64%), and poor results in 9 nerves (9%). The results of the SWM test according to Imai classification showed that 31 nerves (32%) were normal, light touch was diminished in 38 nerves (40%), protective sensation was diminished in 17 nerves (18%), loss of protective sensation occurred in 5 nerves (5%), and 5 nerves (5%) were anesthetic. There was a negative relationship between age, smoking, concomitant injuries, and sensory recovery. Our results demonstrate that concomitant tendon, bone and vascular injuries, older age, and smoking were associated with worse sensory nerve recovery results. However, all digital nerve injuries should be repaired, regardless of these prognostic factors.

A multiparametric assay for quantitative nerve regeneration evaluation.

PubMed

Weyn, B; van Remoortere, M; Nuydens, R; Meert, T; van de Wouwer, G

2005-08-01

We introduce an assay for the semi-automated quantification of nerve regeneration by image analysis. Digital images of histological sections of regenerated nerves are recorded using an automated inverted microscope and merged into high-resolution mosaic images representing the entire nerve. These are analysed by a dedicated image-processing package that computes nerve-specific features (e.g. nerve area, fibre count, myelinated area) and fibre-specific features (area, perimeter, myelin sheet thickness). The assay's performance and correlation of the automatically computed data with visually obtained data are determined on a set of 140 semithin sections from the distal part of a rat tibial nerve from four different experimental treatment groups (control, sham, sutured, cut) taken at seven different time points after surgery. Results show a high correlation between the manually and automatically derived data, and a high discriminative power towards treatment. Extra value is added by the large feature set. In conclusion, the assay is fast and offers data that currently can be obtained only by a combination of laborious and time-consuming tests.

Hierarchical models for epidermal nerve fiber data.

PubMed

Andersson, Claes; Rajala, Tuomas; Särkkä, Aila

2018-02-10

While epidermal nerve fiber (ENF) data have been used to study the effects of small fiber neuropathies through the density and the spatial patterns of the ENFs, little research has been focused on the effects on the individual nerve fibers. Studying the individual nerve fibers might give a better understanding of the effects of the neuropathy on the growth process of the individual ENFs. In this study, data from 32 healthy volunteers and 20 diabetic subjects, obtained from suction induced skin blister biopsies, are analyzed by comparing statistics for the nerve fibers as a whole and for the segments that a nerve fiber is composed of. Moreover, it is evaluated whether this type of data can be used to detect diabetic neuropathy, by using hierarchical models to perform unsupervised classification of the subjects. It is found that using the information about the individual nerve fibers in combination with the ENF counts yields a considerable improvement as compared to using the ENF counts only. Copyright © 2017 John Wiley & Sons, Ltd.

Preoperative transcutaneous electrical nerve stimulation for localizing superficial nerve paths.

PubMed

Natori, Yuhei; Yoshizawa, Hidekazu; Mizuno, Hiroshi; Hayashi, Ayato

2015-12-01

During surgery, peripheral nerves are often seen to follow unpredictable paths because of previous surgeries and/or compression caused by a tumor. Iatrogenic nerve injury is a serious complication that must be avoided, and preoperative evaluation of nerve paths is important for preventing it. In this study, transcutaneous electrical nerve stimulation (TENS) was used for an in-depth analysis of peripheral nerve paths. This study included 27 patients who underwent the TENS procedure to evaluate the peripheral nerve path (17 males and 10 females; mean age: 59.9 years, range: 18-83 years) of each patient preoperatively. An electrode pen coupled to an electrical nerve stimulator was used for superficial nerve mapping. The TENS procedure was performed on patients' major peripheral nerves that passed close to the surgical field of tumor resection or trauma surgery, and intraoperative damage to those nerves was apprehensive. The paths of the target nerve were detected in most patients preoperatively. The nerve paths of 26 patients were precisely under the markings drawn preoperatively. The nerve path of one patient substantially differed from the preoperative markings with numbness at the surgical region. During surgery, the nerve paths could be accurately mapped preoperatively using the TENS procedure as confirmed by direct visualization of the nerve. This stimulation device is easy to use and offers highly accurate mapping of nerves for surgical planning without major complications. The authors conclude that TENS is a useful tool for noninvasive nerve localization and makes tumor resection a safe and smooth procedure. Copyright © 2015 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

Chitin biological absorbable catheters bridging sural nerve grafts transplanted into sciatic nerve defects promote nerve regeneration.

PubMed

Wang, Zhi-Yong; Wang, Jian-Wei; Qin, Li-Hua; Zhang, Wei-Guang; Zhang, Pei-Xun; Jiang, Bao-Guo

2018-06-01

To investigate the efficacy of chitin biological absorbable catheters in a rat model of autologous nerve transplantation. A segment of sciatic nerve was removed to produce a sciatic nerve defect, and the sural nerve was cut from the ipsilateral leg and used as a graft to bridge the defect, with or without use of a chitin biological absorbable catheter surrounding the graft. The number and morphology of regenerating myelinated fibers, nerve conduction velocity, nerve function index, triceps surae muscle morphology, and sensory function were evaluated at 9 and 12 months after surgery. All of the above parameters were improved in rats in which the nerve graft was bridged with chitin biological absorbable catheters compared with rats without catheters. The results of this study indicate that use of chitin biological absorbable catheters to surround sural nerve grafts bridging sciatic nerve defects promotes recovery of structural, motor, and sensory function and improves muscle fiber morphology. © 2018 John Wiley & Sons Ltd.

In-vivo spinal nerve sensing in MISS using Raman spectroscopy

NASA Astrophysics Data System (ADS)

Chen, Hao; Xu, Weiliang; Broderick, Neil

2016-04-01

In modern Minimally Invasive Spine Surgery (MISS), lack of visualization and haptic feedback information are the main obstacles. The spinal cord is a part of the central nervous system (CNS). It is a continuation of the brain stem, carries motor and sensory messages between CNS and the rest of body, and mediates numerous spinal reflexes. Spinal cord and spinal nerves are of great importance but vulnerable, once injured it may result in severe consequences to patients, e.g. paralysis. Raman Spectroscopy has been proved to be an effective and powerful tool in biological and biomedical applications as it works in a rapid, non-invasive and label-free way. It can provide molecular vibrational features of tissue samples and reflect content and proportion of protein, nucleic acids lipids etc. Due to the distinct chemical compositions spinal nerves have, we proposed that spinal nerves can be identified from other types of tissues by using Raman spectroscopy. Ex vivo experiments were first done on samples taken from swine backbones. Comparative spectral data of swine spinal cord, spinal nerves and adjacent tissues (i.e. membrane layer of the spinal cord, muscle, bone and fatty tissue) are obtained by a Raman micro-spectroscopic system and the peak assignment is done. Then the average spectra of all categories of samples are averaged and normalized to the same scale to see the difference against each other. The results verified the feasibility of spinal cord and spinal nerves identification by using Raman spectroscopy. Besides, a fiber-optic Raman sensing system including a miniature Raman sensor for future study is also introduced. This Raman sensor can be embedded into surgical tools for MISS.

Disability following combat-sustained nerve injury of the upper limb.

PubMed

Rivera, J C; Glebus, G P; Cho, M S

2014-02-01

Injuries to the limb are the most frequent cause of permanent disability following combat wounds. We reviewed the medical records of 450 soldiers to determine the type of upper limb nerve injuries sustained, the rate of remaining motor and sensory deficits at final follow-up, and the type of Army disability ratings granted. Of 189 soldiers with an injury of the upper limb, 70 had nerve-related trauma. There were 62 men and eight women with a mean age of 25 years (18 to 49). Disabilities due to nerve injuries were associated with loss of function, neuropathic pain or both. The mean nerve-related disability was 26% (0% to 70%), accounting for over one-half of this cohort's cumulative disability. Patients injured in an explosion had higher disability ratings than those injured by gunshot. The ulnar nerve was most commonly injured, but most disability was associated with radial nerve trauma. In terms of the final outcome, at military discharge 59 subjects (84%) experienced persistent weakness, 48 (69%) had a persistent sensory deficit and 17 (24%) experienced chronic pain from scar-related or neuropathic pain. Nerve injury was the cause of frequent and substantial disability in our cohort of wounded soldiers.

Nerve injuries of the upper extremity and hand

PubMed Central

Dahlin, Lars B.; Wiberg, Mikael

2017-01-01

A nerve injury has a profound impact on the patient’s daily life due to the impaired sensory and motor function, impaired dexterity, sensitivity to cold as well as eventual pain problems. To perform an appropriate treatment of nerve injuries, a correct diagnosis must be made, where the injury is properly classified, leading to an optimal surgical approach and technique, where timing of surgery is also important for the outcome. Knowledge about the nerve regeneration process, where delicate processes occur in neurons, non-neuronal cells (i.e. Schwann cells) and other cells in the peripheral as well as the central nervous systems, is crucial for the treating surgeon. The surgical decision to perform nerve repair and/or reconstruction depends on the type of injury, the condition of the wound as well as the vascularity of the wound. To reconnect injured nerve ends, various techniques can be used, which include both epineurial and fascicular nerve repair, and if a nerve defect is caused by the injury, a nerve reconstruction procedure has to be performed, including bridging the defect using nerve-grafts or nerve transfer techniques. The patients must be evaluated properly and regularly after the surgical procedure and appropriate rehabilitation programmes are useful to improve the final outcome. Cite this article: EFORT Open Rev 2017;2. DOI: 10.1302/2058-5241.2.160071. Originally published online at www.efortopenreviews.org PMID:28630754

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

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.

Selectivity and Longevity of Peripheral-Nerve and Machine Interfaces: A Review

PubMed Central

Ghafoor, Usman; Kim, Sohee; Hong, Keum-Shik

2017-01-01

For those individuals with upper-extremity amputation, a daily normal living activity is no longer possible or it requires additional effort and time. With the aim of restoring their sensory and motor functions, theoretical and technological investigations have been carried out in the field of neuroprosthetic systems. For transmission of sensory feedback, several interfacing modalities including indirect (non-invasive), direct-to-peripheral-nerve (invasive), and cortical stimulation have been applied. Peripheral nerve interfaces demonstrate an edge over the cortical interfaces due to the sensitivity in attaining cortical brain signals. The peripheral nerve interfaces are highly dependent on interface designs and are required to be biocompatible with the nerves to achieve prolonged stability and longevity. Another criterion is the selection of nerves that allows minimal invasiveness and damages as well as high selectivity for a large number of nerve fascicles. In this paper, we review the nerve-machine interface modalities noted above with more focus on peripheral nerve interfaces, which are responsible for provision of sensory feedback. The invasive interfaces for recording and stimulation of electro-neurographic signals include intra-fascicular, regenerative-type interfaces that provide multiple contact channels to a group of axons inside the nerve and the extra-neural-cuff-type interfaces that enable interaction with many axons around the periphery of the nerve. Section Current Prosthetic Technology summarizes the advancements made to date in the field of neuroprosthetics toward the achievement of a bidirectional nerve-machine interface with more focus on sensory feedback. In the Discussion section, the authors propose a hybrid interface technique for achieving better selectivity and long-term stability using the available nerve interfacing techniques. PMID:29163122

High Ulnar Nerve Injuries: Nerve Transfers to Restore Function.

PubMed

Patterson, Jennifer Megan M

2016-05-01

Peripheral nerve injuries are challenging problems. Nerve transfers are one of many options available to surgeons caring for these patients, although they do not replace tendon transfers, nerve graft, or primary repair in all patients. Distal nerve transfers for the treatment of high ulnar nerve injuries allow for a shorter reinnervation period and improved ulnar intrinsic recovery, which are critical to function of the hand. Copyright © 2016 Elsevier Inc. All rights reserved.

Chitosan conduits combined with nerve growth factor microspheres repair facial nerve defects

PubMed Central

Liu, Huawei; Wen, Weisheng; Hu, Min; Bi, Wenting; Chen, Lijie; Liu, Sanxia; Chen, Peng; Tan, Xinying

2013-01-01

Microspheres containing nerve growth factor for sustained release were prepared by a compound method, and implanted into chitosan conduits to repair 10-mm defects on the right buccal branches of the facial nerve in rabbits. In addition, chitosan conduits combined with nerve growth factor or normal saline, as well as autologous nerve, were used as controls. At 90 days post-surgery, the muscular atrophy on the right upper lip was more evident in the nerve growth factor and normal sa-line groups than in the nerve growth factor-microspheres and autologous nerve groups. physiological analysis revealed that the nerve conduction velocity and amplitude were significantly higher in the nerve growth factor-microspheres and autologous nerve groups than in the nerve growth factor and normal saline groups. Moreover, histological observation illustrated that the di-ameter, number, alignment and myelin sheath thickness of myelinated nerves derived from rabbits were higher in the nerve growth factor-microspheres and autologous nerve groups than in the nerve growth factor and normal saline groups. These findings indicate that chitosan nerve conduits bined with microspheres for sustained release of nerve growth factor can significantly improve facial nerve defect repair in rabbits. PMID:25206635

A novel NF1 mutation in a Chinese patient with giant café-au-lait macule in neurofibromatosis type 1 associated with a malignant peripheral nerve sheath tumor and bone abnormality.

PubMed

Tong, H-X; Li, M; Zhang, Y; Zhu, J; Lu, W-Q

2012-08-29

Neurofibromatosis type 1 (NF1; OMIM#162200) is a common neurocutaneous disorder that is characterized by multiple café-au-lait, skinfold freckling, Lisch nodules, and neurofibromas. Mutations in the NF1 gene, which encodes the neurofibromin protein, have been identified as the pathogenic gene of NF1. In this study, we present a clinical and molecular study of a Chinese patient with giant café-au-lait in NF1. The patient showed >6 café-au-lait spots on the body, axillary freckling, and multiple subcutaneous neurofibromas. He also had a malignant peripheral nerve sheath tumor and bone abnormalities. The germline mutational analysis of the NF1 gene revealed a novel missense mutation in exon 13. It is a novel heterozygous nucleotide G>A transition at position 2241 of the NF1 gene. We found no mutation in malignant peripheral nerve sheath tumor DNA from this patient. This expands the database for NF1 gene mutations in NF1. Its absence in the normal chromosomes suggests that it is responsible for the NF1 phenotype. To our knowledge, this is the first case of giant café-au-lait macule in NF1 associated with a malignant peripheral nerve sheath tumor and bone abnormality.

Congenital anomalies of the optic nerve

PubMed Central

Amador-Patarroyo, Manuel J.; Pérez-Rueda, Mario A.; Tellez, Carlos H.

2014-01-01

Congenital optic nerve head anomalies are a group of structural malformations of the optic nerve head and surrounding tissues, which may cause congenital visual impairment and blindness. Each entity in this group of optic nerve anomalies has individually become more prevalent as our ability to differentiate between them has improved due to better characterization of cases. Access to better medical technology (e.g., neuroimaging and genetic analysis advances in recent years) has helped to expand our knowledge of these abnormalities. However, visual impairment may not be the only problem in these patients, some of these entities will be related to ophthalmologic, neurologic and systemic features that will help the physician to identify and predict possible outcomes in these patients, which sometimes may be life-threatening. Herein we present helpful hints, associations and management (when plausible) for them. PMID:25859137

Behavioural, morphological and electrophysiological assessment of the effects of type 2 diabetes mellitus on large and small nerve fibres in Zucker diabetic fatty, Zucker lean and Wistar rats.

PubMed

Garcia-Perez, E; Schönberger, T; Sumalla, M; Stierstorfer, B; Solà, R; Doods, H; Serra, J; Gorodetskaya, N

2018-04-20

Peripheral neuropathy is a common complication in type 2 diabetes mellitus (T2DM). The most common presentation is in the form of a distal axonal sensory-motor polyneuropathy that involves large and small nerve fibres in variable proportion. Zucker Diabetic Fatty (ZDF), Zucker Lean (ZL) and Wistar Han (WH) rats were used to assess the behavioural, morphological and electrophysiological effects that T2DM have on peripheral large and small nerve fibres of 6- to 40-week-old rats. ZDF rats presented mechanical hypersensitivity that initially worsened in parallel to the progression of diabetes and eventually reverted at later stages of the disease. The reversal from hypersensitivity to hyposensitivity paralleled a reduction in the number of intraepithelial skin nerve terminals and in the nerve fibre lengths. However, no increased levels of degeneration of dorsal root ganglion neurons were observed. Nerve conduction studies showed a reduction in sensory and motor nerve conduction velocity (CV) in hyperglycaemic ZDF rats. Microneurography showed significant alterations in several parameters of activity-dependent slowing (ADS) of mechano-insensitive C-nociceptors in ZDF rats. Surprisingly, some of these changes were also observed in ZL rats. Moreover, we found spontaneous activity in all three strains implying that C-nociceptors become hyperexcitable and spontaneously active not only in ageing hyperglycaemic ZDF rats but also in age-matched and apparently normoglycaemic ZL and WH rats fed with the same diet. ZDF rats presented a diabetic neuropathy involving large and small nerve fibres; additionally, ZL and WH rats also showed early small abnormalities in C-fibres, clearly detected by microneurography SIGNIFICANCE: This study provides a functional description of large and small nerve fibre function in a diabetic model that recapitulates many of the findings observed in patients suffering from type 2 diabetes mellitus. © 2018 European Pain Federation - EFIC®.

[Impact of hypoglycemic episodes on nerves conduction and auditory and visual evoked potentials in children with type 1 diabetes].

PubMed

Wysocka-Mincewicz, Marta; Trippenbach-Dulska, Hanna; Emeryk-Szajewska, Barbara; Zakrzewska-Pniewska, Beata; Kochanek, Krzysztof; Pańkowska, Ewa

2007-01-01

Hypoglycemia is an acute disturbance of energy, especially impacting the central nervous system, but direct influence on peripheral nervous function is not detected. The aim of the study was to establish the influence of hypoglycemic moderate and severe episodes on the function of peripheral nerves, hearing and visual pathway. 97 children with type 1 diabetes (mean age 15.4+/-2.16 years, mean duration of diabetes 8.11+/-2.9 years, mean HbA1c 8,58+/-1.06%), at least 10 years old and with at least 3 years duration of diabetes, were included to study. Nerve conduction studies, visual (VEP) and auditory (ABR) evoked potentials were performed with standard surface stimulating and recording techniques. Moderate hypoglycemic episodes were defined as events of low glycemia requiring help of another person but without loss of consciousness and/or convulsions but recurrent frequently in at least one year. Severe hypoglycemia was defined as events with loss of consciousness and/or convulsions. Univariate ANOVA tests of significance or H Kruskal-Wallis test were used, depending on normality of distribution. The subgroups with a history of hypoglycemic episodes had significant delay in all conduction parameters in the sural nerve (amplitude p<0.05, sensory latency p<0.05, and velocity p<0.005) and in motor potential amplitude of tibial nerve (p<0.005). In ABR wave III latency and interval I-III in subgroups with episodes of hypoglycemia (p<0,05) were significantly prolonged. In analyses of VEP parameters no differences were detected. The study showed influence of hypoglycemic episodes on function of all sural nerve parameters and tibial motor amplitude, and in ABR on wave III and interval I-III. Frequent moderate hypoglycemic episodes were strong risk factors for damage of the peripheral and central nervous systems, comparable with impact of several severe hypoglycemias.

The First Experience of Triple Nerve Transfer in Proximal Radial Nerve Palsy.

PubMed

Emamhadi, Mohammadreza; Andalib, Sasan

2018-01-01

Injury to distal portion of posterior cord of brachial plexus leads to palsy of radial and axillary nerves. Symptoms are usually motor deficits of the deltoid muscle; triceps brachii muscle; and extensor muscles of the wrist, thumb, and fingers. Tendon transfers, nerve grafts, and nerve transfers are options for surgical treatment of proximal radial nerve palsy to restore some motor functions. Tendon transfer is painful, requires a long immobilization, and decreases donor muscle strength; nevertheless, nerve transfer produces promising outcomes. We present a patient with proximal radial nerve palsy following a blunt injury undergoing triple nerve transfer. The patient was involved in a motorcycle accident with complete palsy of the radial and axillary nerves. After 6 months, on admission, he showed spontaneous recovery of axillary nerve palsy, but radial nerve palsy remained. We performed triple nerve transfer, fascicle of ulnar nerve to long head of the triceps branch of radial nerve, flexor digitorum superficialis branch of median nerve to extensor carpi radialis brevis branch of radial nerve, and flexor carpi radialis branch of median nerve to posterior interosseous nerve, for restoration of elbow, wrist, and finger extensions, respectively. Our experience confirmed functional elbow, wrist, and finger extensions in the patient. Triple nerve transfer restores functions of the upper limb in patients with debilitating radial nerve palsy after blunt injuries. Copyright © 2017 Elsevier Inc. All rights reserved.

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.

Isoform variants of troponin in skeletal and cardiac muscle cells cultured with and without nerves.

PubMed

Toyota, N; Shimada, Y

1983-05-01

Immunofluorescence microscopy shows that cultured skeletal and cardiac muscle cells of chicken embryos exhibit the same stainabilities with antibodies against skeletal and cardiac troponin components as do those in embryos. Muscle cells of each type cultured with motor or sympathetic nerves or in medium containing the nerve extract exhibit the same reactivities as do those in adult animals. Cardiac muscle cells incubated in the nerve-conditioned medium also change the form of troponin components to the adult type. It appears that the differentiation of individual muscle fibers to specific types is induced by nerves, and especially by the neurohumoral effect.

Sensory and motor peripheral nerve function and longitudinal changes in quadriceps strength.

PubMed

Ward, Rachel E; Boudreau, Robert M; Caserotti, Paolo; Harris, Tamara B; Zivkovic, Sasa; Goodpaster, Bret H; Satterfield, Suzanne; Kritchevsky, Stephen; Schwartz, Ann V; Vinik, Aaron I; Cauley, Jane A; Newman, Anne B; Strotmeyer, Elsa S

2015-04-01

Poor peripheral nerve function is common in older adults and may be a risk factor for strength decline, although this has not been assessed longitudinally. We assessed whether sensorimotor peripheral nerve function predicts strength longitudinally in 1,830 participants (age = 76.3 ± 2.8, body mass index = 27.2 ± 4.6kg/m(2), strength = 96.3 ± 34.7 Nm, 51.0% female, 34.8% black) from the Health ABC study. Isokinetic quadriceps strength was measured semiannually over 6 years. Peroneal motor nerve conduction amplitude and velocity were recorded. Sensory nerve function was assessed with 10-g and 1.4-g monofilaments and average vibration detection threshold at the toe. Lower-extremity neuropathy symptoms were self-reported. Worse vibration detection threshold predicted 2.4% lower strength in men and worse motor amplitude and two symptoms predicted 2.5% and 8.1% lower strength, respectively, in women. Initial 10-g monofilament insensitivity predicted 14.2% lower strength and faster strength decline in women and 6.6% lower strength in men (all p < .05). Poor nerve function predicted lower strength and faster strength decline. Future work should examine interventions aimed at preventing declines in strength in older adults with impaired nerve function. © The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

A brain leptin-renin angiotensin system interaction in the regulation of sympathetic nerve activity

PubMed Central

Hilzendeger, Aline M.; Morgan, Donald A.; Brooks, Leonard; Dellsperger, David; Liu, Xuebo; Grobe, Justin L.; Rahmouni, Kamal; Sigmund, Curt D.

2012-01-01

The sympathetic nervous system, leptin, and renin-angiotensin system (RAS) have been implicated in obesity-associated hypertension. There is increasing evidence for the presence of both leptin and angiotensin II receptors in several key brain cardiovascular and metabolic control regions. We tested the hypothesis that the brain RAS plays a facilitatory role in the sympathetic nerve responses to leptin. In rats, intracerebroventricular (ICV) administration of losartan (5 μg) selectively inhibited increases in renal and brown adipose tissue (BAT) sympathetic nerve activity (SNA) produced by leptin (10 μg ICV) but did not reduce the SNA responses to corticotrophin-releasing factor (CRF) or the melanocortin receptor agonist MTII. In mice with deletion of angiotensin II type-1a receptors (AT1aR−/−), increases in renal and BAT SNA induced by leptin (2 μg ICV) were impaired whereas SNA responses to MTII were preserved. Decreases in food intake and body weight with ICV leptin did not differ in AT1aR−/− vs. AT1aR+/+ mice. ICV leptin in rats increased AT1aR and angiotensin-converting enzyme (ACE) mRNA in the subfornical organ and AT1aR mRNA in the arcuate nucleus, suggesting leptin-induced upregulation of the brain RAS in specific brain regions. To evaluate the role of de novo production of brain angiotensin II in SNA responses to leptin, we treated rats with captopril (12.5 μg ICV). Captopril attenuated leptin effects on renal and BAT SNA. In conclusion, these studies provide evidence that the brain RAS selectively facilitates renal and BAT sympathetic nerve responses to leptin while sparing effects on food intake. PMID:22610169

A brain leptin-renin angiotensin system interaction in the regulation of sympathetic nerve activity.

PubMed

Hilzendeger, Aline M; Morgan, Donald A; Brooks, Leonard; Dellsperger, David; Liu, Xuebo; Grobe, Justin L; Rahmouni, Kamal; Sigmund, Curt D; Mark, Allyn L

2012-07-15

The sympathetic nervous system, leptin, and renin-angiotensin system (RAS) have been implicated in obesity-associated hypertension. There is increasing evidence for the presence of both leptin and angiotensin II receptors in several key brain cardiovascular and metabolic control regions. We tested the hypothesis that the brain RAS plays a facilitatory role in the sympathetic nerve responses to leptin. In rats, intracerebroventricular (ICV) administration of losartan (5 μg) selectively inhibited increases in renal and brown adipose tissue (BAT) sympathetic nerve activity (SNA) produced by leptin (10 μg ICV) but did not reduce the SNA responses to corticotrophin-releasing factor (CRF) or the melanocortin receptor agonist MTII. In mice with deletion of angiotensin II type-1a receptors (AT(1a)R(-/-)), increases in renal and BAT SNA induced by leptin (2 μg ICV) were impaired whereas SNA responses to MTII were preserved. Decreases in food intake and body weight with ICV leptin did not differ in AT(1a)R(-/-) vs. AT(1a)R(+/+) mice. ICV leptin in rats increased AT(1a)R and angiotensin-converting enzyme (ACE) mRNA in the subfornical organ and AT(1a)R mRNA in the arcuate nucleus, suggesting leptin-induced upregulation of the brain RAS in specific brain regions. To evaluate the role of de novo production of brain angiotensin II in SNA responses to leptin, we treated rats with captopril (12.5 μg ICV). Captopril attenuated leptin effects on renal and BAT SNA. In conclusion, these studies provide evidence that the brain RAS selectively facilitates renal and BAT sympathetic nerve responses to leptin while sparing effects on food intake.

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

PubMed

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

2011-01-01

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

Regeneration of long-distance peripheral nerve defects after delayed reconstruction in healthy and diabetic rats is supported by immunomodulatory chitosan nerve guides.

PubMed

Stenberg, Lena; Stößel, Maria; Ronchi, Giulia; Geuna, Stefano; Yin, Yaobin; Mommert, Susanne; Mårtensson, Lisa; Metzen, Jennifer; Grothe, Claudia; Dahlin, Lars B; Haastert-Talini, Kirsten

2017-07-18

Delayed reconstruction of transection or laceration injuries of peripheral nerves is inflicted by a reduced regeneration capacity. Diabetic conditions, more frequently encountered in clinical practice, are known to further impair regeneration in peripheral nerves. Chitosan nerve guides (CNGs) have recently been introduced as a new generation of medical devices for immediate peripheral nerve reconstruction. Here, CNGs were used for 45 days delayed reconstruction of critical length 15 mm rat sciatic nerve defects in either healthy Wistar rats or diabetic Goto-Kakizaki rats; the latter resembling type 2 diabetes. In short and long-term investigations, we comprehensively analyzed the performance of one-chambered hollow CNGs (hCNGs) and two-chambered CNGs (CFeCNGs) in which a chitosan film has been longitudinally introduced. Additionally, we investigated in vitro the immunomodulatory effect provided by the chitosan film. Both types of nerve guides, i.e. hCNGs and CFeCNGs, enabled moderate morphological and functional nerve regeneration after reconstruction that was delayed for 45 days. These positive findings were detectable in generally healthy as well as in diabetic Goto-Kakizaki rats (for the latter only in short-term studies). The regenerative outcome did not reach the degree as recently demonstrated after immediate reconstruction using hCNGs and CFeCNGs. CFeCNG-treatment, however, enabled tissue regrowth in all animals (hCNGs: only in 80% of animals). CFeCNGs did further support with an increased vascularization of the regenerated tissue and an enhanced regrowth of motor axons. One mechanism by which the CFeCNGs potentially support successful regeneration is an immunomodulatory effect induced by the chitosan film itself. Our in vitro results suggest that the pro-regenerative effect of chitosan is related to the differentiation of chitosan-adherent monocytes into pro-healing M2 macrophages. No considerable differences appear for the delayed nerve regeneration

Relationship between the Ulnar Nerve and the Branches of the Radial Nerve to the Medial Head of the Triceps Brachii Muscle.

PubMed

Sh, Cho; Ih, Chung; Uy, Lee

2018-05-17

One branch of the radial nerve to the medial head of the triceps brachii muscle (MHN) has been described as accompanying or joining the ulnar nerve. Mostly two MHN branches have been reported, with some reports of one; however, the topographical anatomy is not well documented. We dissected 52 upper limbs from adult cadavers and found one, two, and three MHN branches in 9.6%, 80.8%, and 9.6% of cases, respectively. The MHN accompanying the ulnar nerve was always the superior MHN. The relationship between the ulnar nerve and the MHN was classified into four types according to whether the MHN was enveloped along with the ulnar nerve in the connective tissue sheath and whether it was in contact with the ulnar nerve. It contacted the ulnar nerve in 75.0% of cases and accompanied it over a mean distance of 73.6 mm (range 36-116 mm). In all cases in which the connective tissue sheath enveloped the branch of the MHN and the ulnar nerve, removing the sheath confirmed that the MHN branch originated from the radial nerve. The detailed findings and anatomical measurements of the MHN in this study will help in identifying its branches during surgical procedures. This article is protected by copyright. All rights reserved. © 2018 Wiley Periodicals, Inc.

Novel drug delivering conduit for peripheral nerve regeneration

NASA Astrophysics Data System (ADS)

Labroo, Pratima; Shea, Jill; Edwards, Kyle; Ho, Scott; Davis, Brett; Sant, Himanshu; Goodwin, Isak; Gale, Bruce; Agarwal, Jay

2017-12-01

Objective. This paper describes the design of a novel drug delivery apparatus integrated with a poly lactic-co-glycolic acid (PLGA) based nerve guide conduit for controlled local delivery of nerve growth factor (NGF) and application in peripheral nerve gap injury. Approach. An NGF dosage curve was acquired to determine the minimum in vitro concentration for optimal neurite outgrowth of dorsal root ganglion (DRG) cells; PLGA based drug delivery devices were then designed and tested in vitro and in vivo across 15 mm rat sciatic nerve gap injury model. Main results. The drug delivery nerve guide was able to release NGF for 28 d at concentrations (0.1-10 ng ml-1) that were shown to enhance DRG neurite growth. Furthermore, the released NGF was bioactive and able to enhance DRG neurite growth. Following these tests, optimized NGF-releasing nerve conduits were implanted across 15 mm sciatic nerve gaps in a rat model, where they demonstrated significant myelination and muscle innervation in vivo as compared to empty nerve conduits (p  <  0.05). This drug delivery nerve guide can release NGF for extended periods of time and enhance axon growth in vitro and in vivo and has the potential to improve nerve regeneration following a peripheral nerve injury. Significance. This integrated drug delivering nerve guide simplifies the design process and provides increased versatility for releasing a variety of different growth factors. This innovative device has the potential for broad applicability and allows for easier customization to change the type of drugs and dosage of individual drugs without devising a completely new biomaterial-drug conjugate each time.

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.

Remodeling of motor units after nerve regeneration studied by quantitative electromyography.

PubMed

Krarup, Christian; Boeckstyns, Michel; Ibsen, Allan; Moldovan, Mihai; Archibald, Simon

2016-02-01

Peripheral nerve has the capacity to regenerate after nerve lesions; during reinnervation of muscle motor units are gradually reestablished. The aim of this study was to follow the time course of reestablishing and remodeling of motor units in relation to recovery of force after different types of nerve repair. Reinnervation of muscle was compared clinically and electrophysiologically in complete median or ulnar nerve lesions with short gap lengths in the distal forearm repaired with a collagen nerve conduit (11 nerves) or nerve suture (10 nerves). Reestablishment of motor units was studied by quantitative EMG and recording of evoked compound muscle action potential (CMAP) during a 24-month observation period after nerve repair. Force recovered partially to about 80% of normal. Denervation activity gradually decreased during reinnervation though it was still increased at 24 months. Nascent motor unit potentials (MUPs) at early reinnervation were prolonged and polyphasic. During longitudinal studies, MUPs remained prolonged and their amplitudes gradually increased markedly. Firing of MUPs was unstable throughout the study. CMAPs gradually increased and the number of motor units recovered to approximately 20% of normal. There was weak evidence of CMAP amplitude recovery after suture ahead of conduit repair but without treatment related differences at 2 years. Surgical repair of nerve lesions with a nerve conduit or suture supported recovery of force and of motor unit reinnervation to the same extent. Changes occurred at a higher rate during early regeneration and slower after 12 months but should be followed for at least 2 years to assess outcome. EMG changes reflected extensive remodeling of motor units from early nascent units to a mature state with greatly enlarged units due to axonal regeneration and collateral sprouting and maturation of regenerated nerve and reinnervated muscle fibers after both types of repair. Remodeling of motor units after peripheral nerve

Nociceptive and Histomorphometric Evaluation of Neural Mobilization in Experimental Injury of the Median Nerve

PubMed Central

Marcioli, Marieli Araujo Rossoni; Coradini, Josinéia Gresele; Kunz, Regina Inês; Ribeiro, Lucinéia de Fátima Chasko; Brancalhão, Rose Meire Costa; Bertolini, Gladson Ricardo Flor

2013-01-01

The carpal tunnel syndrome is the most common peripheral neuropathy in the upper limb, but its treatment with conservative therapies such as neural mobilization (NM) is still controversial. The aim of this study was to investigate the efficacy of the NM as treatment in a model of median nerve compression. 18 Wistar rats were subjected to compression of the median nerve in the right elbow proximal region. Were randomly divided into G1 (untreated), G2 (NM for 1 minute), and G3 (NM for 3 minutes). For treatment, the animals were anesthetized and the right forelimb received mobilization adapted to humans, on alternated days, from the 3rd to the 13th day postoperatively (PO), totaling six days of therapy. Nociception was assessed by withdrawal threshold, and after euthanasia histomorphometric analysis of the median nerve was performed. The nociceptive evaluation showed in G2 and G3 delay in return to baseline. Histomorphometric analysis showed no significant differences in the variables analyzed. It is concluded that the NM was not effective in reducing nociceptive sensation and did not alter the course of nerve regeneration. PMID:23935419

Electromechanical Nerve Stimulator

NASA Technical Reports Server (NTRS)

Tcheng, Ping; Supplee, Frank H., Jr.; Prass, Richard L.

1993-01-01

Nerve stimulator applies and/or measures precisely controlled force and/or displacement to nerve so response of nerve measured. Consists of three major components connected in tandem: miniature probe with spherical tip; transducer; and actuator. Probe applies force to nerve, transducer measures force and sends feedback signal to control circuitry, and actuator positions force transducer and probe. Separate box houses control circuits and panel. Operator uses panel to select operating mode and parameters. Stimulator used in research to characterize behavior of nerve under various conditions of temperature, anesthesia, ventilation, and prior damage to nerve. Also used clinically to assess damage to nerve from disease or accident and to monitor response of nerve during surgery.

Tissue-engineered spiral nerve guidance conduit for peripheral nerve regeneration.

PubMed

Chang, Wei; Shah, Munish B; Lee, Paul; Yu, Xiaojun

2018-06-01

Recently in peripheral nerve regeneration, preclinical studies have shown that the use of nerve guidance conduits (NGCs) with multiple longitudinally channels and intra-luminal topography enhance the functional outcomes when bridging a nerve gap caused by traumatic injury. These features not only provide guidance cues for regenerating nerve, but also become the essential approaches for developing a novel NGC. In this study, a novel spiral NGC with aligned nanofibers and wrapped with an outer nanofibrous tube was first developed and investigated. Using the common rat sciatic 10-mm nerve defect model, the in vivo study showed that a novel spiral NGC (with and without inner nanofibers) increased the successful rate of nerve regeneration after 6 weeks recovery. Substantial improvements in nerve regeneration were achieved by combining the spiral NGC with inner nanofibers and outer nanofibrous tube, based on the results of walking track analysis, electrophysiology, nerve histological assessment, and gastrocnemius muscle measurement. This demonstrated that the novel spiral NGC with inner aligned nanofibers and wrapped with an outer nanofibrous tube provided a better environment for peripheral nerve regeneration than standard tubular NGCs. Results from this study will benefit for future NGC design to optimize tissue-engineering strategies for peripheral nerve regeneration. We developed a novel spiral nerve guidance conduit (NGC) with coated aligned nanofibers. The spiral structure increases surface area by 4.5 fold relative to a tubular NGC. Furthermore, the aligned nanofibers was coated on the spiral walls, providing cues for guiding neurite extension. Finally, the outside of spiral NGC was wrapped with randomly nanofibers to enhance mechanical strength that can stabilize the spiral NGC. Our nerve histological data have shown that the spiral NGC had 50% more myelinated axons than a tubular structure for nerve regeneration across a 10 mm gap in a rat sciatic nerve

Presence of Peripheral Neuropathy Is Associated With Progressive Thinning of Retinal Nerve Fiber Layer in Type 1 Diabetes.

PubMed

Dehghani, Cirous; Srinivasan, Sangeetha; Edwards, Katie; Pritchard, Nicola; Russell, Anthony W; Malik, Rayaz A; Efron, Nathan

2017-05-01

Reduced retinal nerve fiber layer (RNFL) thickness has been demonstrated in patients with diabetic peripheral neuropathy (DPN) in cross-sectional studies. This prospective study defines longitudinal alterations to the RNFL thickness in individuals with type 1 diabetes without (DPN-ve) and with (DPN+ve) DPN and in relation to risk factors for nerve damage. A cohort of 105 individuals with type 1 diabetes (20% DPN+ve) with predominantly mild or no retinopathy and no previous retinal photocoagulation underwent spectral-domain optical coherence tomography (SD-OCT) at baseline, 2 years, and 4 years. SD-OCT scans were acquired at 3.45-mm diameter around the optic nerve head and the overall RNFL and RNFL in the nasal, superior, temporal, and inferior quadrants were quantified. By including serial quantified RNFL parameters, linear mixed models were applied to assess the change in RNFL thickness over time and to explore the associations with other clinical variables. There was a significant decline in the overall RNFL thickness (-0.7 μm/y, P = 0.02) and RNFL in the superior quadrant (-1.9 μm/y, P < 0.01) in the DPN+ve group compared with DPN-ve group. The overall RNFL thickness and RNFL in the superior and nasal quadrants were inversely associated with age (β = -0.29, -0.41, and -0.29, respectively; P ≤ 0.02). Sex, retinopathy, diabetes duration, hemoglobin A1c, lipid profile, blood pressure, cigarette use, alcohol consumption, and body mass index did not show any significant effects (P > 0.05). Individuals with DPN showed a progressive RNFL thinning overall and in the superior quadrant, which was more pronounced in older individuals. There may be common pathways for retinal and peripheral neurodegeneration that are independent of conventional DPN risk factors.

Comparative Evaluation of Chitosan Nerve Guides with Regular or Increased Bendability for Acute and Delayed Peripheral Nerve Repair: A Comprehensive Comparison with Autologous Nerve Grafts and Muscle-in-Vein Grafts.

PubMed

Stößel, Maria; Wildhagen, Vivien M; Helmecke, Olaf; Metzen, Jennifer; Pfund, Charlotte B; Freier, Thomas; Haastert-Talini, Kirsten

2018-05-08

Reconstruction of joint-crossing digital nerves requires the application of nerve guides with a much higher flexibility than used for peripheral nerve repair along larger bones. Nevertheless, collapse-resistance should be preserved to avoid secondary damage to the regrowing nerve tissue. In recent years, we presented chitosan nerve guides (CNGs) to be highly supportive for the regeneration of critical gap length peripheral nerve defects in the rat. Now, we evidently increased the bendability of regular CNGs (regCNGs) by developing a wavy wall structure, that is, corrugated CNGs (corrCNGs). In a comprehensive in vivo study, we compared both types of CNGs with clinical gold standard autologous nerve grafts (ANGs) and muscle-in-vein grafts (MVGs) that have recently been highlighted in the literature as a suitable alternative to ANGs. We reconstructed rat sciatic nerves over a critical gap length of 15 mm either immediately upon transection or after a delay period of 45 days. Electrodiagnostic measurements were applied to monitor functional motor recovery at 60, 90, 120, and 150 (only delayed repair) days postreconstruction. Upon explanation, tube properties were analyzed. Furthermore, distal nerve ends were evaluated using histomorphometry, while connective tissue specimens were subjected to immunohistological stainings. After 120 days (acute repair) or 150 days (delayed repair), respectively, compression-stability of regCNGs was slightly increased while it remained stable in corrCNGs. In both substudies, regCNGs and corrCNGs supported functional recovery of distal plantar muscles in a similar way and to a greater extent when compared with MVGs, while ANGs demonstrated the best support of regeneration. Anat Rec, 2018. © 2018 Wiley Periodicals, Inc. © 2018 Wiley Periodicals, Inc.

Oral sensory nerve damage: Causes and consequences.

PubMed

Snyder, Derek J; Bartoshuk, Linda M

2016-06-01

Oral sensations (i.e., taste, oral somatosensation, retronasal olfaction) are integrated into a composite sense of flavor, which guides dietary choices with long-term health impact. The nerves carrying this input are vulnerable to peripheral damage from multiple sources (e.g., otitis media, tonsillectomy, head injury), and this regional damage can boost sensations elsewhere in the mouth because of central interactions among nerve targets. Mutual inhibition governs this compensatory process, but individual differences lead to variation in whole-mouth outcomes: some individuals are unaffected, others experience severe loss, and some encounter sensory increases that may (if experienced early in life) elevate sweet-fat palatability and body mass. Phantom taste, touch, or pain sensations (e.g., burning mouth syndrome) may also occur, particularly in those expressing the most taste buds. To identify and treat these conditions effectively, emerging clinical tests measure regional vs. whole-mouth sensation, stimulated vs. phantom cues, and oral anatomy. Scaling methods allowing valid group comparisons have strongly aided these efforts. Overall, advances in measuring oral sensory function in health and disease show promise for understanding the varied clinical consequences of nerve damage.

Oral Sensory Nerve Damage: Causes and Consequences

PubMed Central

Snyder, Derek J.; Bartoshuk, Linda M.

2016-01-01

Oral sensations (i.e., taste, oral somatosensation, retronasal olfaction) are integrated into a composite sense of flavor, which guides dietary choices with long-term health impact. The nerves carrying this input are vulnerable to peripheral damage from multiple sources (e.g., otitis media, tonsillectomy, head injury), and this regional damage can boost sensations elsewhere in the mouth because of central interactions among nerve targets. Mutual inhibition governs this compensatory process, but individual differences lead to variation in whole-mouth outcomes: some individuals are unaffected, others experience severe loss, and some encounter sensory increases that may (if experienced early in life) elevate sweet-fat palatability and body mass. Phantom taste, touch, or pain sensations (e.g., burning mouth syndrome) may also occur, particularly in those expressing the most taste buds. To identify and treat these conditions effectively, emerging clinical tests measure regional vs. whole-mouth sensation, stimulated vs. phantom cues, and oral anatomy. Scaling methods allowing valid group comparisons have strongly aided these efforts. Overall, advances in measuring oral sensory function in health and disease show promise for understanding the varied clinical consequences of nerve damage. PMID:27511471

Direct Administration of Nerve-Specific Contrast to Improve Nerve Sparing Radical Prostatectomy

PubMed Central

Barth, Connor W.; Gibbs, Summer L.

2017-01-01

Nerve damage remains a major morbidity following nerve sparing radical prostatectomy, significantly affecting quality of life post-surgery. Nerve-specific fluorescence guided surgery offers a potential solution by enhancing nerve visualization intraoperatively. However, the prostate is highly innervated and only the cavernous nerve structures require preservation to maintain continence and potency. Systemic administration of a nerve-specific fluorophore would lower nerve signal to background ratio (SBR) in vital nerve structures, making them difficult to distinguish from all nervous tissue in the pelvic region. A direct administration methodology to enable selective nerve highlighting for enhanced nerve SBR in a specific nerve structure has been developed herein. The direct administration methodology demonstrated equivalent nerve-specific contrast to systemic administration at optimal exposure times. However, the direct administration methodology provided a brighter fluorescent nerve signal, facilitating nerve-specific fluorescence imaging at video rate, which was not possible following systemic administration. Additionally, the direct administration methodology required a significantly lower fluorophore dose than systemic administration, that when scaled to a human dose falls within the microdosing range. Furthermore, a dual fluorophore tissue staining method was developed that alleviates fluorescence background signal from adipose tissue accumulation using a spectrally distinct adipose tissue specific fluorophore. These results validate the use of the direct administration methodology for specific nerve visualization with fluorescence image-guided surgery, which would improve vital nerve structure identification and visualization during nerve sparing radical prostatectomy. PMID:28255352

Direct Administration of Nerve-Specific Contrast to Improve Nerve Sparing Radical Prostatectomy.

PubMed

Barth, Connor W; Gibbs, Summer L

2017-01-01

Nerve damage remains a major morbidity following nerve sparing radical prostatectomy, significantly affecting quality of life post-surgery. Nerve-specific fluorescence guided surgery offers a potential solution by enhancing nerve visualization intraoperatively. However, the prostate is highly innervated and only the cavernous nerve structures require preservation to maintain continence and potency. Systemic administration of a nerve-specific fluorophore would lower nerve signal to background ratio (SBR) in vital nerve structures, making them difficult to distinguish from all nervous tissue in the pelvic region. A direct administration methodology to enable selective nerve highlighting for enhanced nerve SBR in a specific nerve structure has been developed herein. The direct administration methodology demonstrated equivalent nerve-specific contrast to systemic administration at optimal exposure times. However, the direct administration methodology provided a brighter fluorescent nerve signal, facilitating nerve-specific fluorescence imaging at video rate, which was not possible following systemic administration. Additionally, the direct administration methodology required a significantly lower fluorophore dose than systemic administration, that when scaled to a human dose falls within the microdosing range. Furthermore, a dual fluorophore tissue staining method was developed that alleviates fluorescence background signal from adipose tissue accumulation using a spectrally distinct adipose tissue specific fluorophore. These results validate the use of the direct administration methodology for specific nerve visualization with fluorescence image-guided surgery, which would improve vital nerve structure identification and visualization during nerve sparing radical prostatectomy.

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.

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.

Nerve regeneration in nerve grafts conditioned by vibration exposure.

PubMed

Bergman, S; Widerberg, A; Danielsen, N; Lundborg, G; Dahlin, L B

1995-01-01

Regeneration distances were studied in nerves from vibration-exposed limbs. One hind limb of anaesthetized rats was attached to a vibration exciter and exposed to vibration (80 Hz/32 m/s2) for 5 h/day for 2 or 5 days. Seven days after the latest vibration period a 10-mm long nerve graft was taken from the vibrated sciatic nerve and sutured into a corresponding defect in the con-tralateral sciatic nerve and vice versa, thereby creating two different models within the same animal: (i) regeneration from a freshly transected unvibrated nerve into a vibrated graft and (ii) regeneration from a vibrated nerve into a fresh nerve graft (vibrated recipient side). Four, 6 or 8 days postoperatively (p.o.) the distances achieved by the regenerating axons were determined using the pinch reflex test. Two days of vibration did not influence the regeneration, but 5 days of vibration reduced the initial delay period and a slight reduction of regeneration rate was observed. After 5 days of vibration an increased regeneration distance was observed in both models at day 4 p.o. and at day 6 p.o. in vibrated grafts. This study demonstrates that vibration can condition peripheral nerves and this may be caused by local changes in the peripheral nerve trunk and in the neuron itself.

Intraparotid Neurofibroma of the Facial Nerve: A Case Report.

PubMed

Nofal, Ahmed-Abdel-Fattah; El-Anwar, Mohammad-Waheed

2016-07-01

Intraparotid neurofibromas of the facial nerve are extremely rare and mostly associated with neurofibromatosis type 1 (NF1). This is a case of a healthy 40-year-old man, which underwent surgery for a preoperatively diagnosed benign parotid gland lesion. After identification of the facial nerve main trunk, a single large mass (6 x 3 cm) incorporating the upper nerve division was observed. The nerve portion involved in the mass could not be dissected and was inevitably sacrificed with immediate neuroraphy of the upper division of the facial nerve with 6/0 prolene. The final histopathology revealed the presence of a neurofibroma. Complete left side facial nerve paralysis was observed immediately postoperatively but the function of the lower half was returned within 4 months and the upper half was returned after 1 year. Currently, after 3 years of follow up, there are no signs of recurrence and normal facial nerve function is observed. Neurofibroma should be considered as the diagnosis in a patient demonstrating a parotid mass. In cases where it is diagnosed intraoperatively, excision of part of the nerve with the mass will be inevitable though it can be successfully repaired by end to end anastomosis.

Development of peptide-containing nerves in the human fetal prostate gland.

PubMed

Jen, P Y; Dixon, J S

1995-08-01

Immunohistochemical methods were used to study the developing peptidergic innervation of the human fetal prostate gland in a series of specimens ranging in gestational age from 13 to 30 wk. The overall innervation of each specimen was visualised using protein gene product 9.5 (PGP), a general nerve marker. The onset and development of specific neuropeptide-containing subpopulations were investigated using antisera to neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), substance P (SP), calcitonin gene-related peptide (CGRP), bombesin (BOM), somatostatin (SOM), leu-enkephalin (l-ENK) and met-enkephalin (m-ENK). In addition the occurrence and distribution of presumptive noradrenergic nerves was studied using antisera to dopamine-beta-hydroxylase (D beta H) and tyrosine hydroxylase (TH). At 13 wk numerous branching PGP-immunoreactive (-IR) nerves were observed in the capsule of the developing prostate gland and surrounding the preprostatic urethra but the remainder of the gland was devoid of nerves. The majority of nerves in the capsule contained D beta H and TH and were presumed to be noradrenergic in type while other nerves (in decreasing numbers) contained NPY, l-ENK, SP and CGRP. Nerves associated with the preprostatic urethra did not contain any of the neuropeptides under investigation. At 17 wk the density of nerves in the capsule had increased and occasional m-ENK-, VIP- and BOM-IR nerve fibres were also observed. In addition PGP, D beta H-, TH-, NPY- and l-ENK-IR nerves occurred in association with smooth muscle bundles which at 17 wk were present in the outer part of the gland. Occasional PGP-IR nerves were also present at the base of the epithelium forming some of the prostatic glands. At 23 wk some of the subepithelial nerves showed immunoreactivity for NPY, VIP or l-ENK. At 26 wk smooth muscle bundles occurred throughout the gland and were richly innervated by PGP, D beta H and TH-IR nerves while a less dense plexus was formed by NPY- and l

The role of great auricular-facial nerve neurorrhaphy in facial nerve damage.

PubMed

Sun, Yan; Liu, Limei; Han, Yuechen; Xu, Lei; Zhang, Daogong; Wang, Haibo

2015-01-01

Facial nerve is easy to be damaged, and there are many reconstructive methods for facial nerve reconstructive, such as facial nerve end to end anastomosis, the great auricular nerve graft, the sural nerve graft, or hypoglossal-facial nerve anastomosis. However, there is still little study about great auricular-facial nerve neurorrhaphy. The aim of the present study was to identify the role of great auricular-facial nerve neurorrhaphy and the mechanism. Rat models of facial nerve cut (FC), facial nerve end to end anastomosis (FF), facial-great auricular neurorrhaphy (FG), and control (Ctrl) were established. Apex nasi amesiality observation, electrophysiology and immunofluorescence assays were employed to investigate the function and mechanism. In apex nasi amesiality observation, it was found apex nasi amesiality of FG group was partly recovered. Additionally, electrophysiology and immunofluorescence assays revealed that facial-great auricular neurorrhaphy could transfer nerve impulse and express AChR which was better than facial nerve cut and worse than facial nerve end to end anastomosis. The present study indicated that great auricular-facial nerve neurorrhaphy is a substantial solution for facial lesion repair, as it is efficiently preventing facial muscles atrophy by generating neurotransmitter like ACh.

Multifunctional Silk Nerve Guides for Axon Outgrowth

NASA Astrophysics Data System (ADS)

Tupaj, Marie C.

Peripheral nerve regeneration is a critical issue as 2.8% of trauma patients present with this type of injury, estimating a total of 200,000 nerve repair procedures yearly in the United States. While the peripheral nervous system exhibits slow regeneration, at a rate of 0.5 mm -- 9 mm/day following trauma, this regenerative ability is only possible under certain conditions. Clinical repairs have changed slightly in the last 30 years and standard methods of treatment include suturing damaged nerve ends, allografting, and autografting, with the autograft the gold standard of these approaches. Unfortunately, the use of autografts requires a second surgery and there is a shortage of nerves available for grafting. Allografts are a second option however allografts have lower success rates and are accompanied by the need of immunosuppressant drugs. Recently there has been a focus on developing nerve guides as an "off the shelf" approach. Although some natural and synthetic guidance channels have been approved by the FDA, these nerve guides are unfunctionalized and repair only short gaps, less than 3 cm in length. The goal of this project was to identify strategies for functionalizing peripheral nerve conduits for the outgrowth of neuron axons in vitro . To accomplish this, two strategies (bioelectrical and biophysical) were indentified for increasing axon outgrowth and promoting axon guidance. Bioelectrical strategies exploited electrical stimulation for increasing neurite outgrowth. Biophysical strategies tested a range of surface topographies for axon guidance. Novel methods were developed for integrating electrical and biophysical strategies into silk films in 2D. Finally, a functionalized nerve conduit system was developed that integrated all strategies for the purpose of attaching, elongating, and guiding nervous tissue in vitro. Future directions of this work include silk conduit translation into a rat sciatic nerve model in vivo for the purpose of repairing long

Transtympanic Facial Nerve Paralysis: A Review of the Literature

PubMed Central

Schaefer, Nathan; O’Donohue, Peter; French, Heath; Griffin, Aaron; Gochee, Peter

2015-01-01

Summary: Facial nerve paralysis because of penetrating trauma through the external auditory canal is extremely rare, with a paucity of published literature. The objective of this study is to review the literature on transtympanic facial nerve paralysis and increase physician awareness of this uncommon injury through discussion of its clinical presentation, management and prognosis. We also aim to improve patient outcomes in those that have sustained this type of injury by suggesting an optimal management plan. In this case report, we present the case of a 46-year-old white woman who sustained a unilateral facial nerve paresis because of a garfish penetrating her tympanic membrane and causing direct damage to the tympanic portion of her facial nerve. On follow-up after 12 months, her facial nerve function has largely returned to normal. Transtympanic facial nerve paralysis is a rare injury but can have a favorable prognosis if managed effectively. PMID:26090278

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.

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.

Characteristics of vertigo and the affected vestibular nerve systems in idiopathic bilateral vestibulopathy.

PubMed

Fujimoto, Chisato; Kinoshita, Makoto; Kamogashira, Teru; Egami, Naoya; Sugasawa, Keiko; Yamasoba, Tatsuya; Iwasaki, Shinichi

2016-01-01

Vertigo attacks in IBV patients involving both the superior and inferior vestibular nerve systems were significantly more severe than vertigo attacks in patients with selective involvement of the inferior vestibular nerve system alone. To investigate the relationship between the frequency and duration of vertigo and the affected vestibular nerve system in idiopathic bilateral vestibulopathy (IBV). This study categorized 44 IBV patients into the following three sub-groups according to the affected vestibular nerve system: superior, inferior, and mixed type. These patients were also categorized into the following three sub-groups according to their clinical time course: progressive type showing no episodes of vertigo, sequential type showing recurrent vertigo attacks and single-attack type showing a single episode of vertigo. Ten, 11 and 23 patients were classified as the superior, the inferior, and the mixed type, respectively. Seventeen, 23, and four patients were classified as the progressive, the sequential, and the single-attack type, respectively. For the patients having one or more vertigo attacks, the duration of the vertigo attack was longer than 24 h in 69% of the mixed type, and the duration of vertigo in the mixed type was significantly longer than that in the inferior type (p < 0.05).

Assessment of nerve regeneration across nerve allografts treated with tacrolimus.

PubMed

Haisheng, Han; Songjie, Zuo; Xin, Li

2008-01-01

Although regeneration of nerve allotransplant is a major concern in the clinic, there have been few papers quantitatively assessing functional recovery of animals' nerve allografts in the long term. In this study, functional recovery, histopathological study, and immunohistochemistry changes of rat nerve allograft with FK506 were investigated up to 12 weeks without slaughtering. C57 and SD rats were used for transplantation. The donor's nerve was sliced and transplanted into the recipient. The sciatic nerve was epineurally sutured with 10-0 nylon. In total, 30 models of transplantation were performed and divided into 3 groups that were either treated with FK506 or not. Functional recovery of the grafted nerve was serially assessed by the pin click test, walking track analysis and electrophysiological evaluations. A histopathological study and immunohistochemistry study were done in the all of the models. Nerve allografts treated with FK506 have no immune rejection through 12 weeks. Sensibility had similarly improved in both isografts and allografts. There has been no difference in each graft. Walk track analysis demonstrates significant recovery of motor function of the nerve graft. No histological results of difference were found up to 12 weeks in each graft. In the rodent nerve graft model, FK506 prevented nerve allograft rejection across a major histocompatibility barrier. Sensory recovery seems to be superior to motor function. Nerve isograft and allograft treated with FK506 have no significant difference in function recovery, histopathological result, and immunohistochemistry changes.

[The phrenic nerve in the guinea pig (Cavia porcellus L. 1756)].

PubMed

Salgado, M C; Orsi, A M; Vicentini, C A; Mello Dias, S

1983-01-01

The aim of the present study was the ascertain in the mode of origin of the phrenic nerve and to provide a morphological basis for experimental studies of this nerve in the guinea pig. In sketches made of the dissections, in 10 male and 10 female guinea pigs adults, the modes of origin of the phrenic roots were demonstrated to arise from the fourth to the seventh cervical nerves. Four types of origin could be distinguished. The phrenic nerve of guinea pig has three or four roots.

N-cadherin expression in palisade nerve endings of rat vellus hairs.

PubMed

Kaidoh, Toshiyuki; Inoué, Takao

2008-02-01

Palisade nerve endings (PNs) are mechanoreceptors around vellus hairs of mammals. Each lanceolate nerve ending (LN) of the PN is characterized by a sensory nerve ending symmetrically sandwiched by two processes of type II terminal Schwann cells (tSCIIs). However, the molecular mechanisms underlying the structural organization of the PN are poorly understood. Electron microscopy showed that adherens junctions appeared to adhere to the sensory nerve ending and tSCII processes, so we examined the location of the N-cadherin adhesion system in PNs of rat vellus hairs by using immunoelectron microscopy. N-cadherin localized near both ends of the cell boundary between sensory nerve ending and tSCII processes, which corresponded to the sites of adherens junctions. We further found cadherin-associated proteins, alpha- and beta-catenins, at the linings of adherens junctions. Three-dimensional reconstruction of immunoelectron microscopic serial thin sections showed four linear arrays of N-cadherin arranged longitudinally along the LN beneath the four longitudinal borders of two tSCII processes. In contrast, sensory nerve fibers just proximal to the LNs formed common unmyelinated nerve fibers, in which N-cadherin was located mainly at the mesaxon of type I terminal Schwann cells (tSCIs). These results suggest that the four linear arrays of N-cadherin-mediated junctions adhere the sensory nerve ending and tSCII processes side by side to form the characteristic structure of the LN, and the structural differences between the LNs and the proximal unmyelinated nerve fibers possibly are due to the difference in the pattern of N-cadherin expression between sensory nerve endings and tSCII or tSCI processes. (c) 2007 Wiley-Liss, Inc.

Nanofiber Nerve Guide for Peripheral Nerve Repair and Regeneration

DTIC Science & Technology

2016-04-01

faster regeneration and functional recovery. Peripheral nerve injury is a common complication of complex tissue trauma and often results in significant...having poor regeneration overall, the areas of regenerating nerve tissue could often be found in sections of the nerve guide where luminal spaces of...conducted in this Aim also provided important insight into the NGC design parameters necessary to allow for maximum nerve tissue ingrowth and regeneration

Thumbnail Sketches: EDTA-Type Chelating Agents in Everyday Consumer Products: Some Medicinal and Personal Care Products.

ERIC Educational Resources Information Center

Hart, J. Roger

1984-01-01

Discusses various ethylenediaminetetraacetate (EDTA)-type chelating agents found in ophthalmic products, personal care products, and disinfectants. Also discusses the properties and action of these EDTA agents. (JN)

The role of great auricular-facial nerve neurorrhaphy in facial nerve damage

PubMed Central

Sun, Yan; Liu, Limei; Han, Yuechen; Xu, Lei; Zhang, Daogong; Wang, Haibo

2015-01-01

Background: Facial nerve is easy to be damaged, and there are many reconstructive methods for facial nerve reconstructive, such as facial nerve end to end anastomosis, the great auricular nerve graft, the sural nerve graft, or hypoglossal-facial nerve anastomosis. However, there is still little study about great auricular-facial nerve neurorrhaphy. The aim of the present study was to identify the role of great auricular-facial nerve neurorrhaphy and the mechanism. Methods: Rat models of facial nerve cut (FC), facial nerve end to end anastomosis (FF), facial-great auricular neurorrhaphy (FG), and control (Ctrl) were established. Apex nasi amesiality observation, electrophysiology and immunofluorescence assays were employed to investigate the function and mechanism. Results: In apex nasi amesiality observation, it was found apex nasi amesiality of FG group was partly recovered. Additionally, electrophysiology and immunofluorescence assays revealed that facial-great auricular neurorrhaphy could transfer nerve impulse and express AChR which was better than facial nerve cut and worse than facial nerve end to end anastomosis. Conclusions: The present study indicated that great auricular-facial nerve neurorrhaphy is a substantial solution for facial lesion repair, as it is efficiently preventing facial muscles atrophy by generating neurotransmitter like ACh. PMID:26550216

Effects of Alcohol Injection in Rat Sciatic Nerve

PubMed Central

Mazoch, Mathew J.; Cheema, Gulraiz A.; Suva, Larry J.; Thomas, Ruth L.

2015-01-01

Background Previous studies have shown that the injection of dehydrated alcohol has been successful for the treatment of Morton's neuroma in the foot. In this study, we determined the cellular effect of injection of alcohol into and around the sciatic nerve of rats, and measured the extent of cell necrosis and/or any associated histologic or inflammatory changes. Methods Twenty-two male (~375g) Wistar rats were randomized into two groups each receiving alcohol injections into or around the sciatic nerve after nerve exposure under sterile technique. Group 1 rats were injected with a 0.5ml solution of 0.5% Marcaine in the left sciatic nerve as a control group. In the right sciatic nerve a 0.5ml solution of 4% ethanol with 0.5% Marcaine was injected. Group 2 rats received 0.5ml of 20%ethanol with 0.5% Marcaine injected into the left sciatic nerve and 0.5 ml of 30% ethanol with 0.5% Marcaine injected into the right sciatic nerve. In each group, the rats were placed in 3 subgroups: intraneural, perineural, perimuscular injections. All rats were sacrificed and tissue harvested for histologic evaluation at day 10 post injection. Results No evidence of alcohol-associated cell necrosis, apoptosis or apparent inflammation was observed in histologic specimens of any injected nerves, perineural tissue, or muscles in controls or experimental groups regardless of concentration of ethanol injected on day 10. Conclusion We concluded that alcohol injection (≤30% ethanol) into and/or around the sciatic nerve or the adjacent muscle of rats has no histologic evidence of necrosis or inflammation to the nerve or surrounding tissue. There was no observable histological change in apoptosis, or cell number, in response to the alcohol injection. PMID:25097192

Acceleration of Regeneration of Large Gap Peripheral Nerve Injuries Using Acellular Nerve Allografts plus amniotic Fluid Derived Stem Cells (AFS)

DTIC Science & Technology

2016-09-01

AWARD NUMBER: W811XWH-13-1-0310 TITLE: Acceleration of Regeneration of Large-Gap Peripheral Nerve Injuries Using Acellular Nerve Allografts...plus amniotic Fluid Derived Stem Cells (AFS). PRINCIPAL INVESTIGATOR: Zhongyu Li, MD, PhD RECIPIENT: Wake Forest University Health Sciences...REPORT DATE September 2016 2. REPORT TYPE Annual 3. DATES COVERED 1Sep2015 - 31Aug2016 4. TITLE AND SUBTITLE Acceleration of Regeneration of Large

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

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.