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Sample records for 2-chloroethyl vesicants mustard

  1. Inhibition of NADPH cytochrome P450 reductase by the model sulfur mustard vesicant 2-chloroethyl ethyl sulfide is associated with increased production of reactive oxygen species.

    PubMed

    Gray, Joshua P; Mishin, Vladimir; Heck, Diane E; Laskin, Debra L; Laskin, Jeffrey D

    2010-09-01

    Inhalation of vesicants including sulfur mustard can cause significant damage to the upper airways. This is the result of vesicant-induced modifications of proteins important in maintaining the integrity of the lung. Cytochrome P450s are the major enzymes in the lung mediating detoxification of sulfur mustard and its metabolites. NADPH cytochrome P450 reductase is a flavin-containing electron donor for cytochrome P450. The present studies demonstrate that the sulfur mustard analog, 2-chloroethyl ethyl sulfide (CEES), is a potent inhibitor of human recombinant cytochrome P450 reductase, as well as native cytochrome P450 reductase from liver microsomes of saline and beta-naphthoflavone-treated rats, and cytochrome P450 reductase from type II lung epithelial cells. Using rat liver microsomes from beta-naphthoflavone-treated rats, CEES was found to inhibit CYP 1A1 activity. This inhibition was overcome by microsomal cytochrome P450 reductase from saline-treated rats, which lack CYP 1A1 activity, demonstrating that the CEES inhibitory activity was selective for cytochrome P450 reductase. Cytochrome P450 reductase also generates reactive oxygen species (ROS) via oxidation of NADPH. In contrast to its inhibitory effects on the reduction of cytochrome c and CYP1A1 activity, CEES was found to stimulate ROS formation. Taken together, these data demonstrate that sulfur mustard vesicants target cytochrome P450 reductase and that this effect may be an important mechanism mediating oxidative stress and lung injury. PMID:20561902

  2. Inhibition of NADPH cytochrome P450 reductase by the model sulfur mustard vesicant 2-chloroethyl ethyl sulfide is associated with increased production of reactive oxygen species

    SciTech Connect

    Gray, Joshua P.; Mishin, Vladimir; Heck, Diane E.; Laskin, Debra L.; Laskin, Jeffrey D.

    2010-09-01

    Inhalation of vesicants including sulfur mustard can cause significant damage to the upper airways. This is the result of vesicant-induced modifications of proteins important in maintaining the integrity of the lung. Cytochrome P450s are the major enzymes in the lung mediating detoxification of sulfur mustard and its metabolites. NADPH cytochrome P450 reductase is a flavin-containing electron donor for cytochrome P450. The present studies demonstrate that the sulfur mustard analog, 2-chloroethyl ethyl sulfide (CEES), is a potent inhibitor of human recombinant cytochrome P450 reductase, as well as native cytochrome P450 reductase from liver microsomes of saline and {beta}-naphthoflavone-treated rats, and cytochrome P450 reductase from type II lung epithelial cells. Using rat liver microsomes from {beta}-naphthoflavone-treated rats, CEES was found to inhibit CYP 1A1 activity. This inhibition was overcome by microsomal cytochrome P450 reductase from saline-treated rats, which lack CYP 1A1 activity, demonstrating that the CEES inhibitory activity was selective for cytochrome P450 reductase. Cytochrome P450 reductase also generates reactive oxygen species (ROS) via oxidation of NADPH. In contrast to its inhibitory effects on the reduction of cytochrome c and CYP1A1 activity, CEES was found to stimulate ROS formation. Taken together, these data demonstrate that sulfur mustard vesicants target cytochrome P450 reductase and that this effect may be an important mechanism mediating oxidative stress and lung injury.

  3. Expression of proliferative and inflammatory markers in a full-thickness human skin equivalent following exposure to the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide

    SciTech Connect

    Black, Adrienne T.; Hayden, Patrick J.; Casillas, Robert P.; Heck, Diane E.; Gerecke, Donald R.; Sinko, Patrick J.; Laskin, Debra L.; Laskin, Jeffrey D.

    2010-12-01

    Sulfur mustard is a potent vesicant that induces inflammation, edema and blistering following dermal exposure. To assess molecular mechanisms mediating these responses, we analyzed the effects of the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide, on EpiDerm-FT{sup TM}, a commercially available full-thickness human skin equivalent. CEES (100-1000 {mu}M) caused a concentration-dependent increase in pyknotic nuclei and vacuolization in basal keratinocytes; at high concentrations (300-1000 {mu}M), CEES also disrupted keratin filament architecture in the stratum corneum. This was associated with time-dependent increases in expression of proliferating cell nuclear antigen, a marker of cell proliferation, and poly(ADP-ribose) polymerase (PARP) and phosphorylated histone H2AX, markers of DNA damage. Concentration- and time-dependent increases in mRNA and protein expression of eicosanoid biosynthetic enzymes including COX-2, 5-lipoxygenase, microsomal PGE{sub 2} synthases, leukotriene (LT) A{sub 4} hydrolase and LTC{sub 4} synthase were observed in CEES-treated skin equivalents, as well as in antioxidant enzymes, glutathione S-transferases A1-2 (GSTA1-2), GSTA3 and GSTA4. These data demonstrate that CEES induces rapid cellular damage, cytotoxicity and inflammation in full-thickness skin equivalents. These effects are similar to human responses to vesicants in vivo and suggest that the full thickness skin equivalent is a useful in vitro model to characterize the biological effects of mustards and to develop potential therapeutics.

  4. Role of TNFR1 in lung injury and altered lung function induced by the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide

    SciTech Connect

    Sunil, Vasanthi R.; Patel-Vayas, Kinal; Shen, Jianliang; Gow, Andrew J.; Laskin, Jeffrey D.; Laskin, Debra L.

    2011-02-01

    Lung toxicity induced by sulfur mustard is associated with inflammation and oxidative stress. To elucidate mechanisms mediating pulmonary damage, we used 2-chloroethyl ethyl sulfide (CEES), a model sulfur mustard vesicant. Male mice (B6129) were treated intratracheally with CEES (3 or 6 mg/kg) or control. Animals were sacrificed 3, 7 or 14 days later and bronchoalveolar lavage (BAL) fluid and lung tissue collected. Treatment of mice with CEES resulted in an increase in BAL protein, an indication of alveolar epithelial damage, within 3 days. Expression of Ym1, an oxidative stress marker also increased in the lung, along with inducible nitric oxide synthase, and at 14 days, cyclooxygenase-2 and monocyte chemotactic protein-1, inflammatory proteins implicated in tissue injury. These responses were attenuated in mice lacking the p55 receptor for TNF{alpha} (TNFR1-/-), demonstrating that signaling via TNFR1 is key to CEES-induced injury, oxidative stress, and inflammation. CEES-induced upregulation of CuZn-superoxide dismutase (SOD) and MnSOD was delayed or absent in TNFR1-/- mice, relative to WT mice, suggesting that TNF{alpha} mediates early antioxidant responses to lung toxicants. Treatment of WT mice with CEES also resulted in functional alterations in the lung including decreases in compliance and increases in elastance. Additionally, methacholine-induced alterations in total lung resistance and central airway resistance were dampened by CEES. Loss of TNFR1 resulted in blunted functional responses to CEES. These effects were most notable in the airways. These data suggest that targeting TNF{alpha} signaling may be useful in mitigating lung injury, inflammation and functional alterations induced by vesicants.

  5. Free radical production from the interaction of 2-chloroethyl vesicants (mustard gas) with pyridine nucleotide-driven flavoprotein electron transport systems

    SciTech Connect

    Brimfield, A.A. Mancebo, A.M.; Mason, R.P.; Jiang, J.J.; Siraki, A.G.; Novak, M.J.

    2009-01-01

    The biochemical sequelae to chloroethyl mustard exposure correspond very well to toxic processes initiated by free radicals. Additionally, mustard solutions contain spontaneously formed cyclic onium ions which produce carbon free radicals when reduced electrochemically. Therefore, we hypothesized that the onium ions of sulfur or nitrogen mustards might produce carbon free radicals upon being reduced enzymatically, and that these radicals might constitute a metabolic activation. We set out to document radical production using an in vitro metabolic system and electron paramagnetic resonance (EPR). Our system consisted of NADPH, one of several pyridine nucleotide-driven flavoprotein reductases, cytochrome c as a terminal electron acceptor, various sulfur or nitrogen mustards and the spin trap {alpha}-[4-pyridyl-1-oxide]-N-tert-butylnitrone in buffer. Reactions were started by adding the reductase to the other materials, vortexing and immediately transferring the mixture to a 10 mm EPR flat cell. Repeated scans on a Bruker ESP 300E EPR spectrometer produced a triplet of doublets with hyperfine splitting constants of a{sub N} = 15.483 G and a{sub H} = 2.512 G. The outcome supported our hypothesis that carbon-centered free radicals are produced when mustard-related onium ions are enzymatically reduced. The EPR results varied little with the chloroethyl compound used or with porcine or human cytochrome P450 reductase, the reductase domain of rat brain neuronal nitric oxide synthase or rat liver thioredoxin reductase. Our results offer new insight into the basis for mustard-induced vesication and the outcome of exposure to different mustards. The free radical model provides an explanation for similarities in the lesions arising from mustard exposure and energy-based lesions such as those from heat, ultraviolet and nuclear radiation as well as damage across tissue types such as skin, eyes or airway epithelium.

  6. Regulation of Hsp27 and Hsp70 expression in human and mouse skin construct models by caveolae following exposure to the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide

    SciTech Connect

    Black, Adrienne T.; Hayden, Patrick J.; Casillas, Robert P.; Heck, Diane E.; Gerecke, Donald R.; Sinko, Patrick J.; Laskin, Debra L.; Laskin, Jeffrey D.

    2011-06-01

    Dermal exposure to the vesicant sulfur mustard causes marked inflammation and tissue damage. Basal keratinocytes appear to be a major target of sulfur mustard. In the present studies, mechanisms mediating skin toxicity were examined using a mouse skin construct model and a full-thickness human skin equivalent (EpiDerm-FT{sup TM}). In both systems, administration of the model sulfur mustard vesicant, 2-chloroethyl ethyl sulfide (CEES, 100-1000 {mu}M) at the air surface induced mRNA and protein expression of heat shock proteins 27 and 70 (Hsp27 and Hsp70). CEES treatment also resulted in increased expression of caveolin-1, the major structural component of caveolae. Immunohistochemistry revealed that Hsp27, Hsp70 and caveolin-1 were localized in basal and suprabasal layers of the epidermis. Caveolin-1 was also detected in fibroblasts in the dermal component of the full thickness human skin equivalent. Western blot analysis of caveolar membrane fractions isolated by sucrose density centrifugation demonstrated that Hsp27 and Hsp70 were localized in caveolae. Treatment of mouse keratinocytes with filipin III or methyl-{beta}-cyclodextrin, which disrupt caveolar structure, markedly suppressed CEES-induced Hsp27 and Hsp70 mRNA and protein expression. CEES treatment is known to activate JNK and p38 MAP kinases; in mouse keratinocytes, inhibition of these enzymes suppressed CEES-induced expression of Hsp27 and Hsp70. These data suggest that MAP kinases regulate Hsp 27 and Hsp70; moreover, caveolae-mediated regulation of heat shock protein expression may be important in the pathophysiology of vesicant-induced skin toxicity.

  7. Mustards and Vesicants

    SciTech Connect

    Young, Robert A; Bast, Cheryl B

    2009-01-01

    Vesicants (sulfur mustards, lewisite, and nitrogen mustards) are chemicals that cause blistering of the skin. Developed as chemical warfare agents, their biological activity is complex and not fully understood. These vesicants in liquid or vapor form are capable of causing injury to most any tissue. Contact with the skin results in erythema and blistering. Exposure to vapors produces ocular and respiratory effects which occur at exposures below those causing dermal effects. Systemic and long-lasting effects may occur, especially following acute exposures that result in severe injury. Multi-organ involvement and fluid loss shock resulting in death may follow severe exposures. As alkylating agents, all of the mustards are known or potential carcinogens. The carcinogenic potential of lewisite in humans is equivocal. Toxicity data in animals are available for the vesicants although data on sulfur mustard and lewisite are more extensive than for the nitrogen mustards. Data from tests with human volunteers and occupational exposure information are also available. These data collectively have provided a basis for the development of exposure standards, guidelines, and criteria for use in emergency planning and emergency response, and remediation efforts. The mode of action of the vesicants is complex, not fully understood, and represents an ongoing area of investigation especially with respect to treatment of vesicant-induced injury. Prevention of exposure and decontamination are critical initial steps in eliminating or minimizing injury. With the exception of arsenic chelating antidotes (e.g., British anti-lewisite; BAL) for lewisite, no antidotes exist for the vesicant agents. Medical management currently focuses on palliative treatment of signs and symptoms.

  8. Mustard vesicating agent-induced toxicity in the skin tissue and silibinin as a potential countermeasure.

    PubMed

    Tewari-Singh, Neera; Agarwal, Rajesh

    2016-06-01

    Exposure to the vesicating agents sulfur mustard (SM) and nitrogen mustard (NM) causes severe skin injury with delayed blistering. Depending upon the dose and time of their exposure, edema and erythema develop into blisters, ulceration, necrosis, desquamation, and pigmentation changes, which persist weeks and even years after exposure. Research advances have generated data that have started to explain the probable mechanism of action of vesicant-induced skin toxicity; however, despite these advances, effective and targeted therapies are still deficient. This review highlights studies on two SM analogs, 2-chloroethyl ethyl sulfide (CEES) and NM, and CEES- and NM-induced skin injury mouse models that have substantially added to the knowledge on the complex pathways involved in mustard vesicating agent-induced skin injury. Furthermore, employing these mouse models, studies under the National Institutes of Health Countermeasures Against Chemical Threats program have identified the flavanone silibinin as a novel therapeutic intervention with the potential to be developed as an effective countermeasure against skin injury following exposure to mustard vesicating agents. PMID:27326543

  9. Role of MAP kinases in regulating expression of antioxidants and inflammatory mediators in mouse keratinocytes following exposure to the half mustard, 2-chloroethyl ethyl sulfide

    SciTech Connect

    Black, Adrienne T.; Joseph, Laurie B.; Casillas, Robert P.; Heck, Diane E.; Gerecke, Donald R.; Sinko, Patrick J.; Laskin, Debra L.; Laskin, Jeffrey D.

    2010-06-15

    Dermal exposure to sulfur mustard causes inflammation and tissue injury. This is associated with changes in expression of antioxidants and eicosanoids which contribute to oxidative stress and toxicity. In the present studies we analyzed mechanisms regulating expression of these mediators using an in vitro skin construct model in which mouse keratinocytes were grown at an air-liquid interface and exposed directly to 2-chloroethyl ethyl sulfide (CEES), a model sulfur mustard vesicant. CEES (100-1000 {mu}M) was found to cause marked increases in keratinocyte protein carbonyls, a marker of oxidative stress. This was correlated with increases in expression of Cu,Zn superoxide dismutase, catalase, thioredoxin reductase and the glutathione S-transferases, GSTA1-2, GSTP1 and mGST2. CEES also upregulated several enzymes important in the synthesis of prostaglandins and leukotrienes including cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-2 (mPGES-2), prostaglandin D synthase (PGDS), 5-lipoxygenase (5-LOX), leukotriene A{sub 4} (LTA{sub 4}) hydrolase and leukotriene C{sub 4} (LTC{sub 4}) synthase. CEES readily activated keratinocyte JNK and p38 MAP kinases, signaling pathways which are known to regulate expression of antioxidants, as well as prostaglandin and leukotriene synthases. Inhibition of p38 MAP kinase suppressed CEES-induced expression of GSTA1-2, COX-2, mPGES-2, PGDS, 5-LOX, LTA{sub 4} hydrolase and LTC{sub 4} synthase, while JNK inhibition blocked PGDS and GSTP1. These data indicate that CEES modulates expression of antioxidants and enzymes producing inflammatory mediators by distinct mechanisms. Increases in antioxidants may be an adaptive process to limit tissue damage. Inhibiting the capacity of keratinocytes to generate eicosanoids may be important in limiting inflammation and protecting the skin from vesicant-induced oxidative stress and injury.

  10. Sulfur mustard induces an endoplasmic reticulum stress response in the mouse ear vesicant model

    PubMed Central

    Chang, Yoke-Chen; Wang, James D.; Svoboda, Kathy K.; Casillas, Robert P.; Laskin, Jeffrey D.; Gordon, Marion K.; Gerecke, Donald R.

    2013-01-01

    The endoplasmic reticulum (ER) stress response is a cell survival pathway upregulated when cells are under severe stress. Severely damaged mouse ear skin exposed to the vesicant, sulfur mustard (bis-2-chloroethyl sulfide, SM), resulted in increased expression of ER chaperone proteins that accompany misfolded and incorrectly made proteins targeted for degradation. Time course studies with SM using the mouse ear vesicant model (MEVM) showed progressive histopathologic changes including edema, separation of the epidermis from the dermis, persistent inflammation, upregulation of laminin γ2 (one of the chains of laminin-332, a heterotrimeric skin glycoprotein required for wound repair), and delayed wound healing from 24 h to 168 h post exposure. This was associated with time related increased expression of the cell survival ER stress marker, GRP78/BiP, and the ER stress apoptosis marker, GADD153/CHOP, suggesting simultaneous activation of both cell survival and non-mitochondrial apoptosis pathways. Dual immunofluorescence labeling of a keratinocyte migration promoting protein, laminin γ2 and GRP78/BIP, showed colocalization of the two molecules 72 h post exposure indicating that the laminin γ2 was misfolded after SM exposure and trapped within the ER. Taken together, these data show that ER stress is induced in mouse skin within 24 h of vesicant exposure in a defensive response to promote cell survival; however, it appears that this response is rapidly overwhelmed by the apoptotic pathway as a consequence of severe SM-induced injury. PMID:23357548

  11. Sulfur mustard induces an endoplasmic reticulum stress response in the mouse ear vesicant model

    SciTech Connect

    Chang, Yoke-Chen; Wang, James D.; Svoboda, Kathy K.; Casillas, Robert P.; Laskin, Jeffrey D.; Gordon, Marion K.; Gerecke, Donald R.

    2013-04-15

    The endoplasmic reticulum (ER) stress response is a cell survival pathway upregulated when cells are under severe stress. Severely damaged mouse ear skin exposed to the vesicant, sulfur mustard (bis-2-chloroethyl sulfide, SM), resulted in increased expression of ER chaperone proteins that accompany misfolded and incorrectly made proteins targeted for degradation. Time course studies with SM using the mouse ear vesicant model (MEVM) showed progressive histopathologic changes including edema, separation of the epidermis from the dermis, persistent inflammation, upregulation of laminin γ2 (one of the chains of laminin-332, a heterotrimeric skin glycoprotein required for wound repair), and delayed wound healing from 24 h to 168 h post exposure. This was associated with time related increased expression of the cell survival ER stress marker, GRP78/BiP, and the ER stress apoptosis marker, GADD153/CHOP, suggesting simultaneous activation of both cell survival and non-mitochondrial apoptosis pathways. Dual immunofluorescence labeling of a keratinocyte migration promoting protein, laminin γ2 and GRP78/BIP, showed colocalization of the two molecules 72 h post exposure indicating that the laminin γ2 was misfolded after SM exposure and trapped within the ER. Taken together, these data show that ER stress is induced in mouse skin within 24 h of vesicant exposure in a defensive response to promote cell survival; however, it appears that this response is rapidly overwhelmed by the apoptotic pathway as a consequence of severe SM-induced injury. - Highlights: ► We demonstrated ER stress response in the mouse ear vesicant model. ► We described the asymmetrical nature of wound repair in the MEVM. ► We identified the distribution of various ER stress markers in the MEVM.

  12. Desorption of bis(2-chloroethyl) sulfide, mustard agent, from the surface of hardened cement paste (HCP) wafers.

    PubMed

    Tang, Hairong; Zhou, Xuezhi; Guan, Yingqiang; Zhou, Liming; Wang, Xinming; Yan, Huijuan

    2013-05-01

    The decontamination of surfaces exposed to chemical warfare agents is an interesting scientific topic. The desorption behavior of bis(2-chloroethyl) sulfide (sulfur mustard, HD) from the surface of the HD-contaminated hardened cement paste (HCP) was investigated under different weather conditions, which should provide scientific reference data for protection and decontamination projects involving HD-contaminated HCP in different conditions. The desorption of HD from the surface of HCP wafers was studied, and the effects of the purge air flow rate, water content, sorption temperature, and substrate age were investigated. HD desorption was detected from the surface of HD-contaminated HCP, but the desorption velocity was relatively slow. The desorption quantity remained within an order of magnitude throughout a time span of 36h (25°C at 200mL/min of purge air), and the amount of HD that was desorbed from each square meter of HCP surface was approximately 1.1g (25°C at 200mL/min of purge air), which was approximately 5.5 percent of the total HD that was initially applied. A higher flow rate of the purge air, increased water content, and longer substrate age of HCP all increased the HD desorption. In contrast, increased temperatures suppressed HD desorption. PMID:23395389

  13. Mustard vesicant-induced lung injury: Advances in therapy.

    PubMed

    Weinberger, Barry; Malaviya, Rama; Sunil, Vasanthi R; Venosa, Alessandro; Heck, Diane E; Laskin, Jeffrey D; Laskin, Debra L

    2016-08-15

    Most mortality and morbidity following exposure to vesicants such as sulfur mustard is due to pulmonary toxicity. Acute injury is characterized by epithelial detachment and necrosis in the pharynx, trachea and bronchioles, while long-term consequences include fibrosis and, in some instances, cancer. Current therapies to treat mustard poisoning are primarily palliative and do not target underlying pathophysiologic mechanisms. New knowledge about vesicant-induced pulmonary disease pathogenesis has led to the identification of potentially efficacious strategies to reduce injury by targeting inflammatory cells and mediators including reactive oxygen and nitrogen species, proteases and proinflammatory/cytotoxic cytokines. Therapeutics under investigation include corticosteroids, N-acetyl cysteine, which has both mucolytic and antioxidant properties, inducible nitric oxide synthase inhibitors, liposomes containing superoxide dismutase, catalase, and/or tocopherols, protease inhibitors, and cytokine antagonists such as anti-tumor necrosis factor (TNF)-α antibody and pentoxifylline. Antifibrotic and fibrinolytic treatments may also prove beneficial in ameliorating airway obstruction and lung remodeling. More speculative approaches include inhibitors of transient receptor potential channels, which regulate pulmonary epithelial cell membrane permeability, non-coding RNAs and mesenchymal stem cells. As mustards represent high priority chemical threat agents, identification of effective therapeutics for mitigating toxicity is highly significant. PMID:27212445

  14. Airway tissue factor-dependent coagulation activity in response to sulfur mustard analog 2-chloroethyl ethyl sulfide

    PubMed Central

    Rancourt, Raymond C.; Veress, Livia A.; Guo, XiaoLing; Jones, Tara N.; Hendry-Hofer, Tara B.

    2012-01-01

    Acute lung injury is a principal cause of morbidity and mortality in response to mustard gas (SM) inhalation. Obstructive, fibrin-containing airway casts have recently been reported in a rat inhalation model employing the SM analog 2-chloroethyl ethyl sulfide (CEES). The present study was designed to identify the mechanism(s) causing activation of the coagulation cascade after CEES-induced airway injury. Here we report that CEES inhalation elevates tissue factor (TF) activity and numbers of detached epithelial cells present in lavage fluid (BALF) from rats after exposure (18 h). In vitro studies using 16HBE cells, or with rat BALF, indicated that detached epithelial cells could convert factor X (FX) to the active form FXa when incubated with factor VII and could elicit rapid clotting of plasma. In addition, immunocytochemical analysis demonstrated elevated cell surface (TF) expression on CEES-exposed 16HBE cells as a function of time. However, total cell TF expression did not increase. Since membrane surfaces bearing TF are important determinants of clot initiation, anticoagulants directed against these entities were tested for ability to limit plasma clotting or FX activation capacity of BALF or culture media. Addition of tifacogin, a TF pathway inhibitor, effectively blocked either activity, demonstrating that the procoagulant actions of CEES were TF pathway dependent. Lactadherin, a protein capable of competing with clotting factors for phospholipid-binding sites, was partially effective in limiting these procoagulant actions. These findings indicate that TF pathway inhibition could be an effective strategy to prevent airway obstruction after SM or CEES inhalation. PMID:21964405

  15. 2,6-Dithiopurine, a nucleophilic scavenger, protects against mutagenesis in mouse skin treated in vivo with 2-(chloroethyl) ethyl sulfide, a mustard gas analog

    SciTech Connect

    Boulware, Stephen; Fields, Tammy; McIvor, Elizabeth; Powell, K. Leslie; Abel, Erika L.; Vasquez, Karen M.; MacLeod, Michael C.

    2012-09-01

    Sulfur mustard [bis(2-chloroethyl)sulfide, SM] is a well-known DNA-damaging agent that has been used in chemical warfare since World War I, and is a weapon that could potentially be used in a terrorist attack on a civilian population. Dermal exposure to high concentrations of SM produces severe, long-lasting burns. Topical exposure to high concentrations of 2-(chloroethyl) ethyl sulfide (CEES), a monofunctional analog of SM, also produces severe skin lesions in mice. Utilizing a genetically engineered mouse strain, Big Blue, that allows measurement of mutation frequencies in mouse tissues, we now show that topical treatment with much lower concentrations of CEES induces significant dose- and time-dependent increases in mutation frequency in mouse skin; the mutagenic exposures produce minimal toxicity as determined by standard histopathology and immunohistochemical analysis for cytokeratin 6 and the DNA-damage induced phosphorylation of histone H2AX (γ-H2AX). We attempted to develop a therapeutic that would inhibit the CEES-induced increase in mutation frequency in the skin. We observe that multi-dose, topical treatment with 2,6-dithiopurine (DTP), a known chemical scavenger of CEES, beginning 1 h post-exposure to CEES, completely abolishes the CEES-induced increase in mutation frequency. These findings suggest the possibility that DTP, previously shown to be non-toxic in mice, may be useful as a therapeutic agent in accidental or malicious human exposures to SM. -- Highlights: ► 200 mM 2-(chloroethyl) ethyl sulfide (CEES) induces mutations in mouse skin. ► This dose of CEES is not overtly toxic, as assayed by histopathology. ► 2,6-Dithiopurine (DTP), applied after CEES-treatment, abolishes CEES-mutagenesis. ► This supports the idea that sulfur mustards exhibit long biological half-lives.

  16. Rotational spectra, nuclear quadrupole hyperfine tensors, and conformational structures of the mustard gas simulent 2-chloroethyl ethyl sulfide

    NASA Astrophysics Data System (ADS)

    Tubergen, M. J.; Lesarri, A.; Suenram, R. D.; Samuels, A. C.; Jensen, J. O.; Ellzy, M. W.; Lochner, J. M.

    2005-10-01

    Rotational spectra have been recorded for both the 35Cl and 37Cl isotopic forms of two structural conformations of 2-chloroethyl ethyl sulfide (CEES). The rotational constants of the 35Cl and 37Cl isotopomers were used to identify the conformational isomers. A total of 236 hyperfine transitions have been assigned for 47 rotational transitions of the 35Cl isotope of a GGT conformer, and 146 hyperfine have been assigned for 37 rotational transitions of the 37Cl isotopomer. For the second conformer, a total of 128 (110) hyperfine and 30 (28) rotational transitions have also been assigned to the 35Cl ( 37Cl) isotopes of a TGT conformation. The extensive hyperfine splitting data, measured to high resolution with a compact Fourier transform microwave spectrometer, were used to determine both the diagonal and off-diagonal elements of the 35Cl and 37Cl nuclear quadrupole coupling tensors in the inertial tensor principal axis system. The experimental rotational constant data, as well as the 35Cl and 37Cl nuclear quadrupole coupling tensors, were compared to the results from 27 optimized ab initio (HF/6-311++G ∗∗ and MP2/6-311++G ∗∗) model structures.

  17. Zinc oxide nanocubes as a destructive nanoadsorbent for the neutralization chemistry of 2-chloroethyl phenyl sulfide: A sulfur mustard simulant.

    PubMed

    Kiani, Armin; Dastafkan, Kamran

    2016-09-15

    Zinc oxide nanocubes were surveyed for their destructive turn-over to decontaminate 2-chloro ethyl phenyl sulfide, a sulfur mustard simulant. Prior to the reaction, nanocubes were prepared through sol-gel method using monoethanolamine, diethylene glycol, and anhydrous citric acid as the stabilizing, cross linking/structure directing agents, respectively. The formation of nanoscale ZnO, the cubic morphology, crystalline structure, and chemical-adsorptive characteristics were certified by FESEM-EDS, TEM-SAED, XRD, FTIR, BET-BJH, H2-TPR, and ESR techniques. Adsorption and destruction reactions were tracked by GC-FID analysis in which the effects of polarity of the media, reaction time, and temperature on the destructive capability of the surface of nanocubes were investigated and discussed. Results demonstrated that maximum neutralization occurred in n-heptane solvent after 1/2h at 55°C. Kinetic study construed that the neutralization reaction followed the pseudo-second order model with a squared correlation coefficient and rate constant of 0.9904 and 0.00004gmg(-1)s(-1), respectively. Furthermore, GC-MS measurement confirmed the formation of 2-hydroxy ethyl phenyl sulfide (2-HEPS) and phenyl vinyl sulfide (PVS) as neutralization products that together with Bronsted and Lewis acid/base approaches exemplify the role of hydrolysis and elimination mechanisms on the surface of zinc oxide nanocubes. PMID:27309947

  18. Mustard vesicants alter expression of the endocannabinoid system in mouse skin.

    PubMed

    Wohlman, Irene M; Composto, Gabriella M; Heck, Diane E; Heindel, Ned D; Lacey, C Jeffrey; Guillon, Christophe D; Casillas, Robert P; Croutch, Claire R; Gerecke, Donald R; Laskin, Debra L; Joseph, Laurie B; Laskin, Jeffrey D

    2016-07-15

    Vesicants including sulfur mustard (SM) and nitrogen mustard (NM) are bifunctional alkylating agents that cause skin inflammation, edema and blistering. This is associated with alterations in keratinocyte growth and differentiation. Endogenous cannabinoids, including N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoyl glycerol (2-AG), are important in regulating inflammation, keratinocyte proliferation and wound healing. Their activity is mediated by binding to cannabinoid receptors 1 and 2 (CB1 and CB2), as well as peroxisome proliferator-activated receptor alpha (PPARα). Levels of endocannabinoids are regulated by fatty acid amide hydrolase (FAAH). We found that CB1, CB2, PPARα and FAAH were all constitutively expressed in mouse epidermis and dermal appendages. Topical administration of NM or SM, at concentrations that induce tissue injury, resulted in upregulation of FAAH, CB1, CB2 and PPARα, a response that persisted throughout the wound healing process. Inhibitors of FAAH including a novel class of vanillyl alcohol carbamates were found to be highly effective in suppressing vesicant-induced inflammation in mouse skin. Taken together, these data indicate that the endocannabinoid system is important in regulating skin homeostasis and that inhibitors of FAAH may be useful as medical countermeasures against vesicants. PMID:27125198

  19. Detoxication of sulfur half-mustards by nucleophilic scavengers: robust activity of thiopurines.

    PubMed

    Liu, Jinyun; Powell, K Leslie; Thames, Howard D; MacLeod, Michael C

    2010-03-15

    Sulfur mustard (bis-(2-chloroethyl)sulfide) has been used in chemical warfare since World War I and is well known as an acutely toxic vesicant. It has been implicated as a carcinogen after chronic low-level exposure and is known to form interstrand cross-links in DNA. Sulfur and nitrogen mustards are currently of interest as potential chemical threat agents for terrorists because of ease of synthesis. Sulfur mustard and monofunctional analogues (half-mustards, 2-[chloroethyl] alkyl sulfides) react as electrophiles, damaging cellular macromolecules, and thus are potentially subject to scavenging by nucleophilic agents. We have determined rate constants for the reaction of four purine derivatives that contain nucleophilic thiol moieties with several sulfur-half-mustards. Three of these compounds, 2,6-dithiopurine, 2,6-dithiouric acid, and 9-methyl-6-mercaptopurine, exhibit facile reaction with the electrophilic mustard compounds. At near neutral pH, these thiopurines are much better nucleophilic scavengers of mustard electrophiles than other low molecular weight thiols such as N-acetyl cysteine and glutathione. Progress curves calculated by numerical integration techniques indicate that equimolar concentrations of thiopurine provide significant reductions in the overall exposure to the episulfonium ions, which are the major reactive, electrophiles produced when sulfur mustards are dissolved in aqueous solution. PMID:20050632

  20. Toxicity of vesicant agents scheduled for destruction by the Chemical Stockpile Disposal Program.

    PubMed

    Watson, A P; Griffin, G D

    1992-11-01

    The vesicant agents of the unitary chemical munitions stockpile include various formulations of sulfur mustard [bis-(2-chloroethyl) sulfide; agents H, HD, and HT] and small quantities of the organic arsenical Lewisite [dichloro(2-chlorovinyl) arsine; agent L]. These agents can be dispersed in liquid, aerosol, or vapor form and are capable of producing severe chemical burns upon direct contact with tissue. Moist tissues such as the eyes, respiratory tract, and axillary areas are particularly affected. Available data summarizing acute dose response in humans and laboratory animals are summarized. Vesicant agents are also capable of generating delayed effects such as chronic bronchitis, carcinogenesis, or keratitis/keratopathy of the eye under appropriate conditions of exposure and dose. These effects may not become manifest until years following exposure. Risk analysis derived from carcinogenesis data indicates that sulfur mustard possesses a carcinogenic potency similar to that of benzo[a]pyrene. Because mustard agents are alkylating compounds, they destroy individual cells by reaction with cellular proteins, enzymes, RNA, and DNA. Once begun, tissue reaction is irreversible. Mustard agents are mutagenic; data for cellular and laboratory animal assays are presented. Reproductive effects have not been demonstrated in the offspring of laboratory rats. Acute Lewisite exposure has been implicated in cases of Bowen's disease, an intraepidermal squamous cell carcinoma. Lewisite is not known to generate reproductive or teratogenic effects. PMID:1486858

  1. Toxicity of vesicant agents scheduled for destruction by the Chemical Stockpile Disposal Program.

    PubMed Central

    Watson, A P; Griffin, G D

    1992-01-01

    The vesicant agents of the unitary chemical munitions stockpile include various formulations of sulfur mustard [bis-(2-chloroethyl) sulfide; agents H, HD, and HT] and small quantities of the organic arsenical Lewisite [dichloro(2-chlorovinyl) arsine; agent L]. These agents can be dispersed in liquid, aerosol, or vapor form and are capable of producing severe chemical burns upon direct contact with tissue. Moist tissues such as the eyes, respiratory tract, and axillary areas are particularly affected. Available data summarizing acute dose response in humans and laboratory animals are summarized. Vesicant agents are also capable of generating delayed effects such as chronic bronchitis, carcinogenesis, or keratitis/keratopathy of the eye under appropriate conditions of exposure and dose. These effects may not become manifest until years following exposure. Risk analysis derived from carcinogenesis data indicates that sulfur mustard possesses a carcinogenic potency similar to that of benzo[a]pyrene. Because mustard agents are alkylating compounds, they destroy individual cells by reaction with cellular proteins, enzymes, RNA, and DNA. Once begun, tissue reaction is irreversible. Mustard agents are mutagenic; data for cellular and laboratory animal assays are presented. Reproductive effects have not been demonstrated in the offspring of laboratory rats. Acute Lewisite exposure has been implicated in cases of Bowen's disease, an intraepidermal squamous cell carcinoma. Lewisite is not known to generate reproductive or teratogenic effects. PMID:1486858

  2. Toxicity of vesicant agents scheduled for destruction by the chemical stockpile disposal program

    SciTech Connect

    Watson, A.P.; Griffin, G.D. )

    1992-11-01

    The vesicant agents of the unitary chemical munitions stockpile include various formulations of sulfur mustard [bis-(2-chloroethyl) sulfide; agents H, HD, and HT] and small quantities of the organic arsenical Lewisite [dichloro(2-chlorovinyl)arsine; agent L]. These agents can be dispersed in liquid, aerosol, or vapor form and are capable of producing severe chemical burns upon direct contact with tissue. Moist tissues such as the eyes, respiratory tract, and axillary areas are particularly affected. Available data summarizing acute dose response in humans and laboratory animals are summarized. Vesicant agents are also capable of generating delayed effects such as chronic bronchitis, carcinogenesis, or keratitis/keratopathy of the eye under appropriate conditions of exposure and dose. These effects may not become manifest until years following exposure. Risk analysis derived from carcinogenesis data indicates that sulfur mustard possesses a carcinogenic potency similar to that of benzo[a]pyrene. Because mustard agents are alkylating compounds, they destroy individual cells by reaction with cellular proteins, enzymes, RNA, and DNA. Once begun, tissue reaction is irreversible. Mustard agents are mutagenic; data for cellular and laboratory animal assays are presented. Reproductive effects have not been demonstrated in the offspring of laboratory rats. Acute Lewisite exposure has been implicated in cases of Bowen's disease, an intraepidermal squamous cell carcinoma. Lewisite is not known to generate reproductive or teratogenic effects. 112 refs., 1 fig., 6 tabs.

  3. Quantitative determination of the hydrolysis products of nitrogen mustards in human urine by liquid chromatography-electrospray ionization tandem mass spectrometry.

    PubMed

    Lemire, Sharon W; Ashley, David L; Calafat, Antonia M

    2003-01-01

    Nitrogen mustards are a public health concern because of their extreme vesicant properties and the possible exposure of workers during the destruction of chemical stockpiles. A sensitive, rapid, accurate, and precise analysis for the quantitation of ultratrace levels of N-ethyldiethanolamine (EDEA) and N-methyldiethanolamine (MDEA) in human urine as a means of assessing recent exposure to the nitrogen mustards bis(2-chloroethyl)ethylamine and bis(2-chloroethyl)methylamine, respectively, was developed. The method was based on solid-phase extraction, followed by analysis of the urine extract using isotope-dilution high-performance liquid chromatography-mass spectrometry with TurbolonSpray ionization and multiple-reaction monitoring. The method limits of detection were 0.41 ng/mL for EDEA and 0.96 ng/mL for MDEA in 1 mL of urine with coefficients of variation < 10% for both compounds. PMID:12587675

  4. Cross-Linking of Thioredoxin Reductase by the Sulfur Mustard Analogue Mechlorethamine (Methyl bis(2-chloroethyl) amine) in Human Lung Epithelial Cells and Rat Lung: Selective Inhibition of Disulfide Reduction but Not Redox Cycling

    PubMed Central

    Jan, Yi-Hua; Heck, Diane E.; Malaviya, Rama; Casillas, Robert P.; Laskin, Debra L.; Laskin, Jeffrey D.

    2014-01-01

    Oxidative stress plays a key role in mechlorethamine (methyl bis(2-chloroethyl) amine, HN2) toxicity. The thioredoxin system, consisting of thioredoxin reductase (TrxR), thioredoxin, and NADPH, is important in redox regulation and protection against oxidative stress. HN2 contains two electrophilic side chains that can react with nucleophilic sites in proteins leading to changes in their structure and function. We report that HN2 inhibits the cytosolic (TrxR1) and mitochondrial (TrxR2) forms of TrxR in A549 lung epithelial cells. TrxR exists as homodimers under native conditions; monomers can be detected by denaturing and reducing SDS-PAGE followed by Western blotting. HN2 treatment caused marked decreases in TrxR1 and TrxR2 monomers along with increases in dimers and oligomers under reducing conditions, indicating that HN2 cross-links TrxR. Cross-links were also observed in rat lung after HN2 treatment. Using purified TrxR1, NADPH reduced, but not oxidized, enzyme was inhibited and cross-linked by HN2. LC-MS/MS analysis of TrxR1 demonstrated that HN2 adducted cysteine- and selenocysteine-containing redox centers forming monoadducts, intramolecule and intermolecule cross-links, resulting in enzyme inhibition. HN2 cross-links two dimeric subunits through intermolecular binding to cysteine 59 in one subunit of the dimer and selenocysteine 498 in the other subunit, confirming the close proximity of the N- and C-terminal redox centers of adjacent subunits. Despite cross-linking and inhibition of TrxR activity by HN2, TrxR continued to mediate menadione redox cycling and generated reactive oxygen species. These data suggest that disruption of the thioredoxin system contributes to oxidative stress and tissue injury induced by HN2. PMID:24274902

  5. Clinically-Relevant Cutaneous Lesions by Nitrogen Mustard: Useful Biomarkers of Vesicants Skin Injury in SKH-1 Hairless and C57BL/6 Mice

    PubMed Central

    Tewari-Singh, Neera; Jain, Anil K.; Inturi, Swetha; White, Carl W.; Agarwal, Rajesh

    2013-01-01

    A paucity of clinically applicable biomarkers to screen therapies in laboratory is a limitation in the development of countermeasures against cutaneous injuries by chemical weapon, sulfur mustard (SM), and its analog nitrogen mustard (NM). Consequently, we assessed NM-caused progression of clinical cutaneous lesions; notably, skin injury with NM is comparable to SM. Exposure of SKH-1 hairless and C57BL/6 (haired) mice to NM (3.2 mg) for 12–120 h caused clinical sequelae of toxicity, including microblister formation, edema, erythema, altered pigmentation, wounding, xerosis and scaly dry skin. These toxic effects of NM were similar in both mouse strains, except that wounding and altered pigmentation at 12–24 h and appearance of dry skin at 24 and 72 h post-NM exposure were more pronounced in C57BL/6 compared to SKH-1 mice. Conversely, edema, erythema and microblister formation were more prominent in SKH-1 than C57BL/6 mice at 24–72 h after NM exposure. In addition, 40–60% mortality was observed following 120 h of NM exposure in the both mouse strains. Overall, these toxic effects of NM are comparable to those reported in humans and other animal species with SM, and thus represent clinically-relevant cutaneous injury endpoints in screening and optimization of therapies for skin injuries by vesicating agents. PMID:23826320

  6. Flavanone silibinin treatment attenuates nitrogen mustard-induced toxic effects in mouse skin

    SciTech Connect

    Jain, Anil K.; Tewari-Singh, Neera; Inturi, Swetha; Kumar, Dileep; Orlicky, David J.; Agarwal, Chapla; White, Carl W.; Agarwal, Rajesh

    2015-05-15

    Currently, there is no effective antidote to prevent skin injuries by sulfur mustard (SM) and nitrogen mustard (NM), which are vesicating agents with potential relevance to chemical warfare, terrorist attacks, or industrial/laboratory accidents. Our earlier report has demonstrated the therapeutic efficacy of silibinin, a natural flavanone, in reversing monofunctional alkylating SM analog 2-chloroethyl ethyl sulfide-induced toxic effects in mouse skin. To translate this effect to a bifunctional alkylating vesicant, herein, efficacy studies were carried out with NM. Topical application of silibinin (1 or 2 mg) 30 min after NM exposure on the dorsal skin of male SKH-1 hairless mice significantly decreased NM-induced toxic lesions at 24, 72 or 120 h post-exposure. Specifically, silibinin treatment resulted in dose-dependent reduction of NM-induced increase in epidermal thickness, dead and denuded epidermis, parakeratosis and microvesication. Higher silibinin dose also caused a 79% and 51%reversal in NM-induced increases in myeloperoxidase activity and COX-2 levels, respectively. Furthermore, silibinin completely prevented NM-induced H2A.X phosphorylation, indicating reversal of DNA damage which could be an oxidative DNA damage as evidenced by high levels of 8-oxodG in NM-exposed mouse skin that was significantly reversed by silibinin. Together, these findings suggest that attenuation of NM-induced skin injury by silibinin is due to its effects on the pathways associated with DNA damage, inflammation, vesication and oxidative stress. In conclusion, results presented here support the optimization of silibinin as an effective treatment of skin injury by vesicants. - Highlights: • Silibinin treatment attenuated nitrogen mustard (NM)-induced skin injury. • Silibinin affects pathways associated with DNA damage, inflammation and vesication. • The efficacy of silibinin could also be associated with oxidative stress. • These results support testing and optimization of

  7. Mechanistic insights into the hydrolysis of 2-chloroethyl ethyl sulfide: the expanded roles of sulfonium salts.

    PubMed

    Bae, Su Y; Winemiller, Mark D

    2013-07-01

    The hydrolysis of 2-chloroethyl ethyl sulfide has been examined in an effort to better understand its mechanism under more concentrated conditions. Two salts formed during hydrolysis were synthesized, and an emphasis was placed on determining their effect on the reaction as it proceeded. Unexpected changes in mechanism were seen when excess chloride was added to the reaction. By measuring rates and product distributions as the products were added back into the hydrolysis, a mechanism was developed. The formation of these sulfonium salts represents additional products in the disappearance of 2-chloroethyl ethyl sulfide with k3 in particular causing a deviation away from expected first-order behavior. Sulfonium salts 3 and 4 do not appear to interconvert, and the system as a whole had fewer pathways available than previously proposed. Initial conditions for studying the hydrolysis were very important and could lead to different conclusions depending on the conditions used. This work will aid in better understanding the hydrolysis of the very toxic chemical warfare agent mustard (bis(2-chloroethyl)sulfide) in the environment and during its decontamination. PMID:23767819

  8. Multiphoton imaging the disruptive nature of sulfur mustard lesions

    NASA Astrophysics Data System (ADS)

    Werrlein, Robert J.; Braue, Catherine R.; Dillman, James F.

    2005-03-01

    Sulfur mustard [bis-2-chloroethyl sulfide] is a vesicating agent first used as a weapon of war in WWI. It causes debilitating blisters at the epidermal-dermal junction and involves molecules that are also disrupted by junctional epidermolysis bullosa (JEB) and other blistering skin diseases. Despite its recurring use in global conflicts, there is still no completely effective treatment. We have shown by imaging human keratinocytes in cell culture and in intact epidermal tissues that the basal cells of skin contain well-organized molecules (keratins K5/K14, α6β4 integrin, laminin 5 and α3β1 integrin) that are early targets of sulfur mustard. Disruption and collapse of these molecules is coincident with nuclear displacement, loss of functional asymmetry, and loss of polarized mobility. The progression of this pathology precedes basal cell detachment by 8-24 h, a time equivalent to the "clinical latent phase" that defines the extant period between agent exposure and vesication. Our images indicate that disruption of adhesion-complex molecules also impairs cytoskeletal proteins and the integration of structures required for signal transduction and tissue repair. We have recently developed an optical system to test this hypothesis, i.e., to determine whether and how the early disruption of target molecules alters signal transduction. This environmentally controlled on-line system provides a nexus for real-time correlation of imaged lesions with DNA microarray analysis, and for using multiphoton microscopy to facilitate development of more effective treatment strategies.

  9. Quantitation of biomarkers of exposure to nitrogen mustards in urine from rats dosed with nitrogen mustards and from an unexposed human population.

    PubMed

    Lemire, Sharon W; Barr, John R; Ashley, David L; Olson, Carl T; Hayes, Timothy L

    2004-01-01

    The nitrogen mustards bis(2-chloroethyl)ethylamine (HN1), bis(2-chloroethyl)methylamine (HN2), and tris(2-chloroethyl)amine (HN3) have the potential to be used as chemical terrorism agents because of their extreme vesicant properties. We modified a previously reported method to incorporate automated solid-phase extraction, improve chromatography, and include the urinary metabolite for HN3. The improved method was used to measure levels of the urinary metabolites N-ethyldiethanolamine (EDEA), N-methyldiethanolamine (MDEA), and triethanolamine (TEA) in rats dosed with HN1, HN2, and HN3, respectively, and to establish background levels of EDEA, MDEA, and TEA in human urine samples from a population with no known exposure to nitrogen mustards. Rat dosing experiments confirmed that EDEA, MDEA, and TEA could be detected in urine for at least 48 h after exposure to HN1, HN2, and HN3, respectively. Substantial amounts of EDEA (89 ng/mL), MDEA (170 ng/mL), and TEA (1105 ng/mL) were measured in the urine of rats exposed to 10 mg HN1, HN2, and HN3, respectively, 48 h after exposure. The background concentrations for TEA in the human population ranged from below the limit of detection (LOD 3 ng/mL) to approximately 6500 ng/mL. Neither EDEA (LOD 0.4 ng/mL) nor MDEA (LOD 0.8 ng/mL) was detected above the LOD in the human samples. PMID:15239850

  10. Identification and validation of vesicant therapeutic targets using a high-throughput siRNA screening approach.

    PubMed

    Ruff, Albert L; Beach, Sarah; Lehman, John; Rothwell, Cristin; Dillman, James F

    2016-02-01

    Sulfur mustard [SM, bis-(2-chloroethyl) sulfide] is a highly reactive bifunctional alkylating agent that has been used as a vesicating agent in warfare scenarios to induce severe lung, skin, and eye injury. SM cutaneous lesions are characterized by both vesication and severe inflammation, but the molecular mechanisms that lead to these signs and symptoms are not well understood. There is a pressing need for effective therapeutics to treat this injury. An understanding of the molecular mechanisms of injury and identification of potential therapeutic targets is necessary for rational therapeutic development. We have applied a high-throughput small interfering RNA (siRNA) screening approach to the problem of SM cutaneous injury in an effort to meet these needs. Our siRNA screening efforts have initially focused on SM-induced inflammation in cutaneous injury since chronic inflammation after exposure appears to play a role in progressive clinical pathology, and intervention may improve clinical outcome. Also, targets that mitigate cellular injury should reduce the inflammatory response. Historical microarray data on this injury were mined for targets and pathways implicated in inflammation, and a siRNA library of 2,017 targets was assembled for screening. Primary screening and library deconvolution were performed using human HaCaT keratinocytes and focused on cell death and inflammatory markers as end points. Using this in vitro approach, we have identified and validated novel targets for the potential treatment of SM-induced cutaneous injury. PMID:25537185

  11. Flavanone silibinin treatment attenuates nitrogen mustard-induced toxic effects in mouse skin.

    PubMed

    Jain, Anil K; Tewari-Singh, Neera; Inturi, Swetha; Kumar, Dileep; Orlicky, David J; Agarwal, Chapla; White, Carl W; Agarwal, Rajesh

    2015-05-15

    Currently, there is no effective antidote to prevent skin injuries by sulfur mustard (SM) and nitrogen mustard (NM), which are vesicating agents with potential relevance to chemical warfare, terrorist attacks, or industrial/laboratory accidents. Our earlier report has demonstrated the therapeutic efficacy of silibinin, a natural flavanone, in reversing monofunctional alkylating SM analog 2-chloroethyl ethyl sulfide-induced toxic effects in mouse skin. To translate this effect to a bifunctional alkylating vesicant, herein, efficacy studies were carried out with NM. Topical application of silibinin (1 or 2mg) 30 min after NM exposure on the dorsal skin of male SKH-1 hairless mice significantly decreased NM-induced toxic lesions at 24, 72 or 120 h post-exposure. Specifically, silibinin treatment resulted in dose-dependent reduction of NM-induced increase in epidermal thickness, dead and denuded epidermis, parakeratosis and microvesication. Higher silibinin dose also caused a 79% and 51%reversal in NM-induced increases in myeloperoxidase activity and COX-2 levels, respectively. Furthermore, silibinin completely prevented NM-induced H2A.X phosphorylation, indicating reversal of DNA damage which could be an oxidative DNA damage as evidenced by high levels of 8-oxodG in NM-exposed mouse skin that was significantly reversed by silibinin. Together, these findings suggest that attenuation of NM-induced skin injury by silibinin is due to its effects on the pathways associated with DNA damage, inflammation, vesication and oxidative stress. In conclusion, results presented here support the optimization of silibinin as an effective treatment of skin injury by vesicants. PMID:25791923

  12. High-throughput sample preparation and simultaneous column regeneration liquid chromatography-tandem mass spectrometry method for determination of nitrogen mustard metabolites in human urine.

    PubMed

    Reddy, Muntha K; Mills, Grier; Nixon, Christopher; Wyatt, Shane A; Croley, Timothy R

    2011-08-15

    Nitrogen mustards (NMs) are known to have DNA alkylation and strong vesicant properties. Their availability to terrorist organizations makes them a potential choice for chemical attacks on civilian populations. After an exposure, it is difficult to measure NMs directly because of their rapid metabolism in the human body. Therefore to determine an individual's level of exposure to NMs, it is necessary to analyze for NM metabolites being excreted by the body. The metabolites of NMs are generated by a hydrolysis reaction, and are easily detectable by liquid chromatography tandem mass spectrometry (LC-MS/MS). This work is focused on the development of a high-throughput assay for the quantitation of N-ethyldiethanolamine (EDEA) and N-methyldiethanolamine (MDEA) metabolites of bis (2-chloroethyl) ethylethanamine (HN1) and bis (2-chloroethyl) methylethanamine (HN2), respectively. The method uses automated 96-well plate sample preparation of human urine samples and a 2-position 10-port switching valve to allow for simultaneous regeneration of the liquid chromatography (LC) columns. Using this method, over 18 h was saved through the reduction of sample preparation and analysis time when compared to a conventional method for 96 samples. The validated method provided excellent accuracy for both EDEA (100.9%) and MDEA (100.6%) with precision better than 5.27% for each analyte. PMID:21764395

  13. Role of reactive nitrogen species generated via inducible nitric oxide synthase in vesicant-induced lung injury, inflammation and altered lung functioning

    SciTech Connect

    Sunil, Vasanthi R.; Shen, Jianliang; Patel-Vayas, Kinal; Gow, Andrew J.; Laskin, Jeffrey D.; Laskin, Debra L.

    2012-05-15

    Pulmonary toxicity induced by sulfur mustard and related vesicants is associated with oxidative stress. In the present studies we analyzed the role of reactive nitrogen species (RNS) generated via inducible nitric oxide synthase (iNOS) in lung injury and inflammation induced by vesicants using 2-chloroethyl ethyl sulfide (CEES) as a model. C57Bl/6 (WT) and iNOS −/− mice were sacrificed 3 days or 14 days following intratracheal administration of CEES (6 mg/kg) or control. CEES intoxication resulted in transient (3 days) increases in bronchoalveolar lavage (BAL) cell and protein content in WT, but not iNOS −/− mice. This correlated with expression of Ym1, a marker of oxidative stress in alveolar macrophages and epithelial cells. In contrast, in iNOS −/− mice, Ym1 was only observed 14 days post-exposure in enlarged alveolar macrophages, suggesting that they are alternatively activated. This is supported by findings that lung tumor necrosis factor and lipocalin Lcn2 expression, mediators involved in tissue repair were also upregulated at this time in iNOS −/− mice. Conversely, CEES-induced increases in the proinflammatory genes, monocyte chemotactic protein-1 and cyclooxygenase-2, were abrogated in iNOS −/− mice. In WT mice, CEES treatment also resulted in increases in total lung resistance and decreases in compliance in response to methacholine, effects blunted by loss of iNOS. These data demonstrate that RNS, generated via iNOS play a role in the pathogenic responses to CEES, augmenting oxidative stress and inflammation and suppressing tissue repair. Elucidating inflammatory mechanisms mediating vesicant-induced lung injury is key to the development of therapeutics to treat mustard poisoning. -- Highlights: ► Lung injury, inflammation and oxidative stress are induced by the model vesicant CEES ► RNS generated via iNOS are important in the CEES-induced pulmonary toxicity ► iNOS −/− mice are protected from CEES-induced lung toxicity and

  14. Protection against 2-chloroethyl ethyl sulfide (CEES) - induced cytotoxicity in human keratinocytes by an inducer of the glutathione detoxification pathway

    SciTech Connect

    Abel, Erika L.; Bubel, Jennifer D.; Simper, Melissa S.; Powell, Leslie; McClellan, S. Alex; Andreeff, Michael; MacLeod, Michael C.; DiGiovanni, John

    2011-09-01

    Sulfur mustard (SM or mustard gas) was first used as a chemical warfare agent almost 100 years ago. Due to its toxic effects on the eyes, lungs, and skin, and the relative ease with which it may be synthesized, mustard gas remains a potential chemical threat to the present day. SM exposed skin develops fluid filled bullae resulting from potent cytotoxicity of cells lining the basement membrane of the epidermis. Currently, there are no antidotes for SM exposure; therefore, chemopreventive measures for first responders following an SM attack are needed. Glutathione (GSH) is known to have a protective effect against SM toxicity, and detoxification of SM is believed to occur, in part, via GSH conjugation. Therefore, we screened 6 potential chemopreventive agents for ability to induce GSH synthesis and protect cultured human keratinocytes against the SM analog, 2-chloroethyl ethyl sulfide (CEES). Using NCTC2544 human keratinocytes, we found that both sulforaphane and methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me) stimulated nuclear localization of Nrf2 and induced expression of the GSH synthesis gene, GCLM. Additionally, we found that treatment with CDDO-Me elevated reduced GSH content of NCTC2544 cells and preserved their viability by {approx} 3-fold following exposure to CEES. Our data also suggested that CDDO-Me may act additively with 2,6-dithiopurine (DTP), a nucleophilic scavenging agent, to increase the viability of keratinocytes exposed to CEES. These results suggest that CDDO-Me is a promising chemopreventive agent for SM toxicity in the skin. - Highlights: > CDDO-Me treatment increased intracellular GSH in human keratinocytes. > CDDO-Me increased cell viability following exposure to the half-mustard, CEES. > The cytoprotective effect of CDDO-Me was likely due to scavenging with endogenous GSH.

  15. Linear free energy relationships and cytotoxicities of para-substituted 2-haloethyl aryl selenides and bis(2-chloroethyl) selenides.

    PubMed

    Kang, S I; Spears, C P

    1987-04-01

    Examples of a new class of alkylating agents, selenium mustards, were prepared for study of their chemical kinetic properties and cytotoxicities against human lymphoblastoid CCRF-CEM cells. In a series of para-substituted aryl 2-chloroethyl selenides, a linear free energy relationship between the first-order rate constant, k'nbp and sigma p gave a rho value of -1.3, indicating that formation of a cyclic ethylene selenonium ion is the rate-controlling step for alkylation of 4-(4-nitrobenzyl)pyridine (NBP). Consistent with the ethyleneselenonium ion pathway, rates of solvolyses were extremely sensitive to increasing water content, and a positive correlation was found between reactivity with NBP and nucleophilic selectivity (Swain-Scott s constant). The s constant, which predicts for variation in intracellular product spread, varied from 0.53 up to 0.95, equal to aliphatic nitrogen mustards. Alkylating activities based on extent of NBP alkylation, however, showed relatively low values, 8-23% of that of mechlorethamine, possibly due to hydrolysis occurring by a separate pathway from nucleophilic substitution. Reactivities and nucleophilic selectivities both showed positive correlations with cytotoxicities, suggesting that the rate and extent of alkylation of relatively strong nucleophilic centers mediate the biologic effects of these compounds. Two bifunctional selenium mustards were substantially more cytotoxic than monofunctional aromatic selenides. No additional cytotoxicity due to the selenium atom was observed, with the exception of diselenide (-SeSe-) compounds. Thus, selenium alkylating agents kinetically and biologically resemble classical, mustard-type alkylating agents. PMID:3560155

  16. Decontamination of 2-Chloroethyl Ethyl Sulfide by Pulsed Corona Plasma

    NASA Astrophysics Data System (ADS)

    Li, Zhanguo; Hu, Zhen; Cao, Peng; Zhao, Hongjie

    2014-11-01

    Decontamination of 2-chloroethyl ethyl sulfide (2-CEES, CH3CH2SCH2CH2Cl) by pulsed corona plasma was investigated. The results show that 212.6 mg/m3 of 2-CEES, with the gas flow rate of 2 m3/h, can be decontaminated to 0.09 mg/m3. According to the variation of the inlet and outlet concentration of 2-CEES vapor with retention time, it is found that the reaction of 2-CEES in a pulsed corona plasma system follows the first order reaction, with the reaction rate constant of 0.463 s-1. The decontamination mechanism is discussed based on an analysis of the dissociation energy of chemical bonds and decontamination products. The C-S bond adjacent to the Cl atom will be destroyed firstly to form CH3CH2S· and ·CH2CH2Cl radicals. CH3CH2S· can be decomposed to ·C2H5 and ·S. ·S can be oxidized to SO2, while ·C2H5 can be finally oxidized to CO2 and H2O. The C-Cl bond in the ·CH2CH2Cl radical can be destroyed to form ·CH2CH2. and ·Cl, which can be mineralized to CO2, H2O and HCl. The H atom in the ·CH2CH2Cl radical can also be substituted by ·Cl to form CHCl2-CHCl2.

  17. Inflammatory mechanisms of pulmonary injury induced by mustards.

    PubMed

    Malaviya, Rama; Sunil, Vasanthi R; Venosa, Alessandro; Vayas, Kinal N; Heck, Diane E; Laskin, Jeffrey D; Laskin, Debra L

    2016-02-26

    Exposure of humans and animals to vesicants, including sulfur mustard (SM) and nitrogen mustard (NM), causes severe and debilitating damage to the respiratory tract. Both acute and long term pathological consequences are observed in the lung following a single exposure to these vesicants. Evidence from our laboratories and others suggest that macrophages and the inflammatory mediators they release play an important role in mustard-induced lung injury. In this paper, the pathogenic effects of SM and NM on the lung are reviewed, along with the potential role of inflammatory macrophages and mediators they release in mustard-induced pulmonary toxicity. PMID:26478570

  18. Optical "Turn off" based selective detection and concomitant degradation of 2-chloroethyl ethyl sulfide (CEES) via Mg-porphyrazine complex immobilized on glass.

    PubMed

    Neelam; Singh, Vikram; Gupta, Tarkeshwar

    2014-02-17

    Covalently assembled monolayers (CAMs) of Mg-porphyrazine complex on glass and silicon substrates were fabricated and employed as "Turn off" sensor for ppm level detection and degradation of a sulfur mustard analogue: 2-chloroethyl ethyl sulfide (CEES). The detection process was read-out optically via an off-the-shelf UV/Vis spectrophotometer in transmission mode. Monolayer based sensor system was shown to be quite robust and stable, sufficiently accurate and reversible under given experimental conditions. Notably, the sensor system exhibited marked selectivity for CEES when exposed exclusively or in mix to different potent analytes. Moreover, action of KMnO4 on monolayer-CEES complex lead to CEES degradation and resetting of the sensor to its native state for reuse. PMID:24491785

  19. Liquid chromatography-time-of-flight mass spectrometry analysis of 1-(2-chloroethoxy)-2-[(2-chloroethyl)thio] ethane and related compounds: separation of an eleven component mixture.

    PubMed

    Winemiller, Mark D; Bae, Sue Y

    2008-11-14

    A method of separation for an eleven component mixture comprised of 1-(2-chloroethoxy)-2-[(2-chloroethyl)thio] ethane (4) and its derivatives has been developed using LC-time-of-flight-MS. All analytical figures of merit for compounds 1-11 have been determined. Compound 4 was examined in a substrate extraction study consisting of different sand and soil matrices, and a hydrolysis study of 4 on sand revealed an extremely complex degradation pathway which appeared to be concentration dependent. Substrate extraction and hydrolysis results where compared with sulfur mustard (HD). PMID:18834989

  20. 40 CFR 721.10243 - Phosphonic acid, P-[2-[bis(2-hydroxyethyl)amino]ethyl]-, bis(2-chloroethyl) ester.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Phosphonic acid, P- ethyl]-, bis(2... Specific Chemical Substances § 721.10243 Phosphonic acid, P- ethyl]-, bis(2-chloroethyl) ester. (a... phosphonic acid, P- ethyl]-, bis(2-chloroethyl) ester (PMN P-09-193; CAS No. 55088-28-3) is subject...

  1. 40 CFR 721.10243 - Phosphonic acid, P-[2-[bis(2-hydroxyethyl)amino]ethyl]-, bis(2-chloroethyl) ester.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Phosphonic acid, P- ethyl]-, bis(2... Specific Chemical Substances § 721.10243 Phosphonic acid, P- ethyl]-, bis(2-chloroethyl) ester. (a... phosphonic acid, P- ethyl]-, bis(2-chloroethyl) ester (PMN P-09-193; CAS No. 55088-28-3) is subject...

  2. 40 CFR 721.10243 - Phosphonic acid, P-[2-[bis(2-hydroxyethyl)amino]ethyl]-, bis(2-chloroethyl) ester.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Phosphonic acid, P- ethyl]-, bis(2... Specific Chemical Substances § 721.10243 Phosphonic acid, P- ethyl]-, bis(2-chloroethyl) ester. (a... phosphonic acid, P- ethyl]-, bis(2-chloroethyl) ester (PMN P-09-193; CAS No. 55088-28-3) is subject...

  3. ACUTE EXPOSURE TO TRIS (2-CHLOROETHYL) PHOSPHATE HIPPOCAMPAL NEURONAL LOSS AND IMPAIRS LEARNING IN RATS

    EPA Science Inventory

    Adult female, Fischer 344 rats were exposed to 275 mg/kg of tris(2- chloroethyl)phosphate (TRCP) by gavage. RCP produced consistent signs of convulsive activity within 60-90 minutes after dosing and extensive loss of CA1 hippocampal pyramidal cells when examined 7 days after dosi...

  4. Corneal toxicity induced by vesicating agents and effective treatment options.

    PubMed

    Goswami, Dinesh G; Tewari-Singh, Neera; Agarwal, Rajesh

    2016-06-01

    The vesicating agents sulfur mustard (SM) and lewisite (LEW) are potent chemical warfare agents that primarily cause damage to the ocular, skin, and respiratory systems. However, ocular tissue is the most sensitive organ, and vesicant exposure results in a biphasic injury response, including photophobia, corneal lesions, corneal edema, ulceration, and neovascularization, and may cause loss of vision. There are several reports on ocular injury from exposure to SM, which has been frequently used in warfare. However, there are very few reports on ocular injury by LEW, which indicate that injury symptoms appear instantly after exposure and faster than SM. In spite of extensive research efforts, effective therapies for vesicant-induced ocular injuries, mainly to the most affected corneal tissue, are not available. Hence, we have established primary human corneal epithelial cells and rabbit corneal organ culture models with the SM analog nitrogen mustard, which have helped to test the efficacy of potential therapeutic agents. These agents will then be further evaluated against in vivo SM- and LEW-induced corneal injury models, which will assist in the development of potential broad-spectrum therapies against vesicant-induced ocular injuries. PMID:27327041

  5. A giant vesical calculus.

    PubMed

    Rahman, M; Uddin, A; Das, G C; Akanda, N I

    2007-07-01

    Massive or giant vesical calculus is a rare entity in the recent urological practice. Males are affected more than the females. Vesical calculi are usually secondary to bladder outlet obstruction. These patients present with recurrent urinary tract infection, haematuria or with retention of urine. We report a young male patient who presented with defaecatory problems along with other urinary symptoms. The patient having an average built, non diabetic but hypertensive. The stone could be palpated by physical examination. His urea levels were within normal limits but urine examination shows infection. USG reveals bilateral hydronephrosis with multiple stones in both kidneys along with a giant vesical calculus. After controlling urinary infection and hypertention he underwent an open cystolithotomy. During operation digital rectal help was needed to remove the stone as it was adherent with bladder mucosa. Post operative period was uneventful. His urinary output was quite normal and had no defaecatory problems. Patient left the hospital 10 days after operation. PMID:17917633

  6. Protection against 2-chloroethyl ethyl sulfide (CEES)-induced cytotoxicity in human keratinocytes by an inducer of the glutathione detoxification pathway.

    PubMed

    Abel, Erika L; Bubel, Jennifer D; Simper, Melissa S; Powell, Leslie; McClellan, S Alex; Andreeff, Michael; MacLeod, Michael C; DiGiovanni, John

    2011-09-01

    Sulfur mustard (SM or mustard gas) was first used as a chemical warfare agent almost 100years ago. Due to its toxic effects on the eyes, lungs, and skin, and the relative ease with which it may be synthesized, mustard gas remains a potential chemical threat to the present day. SM exposed skin develops fluid filled bullae resulting from potent cytotoxicity of cells lining the basement membrane of the epidermis. Currently, there are no antidotes for SM exposure; therefore, chemopreventive measures for first responders following an SM attack are needed. Glutathione (GSH) is known to have a protective effect against SM toxicity, and detoxification of SM is believed to occur, in part, via GSH conjugation. Therefore, we screened 6 potential chemopreventive agents for ability to induce GSH synthesis and protect cultured human keratinocytes against the SM analog, 2-chloroethyl ethyl sulfide (CEES). Using NCTC2544 human keratinocytes, we found that both sulforaphane and methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me) stimulated nuclear localization of Nrf2 and induced expression of the GSH synthesis gene, GCLM. Additionally, we found that treatment with CDDO-Me elevated reduced GSH content of NCTC2544 cells and preserved their viability by ~3-fold following exposure to CEES. Our data also suggested that CDDO-Me may act additively with 2,6-dithiopurine (DTP), a nucleophilic scavenging agent, to increase the viability of keratinocytes exposed to CEES. These results suggest that CDDO-Me is a promising chemopreventive agent for SM toxicity in the skin. PMID:21723306

  7. [Operative treatment of vesical diverticula].

    PubMed

    Ye, G; Yang, T; Jin, X

    1997-04-01

    We reviewed the results of operative management of 31 patients with vesical deverticula, and introduce a simple technique for treating large bladder diverticula. In the 31 patients with vesical diverticula analysed, 23 were followed up for at least six months. Of the 31 patients, 25 were male and 6 female. The average age was 54.2 years. Diverticula was secondary to bladderoutlet obstruction. Seven cases had intradiverticular tumors, and 9 stones in the sac. The diagnosis of vesical diverticula was usually made by cystogram or ultrasonography. The operative indications for vesical diverticula included stone formation, intradiverticular tumor, ureteral obstruction, incomplete empting diverticulum and urine retention due to large diverticula. The combined extravesical and intravesical method was often used. 26 patients underwent both operations for outlet obstruction and vesical diverticula at the same time. Of the 23 followed-up cases, 21 had no symptoms of the urinary tract. Five of the 7 patients with intradiverticular tumor died within 2.5 years; one of the rest survived for 2 years, and the others for 6 years. Two patients with large vesical diverticula received intravesical separation of diverticula. No complications encountered in this simple, time-saving and safe procedure. Cystograms revealed normal condition. The choice of operative techniques to treat vesical diverticula varies with each individual patient. The technique of intravesical separation of vesical diverticula is suitable for large, adhesive and posterior diverticula. PMID:10374539

  8. DNA damage and sequence specificity of DNA binding of the new anti-cancer agent 1,4-bis(2'-chloroethyl)-1,4-diazabicyclo-[2.2.1] heptane dimaleate (Dabis maleate)

    PubMed Central

    Broggini, M.; Hartley, J. A.; Mattes, W. B.; Ponti, M.; Kohn, K. W.; D'Incalci, M.

    1990-01-01

    The DNA damage and the sequence specificity of guanine-N7 alkylation produced by the novel, positively charged, antineoplastic agent 1,4-bis(2'-chloroethyl)-1,4-diazabicyclo-[2.2.1] heptane dimaleate (Dabis maleate) and its uncharged tertiary amine analogue 1,4-bis(2'-chloroethyl)-1,4-diazacyclohexane (Dabis analogue) were investigated in L1210 cells and isolated DNA. Both compounds are cytotoxic in vitro causing an arrest of L1210 cells in G2/M phase of the cell cycle. In isolated DNA, Dabis maleate alkylates guanine at the N7-position with some differences in specificity compared to other alkylating agents (e.g. nitrogen mustard). Significant differences are also evident between Dabis maleate and Dabis analogue, suggesting that Dabis analogue is not the sole alkylating species of Dabis maleate. Using the alkaline elution technique a moderate number of DNA interstrand cross-links were detected in L1210 cells treated with both compounds, which were completely repaired within 24 h. Dabis maleate and Dabis analogue do not cause DNA single strand breaks or DNA protein cross-links at the doses at which DNA interstrand cross-links were detected. PMID:2393411

  9. Mustard gas or sulfur mustard: an old chemical agent as a new terrorist threat.

    PubMed

    Wattana, Monica; Bey, Tareg

    2009-01-01

    Sulfur mustard is a member of the vesicant class of chemical warfare agents that causes blistering to the skin and mucous membranes. There is no specific antidote, and treatment consists of systematically alleviating symptoms. Historically, sulfur mustard was used extensively in inter-governmental conflicts within the trenches of Belgium and France during World War I and during the Iran-Iraq conflict. Longitudinal studies of exposed victims show that sulfur mustard causes long-term effects leading to high morbidity. Given that only a small amount of sulfur mustard is necessary to potentially cause an enormous number of casualties, disaster-planning protocol necessitates the education and training of first-line healthcare responders in the recognition, decontamination, triage, and treatment of sulfur mustard-exposed victims in a large-scale scenario. PMID:19557954

  10. Structural Changes in the Skin of Hairless Mice Following Exposure to Sulfur Mustard Correlate with Inflammation and DNA Damage

    PubMed Central

    Joseph, Laurie B.; Gerecke, Donald R.; Heck, Diane E.; Black, Adrienne T.; Sinko, Patrick J.; Cervelli, Jessica A.; Casillas, Robert P.; Babin, Michael C.; Laskin, Debra L.; Laskin, Jeffrey D.

    2011-01-01

    Sulfur mustard (SM, bis(2-chloroethyl)sulfide) is a bifunctional alkylating agent that causes dermal inflammation, edema and blistering. To investigate the pathogenesis of SM-induced injury, we used a vapor cup model which provides an occlusive environment in which SM is in constant contact with the skin. The dorsal skin of SKH-1 hairless mice was exposed to saturated SM vapor or air control. Histopathological changes, inflammatory markers and DNA damage were analyzed 1–14 days later. After 1 day, SM caused epidermal thinning, stratum corneum shedding, basal cell karyolysis, hemorrhage and macrophage and neutrophil accumulation in the dermis. Cleaved caspase-3 and phosphorylated histone 2A.X (phospho-H2A.X), markers of apoptosis and DNA damage, respectively, were increased whereas proliferating cell nuclear antigen (PCNA) was down-regulated after SM exposure. By 3 days, epithelial cell hypertrophy, edema, parakeratosis and loss of epidermal structures were noted. Enzymes generating pro-inflammatory mediators including myeloperoxidase and cyclooxygenase-2 were upregulated. After 7 days, keratin-10, a differentiation marker, was evident in the stratum corneum. This was associated with an underlying eschar, as neoepidermis began to migrate at the wound edges. Trichrome staining revealed increased collagen deposition in the dermis. PCNA expression in the epidermis was correlated with hyperplasia, hyperkeratosis, and parakeratosis. By 14 days, there was epidermal regeneration with extensive hyperplasia, and reduced expression of cleaved caspase-3, cyclooxygenase-2 and phospho-H2A.X. These findings are consistent with the pathophysiology of SM-induced skin injury in humans suggesting that the hairless mouse can be used to investigate the dermatoxicity of vesicants and the potential efficacy of countermeasures. PMID:21672537

  11. Sulfur Mustard

    MedlinePlus

    ... the environment. Sulfur mustard was introduced in World War I as a chemical warfare agent. Historically it ... fatal. When sulfur mustard was used during World War I, it killed fewer than 5% of the ...

  12. A Choline Oxidase Amperometric Bioassay for the Detection of Mustard Agents Based on Screen-Printed Electrodes Modified with Prussian Blue Nanoparticles

    PubMed Central

    Arduini, Fabiana; Scognamiglio, Viviana; Covaia, Corrado; Amine, Aziz; Moscone, Danila; Palleschi, Giuseppe

    2015-01-01

    In this work a novel bioassay for mustard agent detection was proposed. The bioassay is based on the capability of these compounds to inhibit the enzyme choline oxidase. The enzymatic activity, which is correlated to the mustard agents, was electrochemically monitored measuring the enzymatic product, hydrogen peroxide, by means of a screen-printed electrode modified with Prussian Blue nanoparticles. Prussian Blue nanoparticles are able to electrocatalyse the hydrogen peroxide concentration reduction at low applied potential (−50 mV vs. Ag/AgCl), thus allowing the detection of the mustard agents with no electrochemical interferences. The suitability of this novel bioassay was tested with the nitrogen mustard simulant bis(2-chloroethyl)amine and the sulfur mustard simulants 2-chloroethyl ethyl sulfide and 2-chloroethyl phenyl sulfide. The bioassay proposed in this work allowed the detection of mustard agent simulants with good sensitivity and fast response, which are excellent premises for the development of a miniaturised sensor well suited for an alarm system in case of terrorist attacks. PMID:25688587

  13. Biodegradation of Bis(2-Chloroethyl) Ether by Xanthobacter sp. Strain ENV481▿

    PubMed Central

    McClay, Kevin; Schaefer, Charles E.; Vainberg, Simon; Steffan, Robert J.

    2007-01-01

    Degradation of bis(2-chloroethyl) ether (BCEE) was observed to occur in two bacterial strains. Strain ENV481, a Xanthobacter sp. strain, was isolated by enrichment culturing of samples from a Superfund site located in the northeastern United States. The strain was able to grow on BCEE or 2-chloroethylethyl ether as the sole source of carbon and energy. BCEE degradation in strain ENV481 was facilitated by sequential dehalogenation reactions resulting in the formation of 2-(2-chloroethoxy)ethanol and diethylene glycol (DEG), respectively. 2-Hydroxyethoxyacetic acid was detected as a product of DEG catabolism by the strain. Degradation of BCEE by strain ENV481 was independent of oxygen, and the strain was not able to grow on a mixture of benzene, ethylbenzene, toluene, and xylenes, other prevalent contaminants at the site. Another bacterial isolate, Pseudonocardia sp. strain ENV478 (S. Vainberg et al., Appl. Environ. Microbiol. 72:5218-5224, 2006), degraded BCEE after growth on tetrahydrofuran or propane but was not able to grow on BCEE as a sole carbon source. BCEE degradation by strain ENV478 appeared to be facilitated by a monooxygenase-mediated O-dealkylation mechanism, and it resulted in the accumulation of 2-chloroacetic acid that was not readily degraded by the strain. PMID:17873075

  14. Putative roles of inflammation in the dermatopathology or sulfur mustard

    SciTech Connect

    Cowan, F.M.; Broomfield, C.A.

    1993-12-31

    Sulfur mustard (2,2`-dichlorodiethyl sulfide), a radiomimetic agent with mutagenic (Cappizzi et al., 1973; Fox and Scott, 1983), cytotoxic (Wheeler, 1962; Papirmeister and Davison, 1965), and vesicant (Anslow and Houck, 1946; Renshaw, 1946) properties, is also a chemical-warfare blistering agent with no known antidote. Sulfur mustard predominantly effects exposed epithelial tissues of the skin, the eye, and the respiratory tract, although higher doses can produce systemic toxicity (reviewed by Papirmeister et al., 1991). The severity of sulfur mustard toxicity is dose dependent, causing irritation, edema, necrosis and ulceration; characteristic symptoms are unique to the site of exposure, e.g., vesication, conjunctivitis, bronchopneumonia (reviewed by Papirmeister et al., 1991). The basic histopathology of mustard-induced cutaneous lesions has been reviewed by Papirmeister et al. (1985, 1991) and includes degeneration of epidermal cells, especially in the basal layer, followed by the formation of vesicles (and, in man, bullae) that have been variously characterized as intraepidermal or subcorneal but that appear in most cases to result from cleavage at the dermal-epidermal junction. However, despite general agreement concerning the morphologic changes caused by mustard and despite more than 50 years of research, the pathogenesis of mustard injury is still incompletely understood.

  15. Evaluation of the vesicating properties of neutralized chemical agent identification sets. Final report, November 1995-August 1997

    SciTech Connect

    Olajos, E.J.; Salem, H.; Gieseking, J.K.

    1997-08-01

    Vesication and skin irritation studies were conducted in hairless guinea-pigs to determine the vesicant and skin irritation potential of Chemical Agent Identification Sets (CAIS). Guinea-pigs were topically dosed with `test article` NEAT HD, 10% agent/chloroform solutions, or product solutions (wastestreams) and evaluated for skin-damaging effects (gross and light microscopic). Product solutions from the chemical neutralization of neat sulfur mustard resulted in microvesicle formation (vesication). All agent-dosed (agent/chloroform solutions or HD) sites exhibited microblisters, as well as other histopathologic lesions of the skin. Wastestreams from the neutalization of agent (agent/chloroform; agent on charcoal) were devoid of microvesicant activity. Dermal irritant effects (erythema and edema) were consistent with the skin-injurious activity associated with the neutralizing reagent 1,3-dichloro-5,5-dimethylhydantoin (DCDMH).

  16. Immunochemical analysis of poly(ADP-ribosyl)ation in HaCaT keratinocytes induced by the mono-alkylating agent 2-chloroethyl ethyl sulfide (CEES): Impact of experimental conditions.

    PubMed

    Debiak, Malgorzata; Lex, Kirsten; Ponath, Viviane; Burckhardt-Boer, Waltraud; Thiermann, Horst; Steinritz, Dirk; Schmidt, Annette; Mangerich, Aswin; Bürkle, Alexander

    2016-02-26

    Sulfur mustard (SM) is a bifunctional alkylating agent with a long history of use as a chemical weapon. Although its last military use is dated for the eighties of the last century, a potential use in terroristic attacks against civilians remains a significant threat. Thus, improving medical therapy of mustard exposed individuals is still of particular interest. PARP inhibitors were recently brought into the focus as a potential countermeasure for mustard-induced pathologies, supported by the availability of efficient compounds successfully tested in cancer therapy. PARP activation after SM treatment was reported in several cell types and tissues under various conditions; however, a detailed characterization of this phenomenon is still missing. This study provides the basis for such studies by developing and optimizing experimental conditions to investigate poly(ADP-ribosyl)ation (PARylation) in HaCaT keratinocytes upon treatment with the monofunctional alkylating agent 2-chloroethyl ethyl sulfide ("half mustard", CEES). By using an immunofluorescence-based approach, we show that optimization of experimental conditions with regards to the type of solvent, dilution factors and treatment procedure is essential to obtain a homogenous PAR staining in HaCaT cell cultures. Furthermore, we demonstrate that different CEES treatment protocols significantly influence the cytotoxicity profiles of treated cells. Using an optimized treatment protocol, our data reveals that CEES induces a dose- and time-dependent dynamic PARylation response in HaCaT cells that could be completely blocked by treating cells with the clinically relevant pharmacological PARP inhibitor ABT888 (also known as veliparib). Finally, siRNA experiments show that CEES-induced PAR formation is predominantly due to the activation of PARP1. In conclusion, this study provides a detailed analysis of the CEES-induced PARylation response in HaCaT keratinocytes, which forms an experimental basis to study the

  17. Selective cytotoxicity of a system L specific amino acid nitrogen mustard.

    PubMed

    Haines, D R; Fuller, R W; Ahmad, S; Vistica, D T; Marquez, V E

    1987-03-01

    The synthesis and characterization of DL-2-amino-7-bis[(2-chloroethyl)amino]-1,2,3,4-tetrahydro-2-naphthoic acid and DL-2-amino-5-bis[(2-chloroethyl)amino]-1,2,3,4-tetrahydro-2-napthoic+ ++ acid were accomplished. The correct assignment of the site of attachment of the bis(2-chloroethyl)amino side chain was ascertained by selective proton decoupling of the 13C NMR spectra performed on the corresponding nitrospirohydantoin precursors 2 and 3, which were obtained from the nitration of beta-tetralone hydantoin. The two target compounds 6 and 7 were designed as tumor-specific agents capable of being selectively transported into tumor cells by the leucine-preferring transport system (system L). Inhibition analysis of the initial rate of transport of the system L specific substrate 2-amino-bicyclo[2.2.1]heptane-2-carboxylic acid (BCH) by 6 and 7 indicated that the 7-substituted isomer 6 was an extremely potent competitive inhibitor of that transport system in murine L1210 leukemic cells (Ki = 0.2 microM). Evaluation of the selectivity of this compound indicated that it possessed enhanced in vitro antitumor activity and reduced myelosuppressive activity when compared to its prototype amino acid nitrogen mustard, L-phenylalanine mustard (L-PAM). In addition to being more selectively toxic to tumor cells, this compound differs from L-PAM in having a 2-3-fold shorter half-life (t1/2). PMID:3820226

  18. Identification of the nitrogen-based blister agents bis(2-chloroethyl)methylamine (HN-2) and tris(2-chloroethyl)amine (HN-3) and their hydrolysis products on soil using ion trap secondary ion mass spectrometry.

    PubMed

    Gresham, G L; Groenewold, G S; Olson, J E

    2000-12-01

    The nitrogen blister agents HN-2 (bis(2-chloroethyl)methylamine) and HN-3 (tris(2-chloroethyl)amine) were directly analyzed on the surface of soil samples using ion trap secondary ion mass spectrometry (SIMS). In the presence of water, HN-1 (bis(2-choroethyl)ethylamine), HN-2 and HN-3 undergo hydrolysis to form N-ethyldiethanolamine, N-methyldiethanolamine and triethanolamine (TEA), respectively; these compounds can be readily detected as adsorbed species on soil particles. When soil samples spiked with HN-3 in alcohol were analyzed, 2-alkoxyethylamine derivatives were observed on the sample surfaces. This result shows that nitrogen blister agents will undergo condensation reactions with nucleophilic compounds and emphasizes the need for an analytical methodology capable of detecting a range of degradation and condensation products on environmental surfaces. The ability of ion trap SIMS to isolate and accumulate ions, and then perform tandem mass spectrometric analysis improves the detection of low-abundance surface contaminants and the selectivity of the technique. Utilizing these techniques, the limits of detection for HN-3 were studied as a function of surface coverage. It was found that HN-3 could be detected at a surface coverage of 0.01 monolayer, which corresponds to 20 ppm (mass/mass) for a soil having a surface area of 2.2 m(2) g(-1). TEA, the exhaustive hydrolysis product of HN-3, was detected at a surface coverage of 0.001 monolayer, which corresponds to 0.86 ppm. PMID:11180637

  19. Nitrogen Mustards

    MedlinePlus

    ... your clothing, rapidly wash your entire body with soap and water, and get medical care as quickly ... mustard from your skin with large amounts of soap and water. Washing with soap and water will ...

  20. The chemiluminescence determination of 2-chloroethyl ethyl sulfide using luminol-AgNO3-silver nanoparticles system

    NASA Astrophysics Data System (ADS)

    Maddah, Bozorgmehr; Shamsi, Javad; Barsang, Mehran Jam; Rahimi-Nasrabadi, Mehdi

    2015-05-01

    A highly sensitive chemiluminescence (CL) method for the determination of 2-chloroethyl ethyl sulfide (2-CEES) was presented. It was found that 2-chloroethyl ethyl sulfide (2-CEES) could inhibit the CL of the luminol-AgNO3 system in the presence of silver nanoparticles in alkaline solution, which made it applicable for determination of 2-CEES. The presented method is simple, convenient, rapid and sensitive. Under the optimized conditions, the calibration curve was linear in the range of 0.0001-1 ng mL-1, with the correlation coefficient of 0.992; while the limit of detection (LOD), based on signal-to-noise ratio (S/N) of 3, was 6 × 10-6 ng mL-1. Also, the relative standard deviation (RSD, n = 5) for determination of 2-CEES (0.50 ng mL-1) was 3.1%. The method was successfully applied for the determination of 2-CEES in environmental aqueous samples.

  1. The chemiluminescence determination of 2-chloroethyl ethyl sulfide using luminol-AgNO3-silver nanoparticles system.

    PubMed

    Maddah, Bozorgmehr; Shamsi, Javad; Barsang, Mehran Jam; Rahimi-Nasrabadi, Mehdi

    2015-05-01

    A highly sensitive chemiluminescence (CL) method for the determination of 2-chloroethyl ethyl sulfide (2-CEES) was presented. It was found that 2-chloroethyl ethyl sulfide (2-CEES) could inhibit the CL of the luminol-AgNO3 system in the presence of silver nanoparticles in alkaline solution, which made it applicable for determination of 2-CEES. The presented method is simple, convenient, rapid and sensitive. Under the optimized conditions, the calibration curve was linear in the range of 0.0001-1ngmL(-1), with the correlation coefficient of 0.992; while the limit of detection (LOD), based on signal-to-noise ratio (S/N) of 3, was 6×10(-6)ngmL(-1). Also, the relative standard deviation (RSD, n=5) for determination of 2-CEES (0.50ngmL(-1)) was 3.1%. The method was successfully applied for the determination of 2-CEES in environmental aqueous samples. PMID:25703367

  2. Cytometric analysis of DNA changes induced by sulfur mustard

    SciTech Connect

    Smith, W.J.; Sanders, K.M.; Ruddle, S.E.; Gross, C.L.

    1993-05-13

    Sulfur mustard is an alkylating agent which causes severe, potentially debilitating blisters following cutaneous exposure. Its mechanism of pathogenesis is unknown and no antidote exists to prevent its pathology. The biochemical basis of sulfur mustard's vesicating activity has been hypothesized to be a cascade of events beginning with alkylation of DNA. Using human cells in culture, we have assessed the effects of sulfur mustard on cell cycle activity using flow cytometry with propidium iodide. Two distinct patterns emerged, a Gl/S interface block at concentrations equivalent to vesicating doses (>50-micronM) and a G2 block at 10-fold lower concentrations. In addition, noticeable increases in amount of dye uptake were observed at 4 and 24 hours after sulfur mustard exposure. These increases are believed to be related to DNA repair activities and can be prevented by treatment of the cells with niacinamide, which inhibits DNA repair. Other drugs which provide alternate alkylating sites or inhibit cell cycle progression were shown to lower the cytotoxicity of sulfur mustard and to protect against its direct DNA damaging effects.

  3. Covalent DNA-Protein Cross-Linking by Phosphoramide Mustard and Nornitrogen Mustard in Human Cells.

    PubMed

    Groehler, Arnold; Villalta, Peter W; Campbell, Colin; Tretyakova, Natalia

    2016-02-15

    N,N-Bis-(2-chloroethyl)-phosphorodiamidic acid (phosphoramide mustard, PM) and N,N-bis-(2-chloroethyl)-amine (nornitrogen mustard, NOR) are the two biologically active metabolites of cyclophosphamide, a DNA alkylating drug commonly used to treat lymphomas, breast cancer, certain brain cancers, and autoimmune diseases. PM and NOR are reactive bis-electrophiles capable of cross-linking cellular biomolecules to form covalent DNA-DNA and DNA-protein cross-links (DPCs). In the present work, a mass spectrometry-based proteomics approach was employed to characterize PM- and NOR-mediated DNA-protein cross-linking in human cells. Following treatment of human fibrosarcoma cells (HT1080) with cytotoxic concentrations of PM, over 130 proteins were found to be covalently trapped to DNA, including those involved in transcriptional regulation, RNA splicing/processing, chromatin organization, and protein transport. HPLC-ESI(+)-MS/MS analysis of proteolytic digests of DPC-containing DNA from NOR-treated cells revealed a concentration-dependent formation of N-[2-[cysteinyl]ethyl]-N-[2-(guan-7-yl)ethyl]amine (Cys-NOR-N7G) conjugates, confirming that it cross-links cysteine thiols of proteins to the N7 position of guanines in DNA. Cys-NOR-N7G adduct numbers were higher in NER-deficient xeroderma pigmentosum cells (XPA) as compared with repair proficient cells. Furthermore, both XPA and FANCD2 deficient cells were sensitized to PM treatment as compared to that of wild type cells, suggesting that Fanconi anemia and nucleotide excision repair pathways are involved in the removal of cyclophosphamide-induced DNA damage. PMID:26692166

  4. Antineoplastic agents LXIV: 1,4-Bis(2'-chloroethyl)-1,4-diazabicyclo[2.2.1]heptane dihydrogen dimaleate.

    PubMed

    Pettit, G R; Gieschen, D P; Pettit, W E

    1979-12-01

    The 1,4-bis(2'-chloroethyl)-1,4-diazabicyclo[2.2.1]heptane dication (II) exhibits remarkable antineoplastic activity. Detailed evaluation of several dianion derivatives showed a curative response level against the murine P-388 lymphocytic leukemia, colon 26, CD8F1 mammary, and the Walker 256 carcinosarcoma (rat) tumor systems. In addition, significant cancer chemotherapeutic activity was found against the murine L-1210 lymphoid leukemia, colon 38, and B16 melanocarcinoma tumor systems. The bicyclo dication (II) first was isolated, evaluated, and stored as the diperchlorate derivative (IIa). Because of the promising anticancer activity of IIa, procedures were developed for obtaining other anion derivatives for comparative biological purposes. Several naturally occurring substances were evaluated, and the dihydrogen dimaleate derivative (IIi) obtained by an ion-exchange technique was the most suitable. PMID:529047

  5. Wound Healing of Cutaneous Sulfur Mustard Injuries

    PubMed Central

    Graham, John S.; Chilcott, Robert P.; Rice, Paul; Milner, Stephen M.; Hurst, Charles G.; Maliner, Beverly I.

    2005-01-01

    Sulfur mustard is an alkylating chemical warfare agent that primarily affects the eyes, skin, and airways. Sulfur mustard injuries can take several months to heal, necessitate lengthy hospitalizations, and result in significant cosmetic and/or functional deficits. Historically, blister aspiration and/or deroofing (epidermal removal), physical debridement, irrigation, topical antibiotics, and sterile dressings have been the main courses of action in the medical management of cutaneous sulfur mustard injuries. Current treatment strategy consists of symptomatic management and is designed to relieve symptoms, prevent infections, and promote healing. There are currently no standardized or optimized methods of casualty management that prevent or minimize deficits and provide for speedy wound healing. Several laboratories are actively searching for improved therapies for cutaneous vesicant injury, with the aim of returning damaged skin to optimal appearance and normal function in the shortest time. Improved treatment will result in a better cosmetic and functional outcome for the patient, and will enable the casualty to return to normal activities sooner. This editorial gives brief overviews of sulfur mustard use, its toxicity, concepts for medical countermeasures, current treatments, and strategies for the development of improved therapies. PMID:16921406

  6. Sulfur, oxygen, and nitrogen mustards: stability and reactivity.

    PubMed

    Wang, Qi-Qiang; Begum, Rowshan Ara; Day, Victor W; Bowman-James, Kristin

    2012-11-28

    Mustard gas, bis(β-chloroethyl) sulfide (HD), is highly toxic and harmful to humans and the environment. It comprises one class of chemical warfare agents (CWAs) that was used in both World Wars I and II. The three basic analogues or surrogates are: the monochloro derivative, known as the half mustard, 2-chloroethyl ethyl sulfide (CEES); an oxygen analogue, bis(β-chloroethyl) ether (BCEE); and several nitrogen analogues based on the 2,2'-dichlorodiethylamine framework (e.g., HN1, HN2, and HN3). The origin of their toxicity is considered to be from the formation of three-membered heterocyclic ions, a reaction that is especially accelerated in aqueous solution. The reaction of these cyclic ion intermediates with a number of important biological species such as DNA, RNA and proteins causes cell toxicity and is responsible for the deleterious effects of the mustards. While a number of studies have been performed over the last century to determine the chemistry of these compounds, early studies suffered from a lack of more sophisticated NMR and X-ray techniques. It is now well-established that the sulfur and nitrogen mustards are highly reactive in water, while the oxygen analog is much more stable. In this study, we review and summarize results from previous studies, and add results of our own studies of the reactivity of these mustards toward various nonaqueous solvents and nucleophiles. In this manner a more comprehensive evaluation of the stability and reactivity of these related mustard compounds is achieved. PMID:23070251

  7. Silibinin, dexamethasone, and doxycycline as potential therapeutic agents for treating vesicant-inflicted ocular injuries

    SciTech Connect

    Tewari-Singh, Neera; Jain, Anil K.; Inturi, Swetha; Ammar, David A.; Agarwal, Chapla; Tyagi, Puneet; Kompella, Uday B.; Enzenauer, Robert W.; Petrash, J. Mark; Agarwal, Rajesh

    2012-10-01

    There are no effective and approved therapies against devastating ocular injuries caused by vesicating chemical agents sulfur mustard (SM) and nitrogen mustard (NM). Herein, studies were carried out in rabbit corneal cultures to establish relevant ocular injury biomarkers with NM for screening potential efficacious agents in laboratory settings. NM (100 nmol) exposure of the corneas for 2 h (cultured for 24 h), showed increases in epithelial thickness, ulceration, apoptotic cell death, epithelial detachment microbullae formation, and the levels of VEGF, cyclooxygenase-2 (COX-2) and matrix metalloproteinase-9 (MMP-9). Employing these biomarkers, efficacy studies were performed with agent treatments 2 h and every 4 h thereafter, for 24 h following NM exposure. Three agents were evaluated, including prescription drugs dexamethasone (0.1%; anti-inflammatory steroid) and doxycycline (100 nmol; antibiotic and MMP inhibitor) that have been studied earlier for treating vesicant-induced eye injuries. We also examined silibinin (100 μg), a non-toxic natural flavanone found to be effective in treating SM analog-induced skin injuries in our earlier studies. Treatments of doxycycline + dexamethasone, and silibinin were more effective than doxycycline or dexamethasone alone in reversing NM-induced epithelial thickening, microbullae formation, apoptotic cell death, and MMP-9 elevation. However, dexamethasone and silibinin alone were more effective in reversing NM-induced VEGF levels. Doxycycline, dexamethasone and silibinin were all effective in reversing NM-induced COX-2 levels. Apart from therapeutic efficacy of doxycycline and dexamethasone, these results show strong multifunctional efficacy of silibinin in reversing NM-induced ocular injuries, which could help develop effective and safe therapeutics against ocular injuries by vesicants. -- Highlights: ► Established injury biomarkers in rabbit corneal culture with nitrogen mustard (NM) ► This NM model is a cost effective

  8. Detection of vesicant-induced upper airway mucosa damage in the hamster cheek pouch model using optical coherence tomography

    NASA Astrophysics Data System (ADS)

    Hammer-Wilson, Marie J.; Nguyen, Vi; Jung, Woong-Gyu; Ahn, Yehchen; Chen, Zhongping; Wilder-Smith, Petra

    2010-01-01

    Hamster cheek pouches were exposed to 2-chloroethyl ethyl sulfide [CEES, half-mustard gas (HMG)] at a concentration of 0.4, 2.0, or 5.0 mg/ml for 1 or 5 min. Twenty-four hours post-HMG exposure, tissue damage was assessed by both stereomicrography and optical coherence tomography (OCT). Damage that was not visible on gross visual examination was apparent in the OCT images. Tissue changes were found to be dependent on both HMG concentration and exposure time. The submucosal and muscle layers of the cheek pouch tissue showed the greatest amount of structural alteration. Routine light microscope histology was performed to confirm the OCT observations.

  9. Detection of vesicant-induced upper airway mucosa damage in the hamster cheek pouch model using optical coherence tomography.

    PubMed

    Hammer-Wilson, Marie J; Nguyen, Vi; Jung, Woong-Gyu; Ahn, Yehchen; Chen, Zhongping; Wilder-Smith, Petra

    2010-01-01

    Hamster cheek pouches were exposed to 2-chloroethyl ethyl sulfide [CEES, half-mustard gas (HMG)] at a concentration of 0.4, 2.0, or 5.0 mg/ml for 1 or 5 min. Twenty-four hours post-HMG exposure, tissue damage was assessed by both stereomicrography and optical coherence tomography (OCT). Damage that was not visible on gross visual examination was apparent in the OCT images. Tissue changes were found to be dependent on both HMG concentration and exposure time. The submucosal and muscle layers of the cheek pouch tissue showed the greatest amount of structural alteration. Routine light microscope histology was performed to confirm the OCT observations. PMID:20210463

  10. Early Diagnosis of a Large Vesical Calculus Complicating Pregnancy

    PubMed Central

    Pricilla, Ruby Angeline; David, Kirubah Vasandhi; Venkatesan, Sankarapandian; Benjamin, Santosh Joseph

    2013-01-01

    Vesical calculus-complicating pregnancy is rare. This is a case report of a large vesical calculus-complicating pregnancy. The early diagnosis and appropriate surgical management of the large vesical calculus prevented complications like recurrent urinary tract infections and obstructed labor. It enabled the mother to have an uneventful vaginal delivery. PMID:24479053

  11. Pigment Changes Associated with Application of Ethephon ((2-Chloroethyl)phosphonic Acid) to Fig (Ficus carica L.) Fruits.

    PubMed

    Puech, A A; Rebeiz, C A; Crane, J C

    1976-04-01

    The application of (2-chloroethyl)phosphonic acid (Ethephon) to ;Mission' fig fruits (Ficus carica L.) during late period II of their development stimulated ripening and change in color from green to bluish black within 8 days. Chlorophylls a and b decreased rapidly within 4 days after Ethephon treatment, and degradation continued at a decreasing rate for an additional 4 days, at which time the fruits had attained their maximum diameter and were considered fully ripe. Levels of beta-carotene, lutein, violaxanthin, and neoxanthin decreased in a pattern similar to that of chlorophylls a and b. The rates of beta-carotene and lutein degradation were initially greater than those of the xanthophyll pigments. Degradation rates of the various carotenoids were comparable 4 to 8 days after treatment.There was no measurable anthocyanin synthesis during a 2- to 4-day period following Ethephon treatment. Beyond this lag phase, anthocyanin accumulation was linear, and the amount of pigment synthesized was a function of both light intensity and duration. Although Ethephon promoted the rate of anthocyanin accumulation, it did not increase the total amount of pigment synthesized in treated fruits. Etiolation of fruits from the time of Ethephon treatment until maturity stimulated an increase in growth and completely inhibited anthocyanin production in the skin. Ethephon-treated fruits which ripened while etiolated were larger in diameter and higher in both fresh and dry weights than nonetiolated controls. PMID:16659515

  12. Synthesis of magnetron sputtered WO₃ nanoparticles-degradation of 2-chloroethyl ethyl sulfide and dimethyl methyl phosphonate.

    PubMed

    Verma, Monu; Chandra, Ramesh; Gupta, Vinod Kumar

    2015-09-01

    In the present study, tungsten oxide nanoparticles were synthesized using DC magnetron sputtering and investigated their potential for decontamination of 2-chloroethyl ethyl sulfide (CEES) and dimethyl methyl phosphonate (DMMP). The tungsten oxide nanoparticles were characterized by Powder XRD, FE-SEM, EDS, TEM, TGA, N2-BET and FT-IR techniques. The XRD patterns of as-deposited and post annealed tungsten oxide nanoparticles reveal that the crystallite size of detected monoclinic phase WO3 nanoparticle was increased with increasing annealing temperatures. The phase and increase in particles size of WO3 nanoparticles were also confirmed by Raman and TEM analyses. The obtained surface area (∼63-33 m(2)/g) of magnetron sputtered WO3 nanoparticles was found to be enhanced significantly as compared to reported surface area of WO3 nanoparticles synthesis by various techniques. The study of degradation reactions of CEES and DMMP on the surface of obtained nanoparticles was carried out by using GC and GC-MS techniques. The decontamination reactions were found to be pseudo first order steady state with rate constant (k) and half life values 0.143-0.109 h(-1) and 4.82-6.49 h for CEES and 0.018-0.010 h(-1) and 36.87-66.65 h for DMMP, respectively. The FT-IR data reveal the role of hydrolysis reactions in the decontamination of CEES as well as DMMP. PMID:25965433

  13. Pigment Changes Associated with Application of Ethephon ((2-Chloroethyl)phosphonic Acid) to Fig (Ficus carica L.) Fruits

    PubMed Central

    Puech, Antoine A.; Rebeiz, Constantin A.; Crane, Julian C.

    1976-01-01

    The application of (2-chloroethyl)phosphonic acid (Ethephon) to `Mission' fig fruits (Ficus carica L.) during late period II of their development stimulated ripening and change in color from green to bluish black within 8 days. Chlorophylls a and b decreased rapidly within 4 days after Ethephon treatment, and degradation continued at a decreasing rate for an additional 4 days, at which time the fruits had attained their maximum diameter and were considered fully ripe. Levels of β-carotene, lutein, violaxanthin, and neoxanthin decreased in a pattern similar to that of chlorophylls a and b. The rates of β-carotene and lutein degradation were initially greater than those of the xanthophyll pigments. Degradation rates of the various carotenoids were comparable 4 to 8 days after treatment. There was no measurable anthocyanin synthesis during a 2- to 4-day period following Ethephon treatment. Beyond this lag phase, anthocyanin accumulation was linear, and the amount of pigment synthesized was a function of both light intensity and duration. Although Ethephon promoted the rate of anthocyanin accumulation, it did not increase the total amount of pigment synthesized in treated fruits. Etiolation of fruits from the time of Ethephon treatment until maturity stimulated an increase in growth and completely inhibited anthocyanin production in the skin. Ethephon-treated fruits which ripened while etiolated were larger in diameter and higher in both fresh and dry weights than nonetiolated controls. Images PMID:16659515

  14. Potentiation in the intact rat of the hepatotoxicity of acetaminophen by 1,3-bis(2-chloroethyl)-1-nitrosourea.

    PubMed

    Nakae, D; Oakes, J W; Farber, J L

    1988-12-01

    Studies of the killing of cultured hepatocytes by acetaminophen indicate that the cells are injured by an oxidative stress that accompanies the metabolism of the toxin (J. L. Farber et al. (1988) Arch. Biochem. Biophys. 267, 640-650). The present report documents that the essential features of the killing of cultured hepatocytes by acetaminophen are reproduced in the intact animal. Male rats had no evidence of liver necrosis 24 h after administration of up to 1000 mg/kg of acetaminophen. Induction of mixed function oxidase activity by 3-methylcholanthrene increased the hepatotoxicity of acetaminophen. Inhibition of glutathione reductase by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) potentiated the hepatotoxicity of acetaminophen in male rats induced with 3-methylcholanthrene. Whereas the pretreatment with BCNU reduced the GSH content by 40%, a comparable depletion of GSH by diethylmaleate did not potentiate the toxicity of acetaminophen. The antioxidant diphenylphenylenediamine (25 mg/kg) and the ferric iron chelator deferoxamine (1000 mg/kg) prevented the liver necrosis produced by 500 mg/kg acetaminophen in rats pretreated with BCNU. Neither protective agent prevented the fall in GSH produced by acetaminophen. It is concluded the conditions of the irreversible injury of cultured hepatocytes by acetaminophen previously reported are not necessarily different from those that obtain in the intact rat with this toxin. PMID:3214175

  15. Sulfur mustard induces the formation of keratin aggregates in human epidermal keratinocytes.

    PubMed

    Dillman, James F; McGary, Kriston L; Schlager, John J

    2003-12-01

    The vesicant sulfur mustard is an alkylating agent that has the capacity to cross-link biological molecules. We are interested in identifying specific proteins that are altered upon sulfur mustard exposure. Keratins are particularly important for the structural integrity of skin, and several genetically inherited blistering diseases have been linked to mutations in keratin 5 and keratin 14. We examined whether sulfur mustard exposure alters keratin biochemistry in cultured human epidermal keratinocytes. Western blotting with specific monoclonal antibodies revealed the formation of stable high-molecular-weight "aggregates" containing keratin 14 and/or keratin 5. These aggregates begin to form within 15 min after sulfur mustard exposure. These aggregates display a complex gel electrophoresis pattern between approximately 100 and approximately 200 kDa. Purification and analysis of these aggregates by one- and two-dimensional gel electrophoresis and mass spectrometry confirmed the presence of keratin 14 and keratin 5 and indicate that at least some of the aggregates are composed of keratin 14-keratin 14, keratin 14-keratin 5, or keratin 5-keratin 5 dimers. These studies demonstrate that sulfur mustard induces keratin aggregation in keratinocytes and support further investigation into the role of keratin aggregation in sulfur mustard-induced vesication. PMID:14644625

  16. Isophosphoramide mustard, a metabolite of ifosfamide with activity against murine tumours comparable to cyclophosphamide.

    PubMed Central

    Struck, R. F.; Dykes, D. J.; Corbett, T. H.; Suling, W. J.; Trader, M. W.

    1983-01-01

    Isophosphoramide mustard was synthesized and was found to demonstrate activity essentially comparable to cyclophosphamide and ifosfamide against L1210 and P388 leukaemia. Lewis lung carcinoma, mammary adenocarcinoma 16/C, ovarian sarcoma M5076, and colon tumour 6A, in mice and Yoshida ascitic sarcoma in rats. At doses less than, or equivalent to, the LD10, isophosphoramide mustard retained high activity against cyclophosphamide-resistant L1210 and P388 leukaemias, but was less active against intracerebrally-implanted P388 leukaemia while cyclophosphamide produced a 4 log10 tumour cell reduction. It was also less active (one log10 lower cell kill) than cyclophosphamide against the B16 melonoma. Metabolism studies on ifosfamide in mice identified isophosphoramide mustard in blood. In addition, unchanged drug, carboxyifosfamide, 4-ketoifosfamide, dechloroethyl cyclophosphamide, dechloroethylifosfamide, and alcoifosfamide were identified. The latter 4 metabolites were also identified in urine from an ifosfamide-treated dog. In a simulated in vitro pharmacokinetic experiment against L1210 leukaemia in which drugs were incubated at various concentrations for various times, both 4-hydroxycyclophosphamide and isophosphoramide mustard exhibited significant cytoxicity at concentration times time values of 100-1000 micrograms X min ml-1, while acrolein was significantly cytotoxic at 10 micrograms X min ml-1. Treatment of mice with drug followed by L1210 cells demonstrated a shorter duration of effective levels of cytotoxic activity for isophosphoramide mustard and phosphoramide mustard in comparison with cyclophosphamide and ifosfamide. Isophosphoramide mustard and 2-chloroethylamine, a potential hydrolysis product of isophosphoramide mustard and carboxyifosfamide, were less mutagenic in the standard Ames test than the 2 corresponding metabolites of cyclophosphamide [phosphoramide mustard and bis(2-chloroethyl)amine]. PMID:6821629

  17. Toxicology Studies on Lewisite and Sulfur Mustard Agents: Mutagenicity of Sulfur Mustard in the Salmonella Histidine Reversion Assay Final Report

    SciTech Connect

    Stewart, D. L.; Sass, E. J.; Fritz, L. K.; Sasser, L. B.

    1989-07-31

    The mutagenic potential of bis 2-chloroethyl sulfide (HD} a bifunctional sulfur mustard was evaluated in the standard plate incorporation version and the preincubation modification of the Salmonella/microsomal assay with tester strains TA97, TA98, TA100 and TA102, with and without 59 activation. HD-induced point mutations in strain TA102 and frameshift mutations in TA97 but showed little or no mutagenicity against strains TA98 and TA100. Extensive HD-induced cell killing was observed with the excision repair deficient strains (TA100, TA98 and TA97) but not with strain TA102, which is wild-activation by Aroc1or induced rat liver microsomes (S9).

  18. Sulphur mustard injuries of the skin. Pathophysiology and management.

    PubMed

    Rice, Paul

    2003-01-01

    Sulphur mustard is a vesicant (blistering agent), which produces chemical burns with widespread blistering. It was used extensively as a chemical warfare agent in the First World War, and has allegedly been employed in a number of conflicts since then, most recently by Iraq against Iran (1984-1987). The potential further use of mustard in military conflicts and by terrorists remains a significant threat that if realised in practice would result in a large number of casualties with severely incapacitating, partial thickness burns. Such injuries clearly present a huge potential wound care problem. The development and healing of mustard-induced cutaneous injuries has not only been observed in human casualties, but has been studied recently at the microscopic and ultrastructural levels in several animal models. Vesication generally begins on the second day after exposure, and may progress for up to 2 weeks. Wound healing is considerably slower than for a comparable thermal burn, and patients often require extended hospital treatment. The current management strategy is essentially symptomatic and supportive. Recently, two techniques for removing damaged tissue and improving wound healing have been investigated. Mechanical dermabrasion and laser debridement ('lasablation') both produced an increased rate of wound healing in animal models, and may be of benefit in a clinical context. PMID:15071821

  19. Antifibrinolytic Mechanisms in Acute Airway Injury after Sulfur Mustard Analog Inhalation

    PubMed Central

    Ahmad, Aftab; Veress, Livia A.; Rioux, Jacqueline S.; Garlick, Rhonda B.; White, Carl W.

    2014-01-01

    Acute lung injury in response to mustard gas (sulfur mustard [SM]) inhalation results in formation of fibrin casts, which obstruct the airway. The objective of this study was to identify fibrinolytic pathways that could be contributing to the persistence of airway casts after SM exposure. Rats were exposed to the SM analog, 2-chloroethyl ethyl sulfide, via nose-only aerosol inhalation. At 4 and 18 hours after exposure, animals were killed and airway–capillary leak estimated by measuring bronchoalveolar lavage fluid (BALF) protein and IgM content. The fibrin clot–degrading and plasminogen-activating capabilities of BALF were also assessed by activity assays, whereas Western blotting was used to determine the presence and activities of plasminogen activator inhibitor-1, thrombin activatable fibrinolytic inhibitor and α2-antiplasmin. Measurement of tissue-specific steady-state mRNA levels was also conducted for each fibrinolytic inhibitor to assess whether its synthesis occurs in lung or at extrapulmonary sites. The results of this study demonstrate that fibrin-degrading and plasminogen-activating capabilities of the airways become impaired during the onset of 2-chloroethyl ethyl sulfide–induced vascular leak. Findings of functionally active reservoirs of plasminogen activator inhibitor-1, thrombin activatable fibrinolysis inhibitor, and α2-antiplasmin in BALF indicate that airway fibrinolysis is inhibited at multiple levels in response to SM. PMID:24796565

  20. Characterization and study of piperazinium salts, degradation products of nitrogen mustards by nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry.

    PubMed

    Lee, Jin Young; Lee, Yong Han; Byun, Yong Gwan

    2012-03-01

    We synthesized and analyzed the degradation products, piperazinium salts from bis(2-chloroethyl)methylamine (HN2) and bis(2-chloroethyl)ethylamine (HN1) using ¹H nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS). Piperazinium salt is the major degradation product of HN2, not N-methyldiethanolamine above a concentration of 0.01 M in water and is a non-scheduled chemical that may be generally assumed relevant to the Chemical Weapons Convention (CWC) within the context of the Organization for the Prohibition of Chemical Weapons (OPCW) proficiency test. In verification analysis, ¹H NMR offers real-time information about degradation pathway of nitrogen mustards and LC-MS is expected to play an increasing role in the analysis of environmental samples for the degradation products of chemical warfare agents. PMID:22296978

  1. Ionic dependence of sulphur mustard cytotoxicity

    SciTech Connect

    Sawyer, Thomas W. Nelson, Peggy; Bjarnason, Stephen; Vair, Cory; Shei Yimin; Tenn, Catherine; Lecavalier, Pierre; Burczyk, Andrew

    2010-09-15

    The effect of ionic environment on sulphur mustard (bis 2-chloroethyl sulphide; HD) toxicity was examined in CHO-K1 cells. Cultures were treated with HD in different ionic environments at constant osmolar conditions (320 mOsM, pH 7.4). The cultures were refed with fresh culture medium 1 h after HD exposure, and viability was assessed. Little toxicity was apparent when HD exposures were carried out in ion-free sucrose buffer compared to LC{sub 50} values of {approx} 100-150 {mu}M when the cultures were treated with HD in culture medium. Addition of NaCl to the buffer increased HD toxicity in a salt concentration-dependent manner to values similar to those obtained in culture medium. HD toxicity was dependent on both cationic and anionic species with anionic environment playing a much larger role in determining toxicity. Substitution of NaI for NaCl in the treatment buffers increased HD toxicity by over 1000%. The activity of the sodium hydrogen exchanger (NHE) in recovering from cytosolic acidification in salt-free and in different chloride salts did not correlate with the HD-induced toxicity in these buffers. However, the inhibition by HD of intracellular pH regulation correlated with its toxicity in NaCl, NaI and sucrose buffers. Analytical chemical studies and the toxicity of the iodine mustard derivative ruled out the role of chemical reactions yielding differentially toxic species as being responsible for the differences in HD toxicity observed. This work demonstrates that the early events that HD sets into motion to cause toxicity are dependent on ionic environment, possibly due to intracellular pH deregulation.

  2. Possible protein phosphatase inhibition by bis(hydroxyethyl) sulfide, a hydrolysis product of mustard gas

    SciTech Connect

    Brimfield, A.A.

    1995-12-31

    Recently, the natural vesicant cantharidin was shown to bind exclusively to and inhibit protein phosphatase 2A (PP2A) in mouse tissue extracts (Li and Casida (1992) Proc. Nati. Acad. Sci. USA 89, 11867-11870). To explore the generality of this effect in vesicant action, we measured the protein serinelthreonine phosphatase activity in mouse liver cytosol (in the form of the okadaic acid inhibitable increment of p-nitrophenyl phosphate (p-NPP) phosphatase activity) in the presence of aqueous sulfur mustard or its hydrolysis product, bis(hydroxyethyl)sulfide (TDG). Sulfur mustard inhibited p-NPP hydrolysis. However, inhibition correlated with the time elapsed between thawing and the addition of mustard to the enzyme preparation, not with concentration. TDG exhibited a direct, concentration-related inhibition of p-NPP hydrolysis between 30 and 300 1LM. We conclude that sulfur mustard also has an inhibitory effect on protein serinelthreonine phosphatases. However, the inhibition is an effect of its non-alkykating hydrolysis product TDG, not of sulfur mustard itself.

  3. [Intermittent hematuria. Vesical schistosomosis. Concerning one case].

    PubMed

    Morales Senosiáin, D; Molina, J; Martínez Oríz, A; Martínez Artola, V; Beristáin, X

    2009-01-01

    We present a clinical case of vesical schistosomiasis that we consider unusual in our environment. The clinical features of this parasitosis include an intermittent hematuria of several weeks evolution which is not resolved with the usual treatment. Due to the increase in the immigrant population arriving from endemic areas, we must pay greater attention to this emergent pathology. The process is resolved satisfactorily with treatment and complications are avoided. PMID:19738650

  4. Sulphur mustard degradation on zirconium doped Ti-Fe oxides.

    PubMed

    Štengla, Václav; Grygar, Tomáš Matys; Opluštil, František; Němec, Tomáš

    2011-09-15

    Zirconium doped mixed nanodispersive oxides of Ti and Fe were prepared by homogeneous hydrolysis of sulphate salts with urea in aqueous solutions. Synthesized nanodispersive metal oxide hydroxides were characterised as the Brunauer-Emmett-Teller (BET) surface area and Barrett-Joiner-Halenda porosity (BJH), X-ray diffraction (XRD), infrared (IR) spectroscopy, scanning electron microscopy (SEM) with energy-dispersive X-ray (EDX) microanalysis, and acid-base titration. These oxides were taken for an experimental evaluation of their reactivity with sulphur mustard (chemical warfare agent HD or bis(2-chloroethyl)sulphide). The presence of Zr(4+) dopant tends to increase both the surface area and the surface hydroxylation of the resulting doped oxides in such a manner that it can contribute to enabling the substrate adsorption at the oxide surface and thus accelerate the rate of degradation of warfare agents. The addition of Zr(4+) to the hydrolysis of ferric sulphate with urea shifts the reaction route and promotes formation of goethite at the expense of ferrihydrite. We discovered that Zr(4+) doped oxo-hydroxides of Ti and Fe exhibit a higher degradation activity towards sulphur mustard than any other yet reported reactive sorbents. The reaction rate constant of the slower parallel reaction of the most efficient reactive sorbents is increased with the increasing amount of surface base sites. PMID:21775058

  5. Functional and inflammatory alterations in the lung following exposure of rats to nitrogen mustard

    SciTech Connect

    Sunil, Vasanthi R.; Patel, Kinal J.; Shen, Jianliang; Reimer, David; Gow, Andrew J.; Laskin, Jeffrey D.; Laskin, Debra L.

    2011-01-01

    Nitrogen mustard is a vesicant that causes damage to the respiratory tract. In these studies, we characterized the acute effects of nitrogen mustard on lung structure, inflammatory mediator expression, and pulmonary function, with the goal of identifying mediators potentially involved in toxicity. Treatment of rats (male Wistar, 200-225 g) with nitrogen mustard (mechlorethamine hydrochloride, i.t., 0.25 mg/kg) resulted in marked histological changes in the respiratory tract, including necrotizing bronchiolitis, thickening of alveolar septa, and inflammation which was evident within 24 h. This was associated with increases in bronchoalveolar lavage protein and cells, confirming injury to alveolar epithelial regions of the lung. Nitrogen mustard administration also resulted in increased expression of inducible nitric oxide synthase and cyclooxygenase-2, pro-inflammatory proteins implicated in lung injury, in alveolar macrophages and alveolar and bronchial epithelial cells. Expression of connective tissue growth factor and matrix metalloproteinase-9, mediators regulating extracellular matrix turnover was also increased, suggesting that pathways leading to chronic lung disease are initiated early in the pathogenic process. Following nitrogen mustard exposure, alterations in lung mechanics and function were also observed. These included decreases in baseline static compliance, end-tidal volume and airway resistance, and a pronounced loss of methacholine responsiveness in resistance, tissue damping and elastance. Taken together, these data demonstrate that nitrogen mustard induces rapid structural and inflammatory changes in the lung which are associated with altered lung functioning. Understanding the nature of the injury induced by nitrogen mustard and related analogs may aid in the development of efficacious therapies for treatment of pulmonary injury resulting from exposure to vesicants.

  6. Mesoporous titanium-manganese dioxide for sulphur mustard and soman decontamination

    SciTech Connect

    Stengl, Vaclav; Bludska, Jana; Oplustil, Frantisek; Nemec, Tomas

    2011-11-15

    Highlights: {yields} New nano-dispersive materials for warfare agents decontamination. {yields} 95% decontamination activities for sulphur mustard. {yields} New materials base on titanium and manganese oxides. -- Abstract: Titanium(IV)-manganese(IV) nano-dispersed oxides were prepared by a homogeneous hydrolysis of potassium permanganate and titanium(IV) oxo-sulphate with 2-chloroacetamide. Synthesised samples were characterised using Brunauer-Emmett-Teller (BET) surface area and Barrett-Joiner-Halenda porosity (BJH), X-ray diffraction (XRD), infrared spectroscopy (IR), and scanning electron microscopy (SEM). These oxides were taken for an experimental evaluation of their reactivity with sulphur mustard (HD or bis(2-chloroethyl)sulphide) and soman (GD or (3,3'-dimethylbutan-2-yl)-methylphosphonofluoridate). Mn{sup 4+} content affects the decontamination activity; with increasing Mn{sup 4+} content the activity increases for sulphur mustard and decreases for soman. The best decontamination activities for sulphur mustard and soman were observed for samples TiMn{sub 3}7 with 18.6 wt.% Mn and TiMn{sub 5} with 2.1 wt.% Mn, respectively.

  7. Quantum chemical calculations on the geometrical, conformational, spectroscopic and nonlinear optical parameters of 5-(2-Chloroethyl)-2,4-dichloro-6-methylpyrimidine.

    PubMed

    Gümüş, Hacer Pir; Tamer, Ömer; Avcı, Davut; Atalay, Yusuf

    2014-08-14

    The optimized geometry, (1)H and (13)C NMR chemical shifts, conformational and natural bond orbital (NBO) analyses, thermodynamic parameters, molecular surfaces, Mulliken, NBO and APT charges for 5-(2-Chloroethyl)-2,4-dichloro-6-methylpyrimidine [C7H7Cl3N2] were investigated by the ab initio HF and density functional theory (DFT/B3LYP) methods with 6-311++G(d,p) basis set. The calculated structural parameters (bond lengths, bond angles and dihedral angles) and (1)H and (13)C NMR chemical shifts values are compared with experimental values of the investigated compound. The observed and the calculated values are found to be in good agreement. The energies of the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) were calculated, and the obtained energies displayed that charge transfer occurs in 5-(2-Chloroethyl)-2,4-dichloro-6-methylpyrimidine compound. In addition, the linear polarizability (α) and the first order hyperpolarizability (β) values of the investigated compound have been computed by using HF and DFT methods. PMID:24732007

  8. Quantum chemical calculations on the geometrical, conformational, spectroscopic and nonlinear optical parameters of 5-(2-Chloroethyl)-2,4-dichloro-6-methylpyrimidine

    NASA Astrophysics Data System (ADS)

    Gümüş, Hacer Pir; Tamer, Ömer; Avcı, Davut; Atalay, Yusuf

    2014-08-01

    The optimized geometry, 1H and 13C NMR chemical shifts, conformational and natural bond orbital (NBO) analyses, thermodynamic parameters, molecular surfaces, Mulliken, NBO and APT charges for 5-(2-Chloroethyl)-2,4-dichloro-6-methylpyrimidine [C7H7Cl3N2] were investigated by the ab initio HF and density functional theory (DFT/B3LYP) methods with 6-311++G(d,p) basis set. The calculated structural parameters (bond lengths, bond angles and dihedral angles) and 1H and 13C NMR chemical shifts values are compared with experimental values of the investigated compound. The observed and the calculated values are found to be in good agreement. The energies of the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) were calculated, and the obtained energies displayed that charge transfer occurs in 5-(2-Chloroethyl)-2,4-dichloro-6-methylpyrimidine compound. In addition, the linear polarizability (α) and the first order hyperpolarizability (β) values of the investigated compound have been computed by using HF and DFT methods.

  9. Epigenetic: A missing paradigm in cellular and molecular pathways of sulfur mustard lung: a prospective and comparative study

    PubMed Central

    Imani, Saber; Panahi, Yunes; Salimian, Jafar; Fu, Junjiang; Ghanei, Mostafa

    2015-01-01

    Sulfur mustard (SM, bis- (2-chloroethyl) sulphide) is a chemical warfare agent that causes DNA alkylation, protein modification and membrane damage. SM can trigger several molecular pathways involved in inflammation and oxidative stress, which cause cell necrosis and apoptosis, and loss of cells integrity and function. Epigenetic regulation of gene expression is a growing research topic and is addressed by DNA methylation, histone modification, chromatin remodeling, and noncoding RNAs expression. It seems SM can induce the epigenetic modifications that are translated into change in gene expression. Classification of epigenetic modifications long after exposure to SM would clarify its mechanism and paves a better strategy for the treatment of SM-affected patients. In this study, we review the key aberrant epigenetic modifications that have important roles in chronic obstructive pulmonary disease (COPD) and compared with mustard lung. PMID:26557960

  10. Epigenetic: A missing paradigm in cellular and molecular pathways of sulfur mustard lung: a prospective and comparative study.

    PubMed

    Imani, Saber; Panahi, Yunes; Salimian, Jafar; Fu, Junjiang; Ghanei, Mostafa

    2015-08-01

    Sulfur mustard (SM, bis- (2-chloroethyl) sulphide) is a chemical warfare agent that causes DNA alkylation, protein modification and membrane damage. SM can trigger several molecular pathways involved in inflammation and oxidative stress, which cause cell necrosis and apoptosis, and loss of cells integrity and function. Epigenetic regulation of gene expression is a growing research topic and is addressed by DNA methylation, histone modification, chromatin remodeling, and noncoding RNAs expression. It seems SM can induce the epigenetic modifications that are translated into change in gene expression. Classification of epigenetic modifications long after exposure to SM would clarify its mechanism and paves a better strategy for the treatment of SM-affected patients. In this study, we review the key aberrant epigenetic modifications that have important roles in chronic obstructive pulmonary disease (COPD) and compared with mustard lung. PMID:26557960

  11. The design, synthesis and anticancer activity of new nitrogen mustard derivatives of natural indole phytoalexin 1-methoxyspirobrassinol.

    PubMed

    Mezencev, R; Kutschy, P; Salayova, A; Updegrove, T; McDonald, J F

    2009-01-01

    Nitrogen mustards cis-1-methoxy-2-deoxy-2-[N,N-bis(2 -chloroethyl)amino]spirobrassinol (4) and trans-1-methoxy-2-deoxy-2-[N,N-bis(2 -chloroethyl)amino]spirobrassinol (5) derived from 1-methoxyspirobrassinol, an indole phytoalexin produced by the Japanese radish Raphanus sativus var. hortensis were designed as prospective dual-action compounds with DNA-alkylating effect and glutathione-depleting effects that may sensitize cancer cells to alkylating agents. Both new compounds demonstrated cytostatic/cytotoxic effects on various leukemia and ovarian cancer cell lines and dsDNA-destabilizing effects in vitro. Compound 4, the more promising of the two compounds, exerts earlier onset of anticancer effects on Jurkat cells via induction of apoptosis compared to the traditional alkylating anticancer agent melphalan. In addition, it demonstrated higher potency on ovarian cancer OVCAR-3 cell line and lower fold resistance between Jurkat and Jurkat-M cells selected for the resistance to melphalan. Therefore, compound 4 may be less affected by certain cancer drug resistance mechanisms than melphalan and it may become a prototype of a new class of anticancer active nitrogen mustards that combine DNA-damaging and DNA-damage-sensitizing properties. PMID:19473057

  12. Inhibition of sulfur mustard-increased protease activity by niacinamide, N-acetyl-L-cysteine or dexamethasone

    SciTech Connect

    Cowan, F.M.; Broomfield, C.A.; Smith, W.J.

    1991-03-11

    The pathologic mechanism of sulfur mustard-induced skin vesication is as yet undefined. Papirmeister et al. have postulated a biochemical mechanism for sulfur mustard-induced cutaneous injury involving sequelae of DNA alkylation, metabolic disruption resulting in NAD+ depletion and activation of protease. The authors have utilized a chromogenic peptide substrate assay to establish that human peripheral blood lymphocytes exposed 24 hr previously to sulfur mustard exhibited an increase in proteolytic activity. Doses of compounds known to alter the biochemical events associated with sulfur mustard exposure or reduce protease activity were tested in this system for their ability to block the sulfur mustard-induced protease activity. Treatment with niacinamide 1 hr after or with N-acetyl-L-cysteine or dexamethasone 24 hr prior to sulfur mustard exposure resulted in a decrease of 39%, 33% and 42% respectively of sulfur mustard-increased protease activity. These data suggest that therapeutic intervention into the biochemical pathways that culminate in protease activation might serve as an approach to treatment of sulfur mustard-induced pathology.

  13. Effect of temperature on the desorption and decomposition of mustard from activated carbon

    SciTech Connect

    Karwacki, C.J.; Buchanan, J.H.; Mahle, J.J.; Buettner, L.C.; Wagner, G.W.

    1999-12-07

    Experimental data are reported for the desorption of bis-2-chloroethyl sulfide, (a sulfur mustard or HD) and its decomposition products from activated coconut shell carbon (CSC). The results show that under equilibrium conditions changes in the HD partial pressure are affected primarily by its loading and temperature of the adsorbent. The partial pressure of adsorbed HD is found to increase by about a decade for each 25 C increase in temperature for CSC containing 0.01--0.1 g/g HD. Adsorption equilibria of HD appear to be little affected by coadsorbed water. Although complicated by its decomposition, the distribution of adsorbed HD (of known amount) appears to occupy pores of similar energy whether dry or in the presence of adsorbed water. On dry CSC adsorbed HD appears stable, while in the presence of water its decomposition is marked by hydrolysis at low temperature and thermal decomposition at elevated temperatures. The principal volatile products desorbed are 1,4-thioxane, 2-chloroethyl vinyl sulfide and 1,4-dithiane, with the latter favoring elevated temperatures.

  14. Final report : multicomponent forensic signature development : interactions with common textiles; mustard precursors and simulants.

    SciTech Connect

    Van Benthem, Mark Hilary; Mowry, Curtis Dale; Kotula, Paul Gabriel; Borek, Theodore Thaddeus, III

    2010-02-01

    2-Chloroethyl phenyl sulfide (CEPS), a surrogate compound of the chemical warfare agent sulfur mustard, was examined using thermal desorption coupled gas chromatography-mass spectrometry (TD/GC-MS) and multivariate analysis. This work describes a novel method of producing multiway data using a stepped thermal desorption. Various multivariate analysis schemes were employed to analyze the data. These methods may be able to discern different sources of CEPS. In addition, CEPS was applied to cotton, nylon, polyester, and silk swatches. These swatches were placed in controlled humidity chambers maintained at 23%, 56%, and 85% relative humidity. At regular intervals, samples were removed from each test swatch, and the samples analyzed using TD/GC-MS. The results were compared across fabric substrate and humidity.

  15. The Reaction of DABCO with 4-Chloro-5H-1,2,3-dithiazoles: Synthesis and Chemistry of 4-[N-(2-Chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazoles.

    PubMed

    Koyioni, Maria; Manoli, Maria; Koutentis, Panayiotis A

    2016-01-15

    N-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)anilines react with DABCO in hot PhCl to give N-{4-[N-(2-chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-ylidene}anilines in high yields (70-92%). The reaction also works with 4-chloro-5H-1,2,3-dithiazol-5-one and -thione, giving the corresponding products in 85% and 76% yields, respectively. While the reaction of several (4-chloro-5H-1,2,3-dithiazol-5-ylidene)methanes with DABCO failed to give {4-[N-(2-chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazol-5-ylidene}methanes, these can be prepared in moderate yields via classical cycloaddition-retrocycloaddition strategies from 4-[N-(2-chloroethyl)piperazin-1-yl]-5H-1,2,3-dithiazole-5-thione. The 2-chloroethyl moiety on selected dithiazoles was also modified without cleavage of the 1,2,3-dithiazole by reaction with various nucleophiles, giving access to 4-[N-(2-substituted)piperazin-1-yl]-5H-1,2,3-dithiazoles in moderate to high yields. PMID:26671065

  16. The effect of mustard gas on the biological activity of soil.

    PubMed

    Medvedeva, N; Polyak, Yu; Kuzikova, I; Orlova, O; Zharikov, G

    2008-03-01

    A special group of substances that are very dangerous for the biosphere includes war gases such as mustard gas (bis(2-chloroethyl)sulphide). The influence of mustard gas hydrolysis products (MGHPs) on soil microbiota has been investigated. These substances bear numerous toxic effects on soil microorganisms. They change significantly the number and the specific composition of soil microbiota and inhibit the enzyme activity of soils. The main "ecological targets" of mustard and its hydrolysis products' toxic action have been determined. MGHPs affect the growth and reproduction of soil micromycetes, as well as their morphological and cultural properties. Increase in number and size of mitochondria in the fungal cells is accompanied by increase in dehydrogenases activity. Cell permeability influenced by MGHPs grows in connection with concentration of toxicants. Increase of permeability corresponds to growth of the amount of unsaturated fatty acids. The changes in the fatty acid composition of lipids in the cells of the soil micromycetes display their adaptation to adverse impact of the substances studied. MGHPs and thiodiglycol enhance synthesis of polysaccharides and pigments. PMID:17537425

  17. Liquid sulfur mustard exposure.

    PubMed

    Newmark, Jonathan; Langer, Janice M; Capacio, Benedict; Barr, John; McIntosh, Roger G

    2007-02-01

    A 35-year-old active duty service member sustained a 6.5% body surface area burn as a result of exposure to the chemical warfare agent sulfur mustard, which is the most severe mustard exposure of a U.S. military member since World War II that is known to us. New techniques were used to demonstrate the detectable persistence of mustard metabolites in the patient's blood for at least 41 days after exposure, validating these techniques for the first time for a human mustard patient; they were also used for the first time with human mustard blister fluid. The techniques extend eightfold the period of time that mustard exposure can be definitively diagnosed, compared with previous techniques. Although this patient's lesions were never life-threatening, he required 2 weeks of intensive burn care. He has been left with ongoing posttraumatic stress disorder and has had an incomplete dermatological recovery. In a major terrorist attack involving many patients exposed to sulfur mustard, care resources would be depleted quickly. PMID:17357776

  18. Urinary bladder calculi complicating ventriculo-vesical shunt.

    PubMed

    Shahul Hameed, A S; Yousaf, I; Choudhari, K A

    2005-10-01

    A rare case of vesical calculi complicating the procedure of ventriculo-vesical shunt is presented. In addition to highlighting technical difficulties in placing shunt catheters into the urinary system, the potential complications are discussed. We consider this route of cerebrospinal fluid(CSF) diversion less physiological compared with the peritoneal, pleural or the venous sites, and discourage use of the urinary bladder as the drainage site for the shunting of CSF. PMID:16455572

  19. Sulforaphane induces phase II detoxication enzymes in mouse skin and prevents mutagenesis induced by a mustard gas analog

    SciTech Connect

    Abel, E.L.; Boulware, S.; Fields, T.; McIvor, E.; Powell, K.L.; DiGiovanni, J.; Vasquez, K.M.; MacLeod, M.C.

    2013-02-01

    Mustard gas, used in chemical warfare since 1917, is a mutagenic and carcinogenic agent that produces severe dermal lesions for which there are no effective therapeutics; it is currently seen as a potential terrorist threat to civilian populations. Sulforaphane, found in cruciferous vegetables, is known to induce enzymes that detoxify compounds such as the sulfur mustards that react through electrophilic intermediates. Here, we observe that a single topical treatment with sulforaphane induces mouse epidermal levels of the regulatory subunit of glutamate-cysteine ligase, the rate-limiting enzyme in glutathione biosynthesis, and also increases epidermal levels of reduced glutathione. Furthermore, a glutathione S-transferase, GSTA4, is also induced in mouse skin by sulforaphane. In an in vivo model in which mice are given a single mutagenic application of the sulfur mustard analog 2-(chloroethyl) ethyl sulfide (CEES), we now show that therapeutic treatment with sulforaphane abolishes the CEES-induced increase in mutation frequency in the skin, measured four days after exposure. Sulforaphane, a natural product currently in clinical trials, shows promise as an effective therapeutic against mustard gas. -- Highlights: ► Sulforaphane induces increased levels of glutathione in mouse skin. ► Sulforaphane induces increased levels of GSTA4 in mouse skin. ► Sulforaphane, applied after CEES-treatment, completely abolishes CEES-mutagenesis. ► The therapeutic effect may suggest a long biological half-life for CEES in vivo.

  20. Notes from the field: Exposures to discarded sulfur mustard munitions - Mid-Atlantic and New England States 2004-2012.

    PubMed

    2013-04-26

    Before the 1970s, the United States sometimes disposed of at sea excess, obsolete, or unserviceable munitions, including chemical munitions. Chemical munitions known to have been disposed of at sea included munitions filled with sulfur mustard, a vesicant (i.e., an agent that causes chemical burns or blisters of the skin and mucous membranes). Signs and symptoms of exposure to a mustard agent can include redness and blistering of the skin, eye irritation, rhinorrhea, hoarseness, shortness of breath, and (rarely) diarrhea and abdominal discomfort. Since 2004, CDC has received notification of three separate incidents of exposure to sulfur mustard munitions. In one incident, a munition was found with ocean-dredged marine shells used to pave a driveway. The other two incidents involved commercial clam fishing operations. This report highlights the importance of considering exposure to sulfur mustard in the differential diagnosis of signs and symptoms compatible with exposure to a vesicant agent, especially among persons involved with clam fishing or sea dredging operations. PMID:23615677

  1. Sulfur mustard-induced increase in intracellular calcium: A mechanism of mustard toxicity

    SciTech Connect

    Ray, R.; Majerus, B.J.; Munavalli, G.S.; Petrali, J.P.

    1993-05-13

    The effect of sulfur mustard SM, bis-(2-chloroethyl) sulfide on intracellular free Ca2+ concentration (Ca2+)i was studied in vitro using the clonal mouse neuroblastoma-rat glioma hybrid NG108-15 and primary normal human epidermal keratinocyte (NHEK) cell culture models. SM depletes cellular glutathione (GSH) and thus may inhibit GSH-dependent Ca2+-ATPase (Ca2+ pump), leading to a high (Ca2+) and consequent cellular toxicity. Following 0.3 mM SM exposure, GSH levels decreased 20-34% between 1-6 hr in NG108-15 cells. SM increased (Ca2+)i, measured using the Ca2+-specific fluorescent probe Fluo-3 AM, in both NG108-15 cells (1030% between 2-6 hr) and NHEK (23-30% between 0.5-3 hr) . Depletion of cellular GSH by buthionine sulfoximine (1 mM), a specific GSH biosynthesis inhibitor, also increased Ca2+, (88% at 1 hr) in NHEK, suggesting that GSH depletion may lead to increased (Ca2+)i. Calcium, localized cytochemically with antimony, accumulated in increased amounts around mitochondria and endoplasmic reticula, in the cytosol, and in particular in the euchromatin regions of the nucleus beginning at 6 hr after 0.3 mM SM exposure of NG108-15 cells. Cell membrane integrity examined with the fluorescent membrane probe calcein AM was unaffected through 6 hr following 1 mM SM exposure; and cell viability (NG108-15 cells) measured by trypan blue exclusion was >80% of control through 9 hr following 0.3 mM SM exposure.

  2. Detection and monitoring of early airway injury effects of half-mustard (2-chloroethylethylsulfide) exposure using high-resolution optical coherence tomography

    PubMed Central

    Kreuter, Kelly A.; Mahon, Sari B.; Mukai, David S.; Su, Jianping; Jung, Woong-Gyu; Narula, Navneet; Guo, Shuguang; Wakida, Nicole; Raub, Chris; Berns, Michael W.; George, Steven C.; Chen, Zhongping; Brenner, Matthew

    2009-01-01

    Optical coherence tomography (OCT) is a non-invasive, high-resolution imaging technology capable of delivering real-time, near-histologic images of tissues. Mustard gas is a vesicant-blistering agent that can cause severe and lethal damage to airway and lungs. The ability to detect and assess airway injury in the clinical setting of mustard exposure is currently limited. The purpose of this study is to assess the ability to detect and monitor progression of half-mustard [2-chloroethylethylsulfide (CEES)] airway injuries with OCT techniques. A ventilated rabbit mustard exposure airway injury model is developed. A flexible fiber optic OCT probe is introduced into the distal trachea to image airway epithelium and mucosa in vivo. Progression of airway injury is observed over eight hours with OCT using a prototype time-domain superluminescent diode OCT system. OCT tracheal images from CEES exposed animals are compared to control rabbits for airway mucosal thickening and other changes. OCT detects the early occurrence and progression of dramatic changes in the experimental group after exposure to CEES. Histology and immunofluorescence staining confirms this finding. OCT has the potential to be a high resolution imaging modality capable of detecting, assessing, and monitoring treatment for airway injury following mustard vesicant agent exposures. PMID:19725748

  3. Detection and monitoring of early airway injury effects of half-mustard (2-chloroethylethylsulfide) exposure using high-resolution optical coherence tomography

    NASA Astrophysics Data System (ADS)

    Kreuter, Kelly A.; Mahon, Sari B.; Mukai, David S.; Su, Jianping; Jung, Woong-Gyu; Narula, Navneet; Guo, Shuguang; Wakida, Nicole; Raub, Chris; Berns, Michael W.; George, Steven C.; Chen, Zhongping; Brenner, Matthew

    2009-07-01

    Optical coherence tomography (OCT) is a noninvasive, high-resolution imaging technology capable of delivering real-time, near-histologic images of tissues. Mustard gas is a vesicant-blistering agent that can cause severe and lethal damage to airway and lungs. The ability to detect and assess airway injury in the clinical setting of mustard exposure is currently limited. The purpose of this study is to assess the ability to detect and monitor progression of half-mustard [2-chloroethylethylsulfide (CEES)] airway injuries with OCT techniques. A ventilated rabbit mustard exposure airway injury model is developed. A flexible fiber optic OCT probe is introduced into the distal trachea to image airway epithelium and mucosa in vivo. Progression of airway injury is observed over eight hours with OCT using a prototype time-domain superluminescent diode OCT system. OCT tracheal images from CEES exposed animals are compared to control rabbits for airway mucosal thickening and other changes. OCT detects the early occurrence and progression of dramatic changes in the experimental group after exposure to CEES. Histology and immunofluorescence staining confirms this finding. OCT has the potential to be a high resolution imaging modality capable of detecting, assessing, and monitoring treatment for airway injury following mustard vesicant agent exposures.

  4. Sulfur mustard-induced poikiloderma: a case report.

    PubMed

    Emadi, Seyed Naser; Kaffashi, Mohammad; Poursaleh, Zohreh; Akhavan-Moghaddam, Jamal; Soroush, Mohammad Reza; Emadi, Seyed Emad; Taghavi, Nez'hat-o-Sadat

    2011-06-01

    Sulfur mustard (SM) is a potent chemical warfare agent that was widely used during the First World War and the Iran-Iraq conflict. This vesicant agent causes several acute and chronic effects on the skin, eye, and respiratory system. We report the case of a 41-year-old man who was injured with SM in Iraq chemical attack in 1988. After exposure, he developed severe skin blisters on his upper trunk, dorsum of hands, and genitalia. Based on several clinical observations, such as atrophy, pigmentation, and vascular changes on genitalia with relevant findings in histopathological studies, persistent pigmentation, and damaged skin appendix in hand lesions, a diagnosis of "SM-induced poikiloderma" was postulated. The absence of any complication on the palmar aspect of hands is another remarkable finding in presented case, which suggests a plausible role of the palms as a vector for transporting SM to other sites of the skin. PMID:21142708

  5. Tris(2-chloroethyl)phosphate-induced cell growth arrest via attenuation of SIRT1-independent PI3K/Akt/mTOR pathway.

    PubMed

    Zhang, Wenjuan; Zhang, Youjian; Wang, Zhiyuan; Xu, Tian; Huang, Cheng; Yin, Wenjun; Wang, Jing; Xiong, Wei; Lu, Wenhong; Zheng, Hongyan; Yuan, Jing

    2016-07-01

    Tris(2-chloroethyl)phosphate (TCEP) as an organophosphorus flame retardant and plasticizer has been widely used in industrial and household products. It not only was detected in residential indoor air and dust, surface and drinking water, but also in human plasma and breast milk, and tissue samples of liver, kidneys and brain from rodents. TCEP is classified as carcinogenic category 2 and toxic for reproduction category 1B. Sufficient evidence from experimental animals indicated carcinogenicity of TCEP in the liver, and kidneys as well as cell loss in the brain. However, the underlying mechanisms of TCEP-induced hepatotoxicity are mostly unknown. We investigated the in vitro effects of TCEP as well as TCEP-induced cell growth in the L02 and HepG2 cells through the PI3K/Akt/mTOR pathway. We found that TCEP reduced cell viability of these cell lines, induced the cell growth arrest, upregulated mRNA and protein levels of SIRT1, and attenuated the PI3K/Akt/mTOR pathway. However, growth arrest of the L02 and HepG2 cells were aggravated after inhibiting the SIRT1 expression with EX-527. The findings above suggested that TCEP induced the cell growth arrest of L02 and HepG2 cells via attenuation of the SIRT1-independent PI3K/Akt/mTOR pathway. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26378621

  6. 1,3-Bis(2-chloroethyl)-1-nitrosourea-loaded bovine serum albumin nanoparticles with dual magnetic resonance–fluorescence imaging for tracking of chemotherapeutic agents

    PubMed Central

    Wei, Kuo-Chen; Lin, Feng-Wei; Huang, Chiung-Yin; Ma, Chen-Chi M; Chen, Ju-Yu; Feng, Li-Ying; Yang, Hung-Wei

    2016-01-01

    To date, knowing how to identify the location of chemotherapeutic agents in the human body after injection is still a challenge. Therefore, it is urgent to develop a drug delivery system with molecular imaging tracking ability to accurately understand the distribution, location, and concentration of a drug in living organisms. In this study, we developed bovine serum albumin (BSA)-based nanoparticles (NPs) with dual magnetic resonance (MR) and fluorescence imaging modalities (fluorescein isothiocyanate [FITC]-BSA-Gd/1,3-bis(2-chloroethyl)-1-nitrosourea [BCNU] NPs) to deliver BCNU for inhibition of brain tumor cells (MBR 261-2). These BSA-based NPs are water dispersible, stable, and biocompatible as confirmed by XTT cell viability assay. In vitro phantoms and in vivo MR and fluorescence imaging experiments show that the developed FITC-BSA-Gd/BCNU NPs enable dual MR and fluorescence imaging for monitoring cellular uptake and distribution in tumors. The T1 relaxivity (R1) of FITC-BSA-Gd/BCNU NPs was 3.25 mM−1 s−1, which was similar to that of the commercial T1 contrast agent (R1 =3.36 mM−1 s−1). The results indicate that this multifunctional drug delivery system has potential bioimaging tracking of chemotherapeutic agents ability in vitro and in vivo for cancer therapy. PMID:27601895

  7. 1,3-Bis(2-chloroethyl)-1-nitrosourea-loaded bovine serum albumin nanoparticles with dual magnetic resonance-fluorescence imaging for tracking of chemotherapeutic agents.

    PubMed

    Wei, Kuo-Chen; Lin, Feng-Wei; Huang, Chiung-Yin; Ma, Chen-Chi M; Chen, Ju-Yu; Feng, Li-Ying; Yang, Hung-Wei

    2016-01-01

    To date, knowing how to identify the location of chemotherapeutic agents in the human body after injection is still a challenge. Therefore, it is urgent to develop a drug delivery system with molecular imaging tracking ability to accurately understand the distribution, location, and concentration of a drug in living organisms. In this study, we developed bovine serum albumin (BSA)-based nanoparticles (NPs) with dual magnetic resonance (MR) and fluorescence imaging modalities (fluorescein isothiocyanate [FITC]-BSA-Gd/1,3-bis(2-chloroethyl)-1-nitrosourea [BCNU] NPs) to deliver BCNU for inhibition of brain tumor cells (MBR 261-2). These BSA-based NPs are water dispersible, stable, and biocompatible as confirmed by XTT cell viability assay. In vitro phantoms and in vivo MR and fluorescence imaging experiments show that the developed FITC-BSA-Gd/BCNU NPs enable dual MR and fluorescence imaging for monitoring cellular uptake and distribution in tumors. The T1 relaxivity (R1) of FITC-BSA-Gd/BCNU NPs was 3.25 mM(-1) s(-1), which was similar to that of the commercial T1 contrast agent (R1 =3.36 mM(-1) s(-1)). The results indicate that this multifunctional drug delivery system has potential bioimaging tracking of chemotherapeutic agents ability in vitro and in vivo for cancer therapy. PMID:27601895

  8. Toxicology and pharmacology of the chemical warfare agent sulfur mustard.

    PubMed

    Dacre, J C; Goldman, M

    1996-06-01

    There have been reports of chemical attacks in which sulfur mustard might have been used (a) on Iranian soldiers and civilians during the Gulf War in 1984 and 1985 and (b) in an Iraqi chemical attack on the Iranian-occupied village of Halbja in 1988, resulting in many civilian casualties. Heavy use of chemical warfare in Afghanistan by the Soviet military is a recent innovation in military tactics that has been highly successful and may ensure further use of chemical agents in future military conflicts and terrorist attacks as a profitable adjunct to conventional military arms. Mustard is a poisonous chemical agent that exerts a local action on the eyes, skin, and respiratory tissue, with subsequent systemic action on the nervous, cardiac, and digestive systems in humans and laboratory animals, causing lacrimation, malaise, anorexia, salivation, respiratory distress, vomiting, hyperexcitability, and cardiac distress. Under extreme circumstances, dependent upon the dose and length of exposure to the agent, necrosis of the skin and mucous membranes of the respiratory system, bronchitis, bronchopneumonia, intestinal lesions, hemoconcentration, leucopenia, convulsions with systemic distress, and death occur. Severe mustard poisoning in humans is associated with systemic injury, which is manifested as headache, epigastric distresses, anorexia, diarrhea, and cachexia and is usually observed at mustard doses of 1000 mg/min/m3 with damage to hematopoietic tissues and progressive leucopenia. Sulfur mustard is a cell poison that causes disruption and impairment of a variety of cellular activities that are dependent upon a very specific integral relationship. These cytotoxic effects are manifested in widespread metabolic disturbances whose variable characteristics are observed in enzymatic deficiencies, vesicant action, abnormal mitotic activity and cell division, bone marrow disruption, disturbances in hematopoietic activity, and systemic poisoning. Indeed, mustard gas

  9. Various concentrations of erucic acid in mustard oil and mustard.

    PubMed

    Wendlinger, Christine; Hammann, Simon; Vetter, Walter

    2014-06-15

    Erucic acid is a typical constituent of mustard or rape. Foodstuff with a high content of erucic acid is considered undesirable for human consumption because it has been linked to myocardial lipidosis and heart lesions in laboratory rats. As a result, several countries have restricted its presence in oils and fats. In this study, the erucic acid content in several mustard oils and prepared mustard samples from Germany and Australia was determined. Seven of nine mustard oil samples exceeded the permitted maximum levels established for erucic acid (range: 0.3-50.8%, limit: 5%). The erucic acid content in mustard samples (n=15) varied from 14% to 33% in the lipids. Two servings (i.e. 20 g) of the mustards with the highest erucic acid content already surpassed the tolerable daily intake established by Food Standards Australia New Zealand. However, a careful selection of mustard cultivars could lower the nutritional intake of erucic acid. PMID:24491745

  10. Vesical nephrogenic adenoma: an unusual presentation of a bladder tumour

    PubMed Central

    Martínez-Sanchíz, Carlos; Martínez-Ruiz, Jesús; Anguita-Fernandez, Pedro J.; Giménez-Bachs, José M.; Atiénzar-Tobarra, Manuel; Rodríguez, Julio Antonio Virseda; Salinas-Sánchez, Antonio S.

    2011-01-01

    Vesical nephrogenic adenoma is a rare, benign entity that appears most commonly in middle-aged males. Its etiology is unknown, but it has been linked to chronic irritating factors, such as infection, trauma, urological surgery, kidney stones, foreign bodies and chemical agents, such as Bacille Calmette-Guerin. We report 2 new cases with a history of transurethral resection of the bladder and the prostate and a history of prolonged voiding symptoms. In both cases, the findings of encysted tubular structures lined with flattened cuboidal cells without atypia were consistent with the diagnosis of vesical nephrogenic adenoma. PMID:21989174

  11. Over-representation of specific regions of chromosome 22 in cells from human glioma correlate with resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea

    PubMed Central

    Hank, Nicole C; Shapiro, Joan Rankin; Scheck, Adrienne C

    2006-01-01

    Background Glioblastoma multiforme is the most malignant form of brain tumor. Despite treatment including surgical resection, adjuvant chemotherapy, and radiation, these tumors typically recur. The recurrent tumor is often resistant to further therapy with the same agent, suggesting that the surviving cells that repopulate the tumor mass have an intrinsic genetic advantage. We previously demonstrated that cells selected for resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) are near-diploid, with over-representation of part or all of chromosomes 7 and 22. While cells from untreated gliomas often have over-representation of chromosome 7, chromosome 22 is typically under-represented. Methods We have analyzed cells from primary and recurrent tumors from the same patient before and after in vitro selection for resistance to clinically relevant doses of BCNU. Karyotypic analyses were done to demonstrate the genetic makeup of these cells, and fluorescent in situ hybridization analyses have defined the region(s) of chromosome 22 retained in these BCNU-resistant cells. Results Karyotypic analyses demonstrated that cells selected for BCNU resistance were near-diploid with over-representation of chromosomes 7 and 22. In cells where whole copies of chromosome 22 were not identified, numerous fragments of this chromosome were retained and inserted into several marker and derivative chromosomes. Fluorescent in situ hybridization analyses using whole chromosome paints confirmed this finding. Additional FISH analysis using bacterial artificial chromosome probes spanning the length of chromosome 22 have allowed us to map the over-represented region to 22q12.3–13.32. Conclusion Cells selected for BCNU resistance either in vivo or in vitro retain sequences mapped to chromosome 22. The specific over-representation of sequences mapped to 22q12.3–13.32 suggest the presence of a DNA sequence important to BCNU survival and/or resistance located in this region of chromosome 22

  12. Beam damage of poly(2-chloroethyl methylacrylate) [PCEMA] films as observed by x-ray photoelectron spectroscopy at 143 K, 303 K, and 373 K

    SciTech Connect

    Engelhard, Mark H.; Baer, Donald R.; Lea, Alan S.

    2003-03-08

    X-ray beam damage is often observed during surface analysis of beam sensitive materials as indicated in the introduction to this issue and in a wide variety of references. While damage occurs in a wide range of materials, those that are most susceptible to damage are materials that contain low energy covalent bonds such as polymers or other organic materials. Even amongst the relatively easily damaged polymers, there is a wide range of damage rates. The focus of this submission is on poly(2-chloroethyl methylacrylate) [PCEMA] films. In order to determine the extent to which localized sample heating could influence damage rates the temperature of the substrate holding the PECMA was controlled during irradiation. PCEMA presumably degrades primarily by photo-ionization, resulting in the production of HCl through H and Cl bond cleavage. PCEMA has been recommended as a polymer for use as a reference for evaluating x-ray damage. PCEMA has been shown to be more sensitive to degradation than PVC which has also been used as a damage sensitive material useful for comparison of damage rates. Measurements of several relatively common materials on one instrument can provide a data base that allows damage rates on one instrument to be linked or compared to other damage data in the literature. Therefore for purposes of comparison, damage rates for bulk PVC at the same three different temperatures used for the PCEMA data have been collected and are also presented in this volume. Other data collected at the same x-ray parameters include thin films of PVC (for which damage rates are essentially identical to the bulk material) and of poly(acrylonitrile) PAN which is more stable that either PCEMA or PVC.

  13. Miscoding properties of 1,N{sup 6}-ethanoadenine, a DNA adduct derived from reaction with antitumor agent 1,3-bis(2-chloroethyl)-1-nitrosourea

    SciTech Connect

    Hang, Bo; Guliaev, Anton B.; Chenna, Ahmed; Singer, B.

    2003-03-05

    1,N{sup 6}-Ethanoadenine (EA) is an exocyclic adduct formed from DNA reaction with the antitumor agent, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). To understand the role of this adduct in the mechanism of mutagenicity or carcinogenicity by BCNU, an oligonucleotide with a site-specific EA was synthesized using phosphoramidite chemistry. We now report the in vitro miscoding properties of EA in translesion DNA synthesis catalyzed by mammalian DNA polymerases (pols) {alpha}, {beta}, {eta} and {iota}. These data were also compared with those obtained for the structurally related exocyclic adduct, 1,N{sup 6}-ethenoadenine ({var_epsilon}A). Using a primer extension assay, both pols {alpha} and {beta} were primarily blocked by EA or {var_epsilon}A with very minor extension. Pol {eta} a member of the Y family of polymerases, was capable of catalyzing a significant amount of bypass across both adducts. Pol {eta} incorporated all four nucleotides opposite EA and {var_epsilon}A, but with differential preferences and mainly in an error-prone manner. Human pol {iota}, a paralog of human pol {eta}, was blocked by both adducts with a very small amount of synthesis past {var_epsilon}A. It incorporated C and, to a much lesser extent, T, opposite either adduct. In addition, the presence of an A adduct, e.g. {var_epsilon}A, could affect the specificity of pol {iota} toward the template T immediately 3 feet to the adduct. In conclusion, the four polymerases assayed on templates containing an EA or {var_epsilon}A showed differential bypass capacity and nucleotide incorporation specificity, with the two adducts not completely identical in influencing these properties. Although there was a measurable extent of error-free nucleotide incorporation, all these polymerases primarily misincorporated opposite EA, indicating that the adduct, similar to {var_epsilon}A, is a miscoding lesion.

  14. Lipid peroxidation and oxidative stress responses in juvenile salmon exposed to waterborne levels of the organophosphate compounds tris(2-butoxyethyl)- and tris(2-chloroethyl) phosphates.

    PubMed

    Arukwe, Augustine; Carteny, Camilla Catarci; Eggen, Trine

    2016-01-01

    There is limited knowledge on the toxicological, physiological, and molecular effects attributed to organophosphate (OP) compounds currently used as flame retardants or additives in consumer products. This study investigated the effects on oxidative stress and lipid peroxidation in juvenile Atlantic salmon liver and brain samples after exposure to two OP compounds, tris(2-butoxyethyl) phosphate (TBOEP) and tris(2-chloroethyl) phosphate (TCEP). In this study, groups of juvenile Atlantic salmon were exposed using a semistatic experimental protocol over a 7-d period to 3 different concentrations (0.04, 0.2, or 1 mg/L) of TBOEP and TCEP. When toxicological factors such as bioaccumulation and bioconcentration, and chemical structural characteristics and behavior, including absorption to solid materials, are considered, these concentrations represent environmentally relevant concentrations. The concentrations of the contaminants were derived from levels of their environmental occurrence. The expression of genes related to oxidative stress-glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST)-and to lipid peroxidation-peroxisome proliferator-activated receptors (PPAR)-were determined using quantitative (real-time) polymerase chain reaction (PCR). The presence of PPAR proteins was also investigated using immunochemical methods. Levels of thiobarbituric acid-reactive substances (TBARS) in liver were used as a measure of lipid peroxidation. Overall, our data show an increase in lipid peroxidation, and this was associated with an augmented expression of genes from the glutathione family of responses. Interestingly, PPAR expression in liver after exposure to TBOEP and TCEP was consistently decreased compared to controls, while expression in brain did not show a similar trend. The results suggest that OP contaminants may induce oxidative stress and thus production of reactive oxygen substances (ROS), and modulate lipid peroxidation processes

  15. HILIC-MS Determination of Genotoxic Impurity of 2-Chloro-N-(2-Chloroethyl)Ethanamine in the Vortioxetine Manufacturing Process.

    PubMed

    Douša, Michal; Klvaňa, Robert; Doubský, Jan; Srbek, Jan; Richter, Jindřich; Exner, Marek; Gibala, Petr

    2016-02-01

    In the last decade, pharmaceutical regulatory agencies are focused on monitoring and evaluation of trace-level genotoxic impurities (GTIs) in drug substances, which requires manufacturers to deliver innovative approaches for their analysis and control. GTIs in the low p.p.m. level rising from the process of drug production have to be positively identified and quantified. Therefore, sensitive and selective analytical methods are necessary for required quantification level of these GTIs. Unfortunately, general guidance on how to develop strategy of the analysis and control of GTIs is currently missing in the pharmaceutical industry. Therefore, practical example of the analytical control of 2-chloro-N-(2-chloroethyl)ethanamine GTI in the vortioxetine (VOR) manufacturing process was demonstrated in this work. QDa mass detection with electrospray ionization in selected-ion recording mode was utilized for quantitation of GTIs. The method of hydrophilic interaction liquid chromatography coupled with mass spectrometry detection (HILIC-MS) was validated as per International Conference on Harmonization guidelines and was able to quantitate GTIs at 75 p.p.m. with respect to VOR. The HILIC-MS method was achieved using a Primesep B column (150 × 4.6 mm, 5.0 µm; Sielc, USA) using mobile phase consisting of 10 mM ammonium formate buffer pH 3.0 and acetonitrile (5 : 95, v/v) at 0.8 mL/min flow rate. The QDa mass detector was operated in the positive ion mode. Quadrupole mass analyzer was employed in selected-ion monitoring mode using target ion at m/z 142 as [M+H](+). PMID:26223463

  16. Neurotoxicity after intracarotid 1,3-bis(2-chloroethyl)-1-nitrosourea administration in the rat: Hemodynamic changes studied by double-tracer autoradiography

    SciTech Connect

    Nagahiro, S.; Yamamoto, Y.L.; Diksic, M.; Mitsuka, S.; Sugimoto, S.; Feindel, W. )

    1991-07-01

    Changes in blood-brain (BBB) permeability and local cerebral blood flow after intracarotid administration of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) were examined quantitatively in rats with double-tracer autoradiography using (14C)alpha-amino-isobutyric acid and (18F)fluoroantipyrine. Forty-eight female Wistar rats were divided into four groups. The control group (Group 1) received 1 ml of 5% dextrose. The other three groups received three different doses of BCNU dissolved in 5% dextrose: Group 2 rats received 1 mg, Group 3 3 mg, and Group 4 10 mg. The tracer study was performed on Day 1 or Days 4 to 12 after intracarotid administration of BCNU. In 11 rats in Group 2, there were no changes of BBB permeability. Transient BBB permeability changes were seen in the striatum or hippocampus in 3 of the 5 rats (60%) in Group 3 within 24 hours. In 8 of 9 rats (89%) in the same group, late BBB permeability changes were observed in the hypothalamus with or without histological changes. BBB permeability changes were seen in all rats of Group 4. Focal increase of local cerebral blood flow on the infused side compared with the non-infused side of the brain was observed, although not at a significant level, in 5 of 25 rats examined with (18F)fluoroantipyrine. The results of BBB permeability and histological examinations and study of heterogenous distribution by (18F)fluorodeoxyglucose indicated that the ipsilateral subcortical structures such as the hypothalamus, amygdala, internal capsule, and caudate putamen have the highest incidence of neurotoxicity, which are closely related to histopathological damage seen in human BCNU leucoencephalopathy.

  17. Effect of sulfur mustard on mast cells in hairless guinea pig skin

    SciTech Connect

    Graham, J.S.; Bryant, M.A.; Braue, E.H.

    1993-05-13

    The skin of 24 anesthetized hairless guinea pigs was exposed to saturated sulfur mustard (bis-2-chloroethyl sulfide; HD) for 5 and 7 minutes using 14-mm diameter vapor cups. Animals were euthanatized 24 hours after exposure and skin specimens taken for morphometric evaluation of granulated mast cells with an image analysis system (IAS). Tissue specimens were processed in paraffin, sectioned at 5 microns and stained with Unna's stain for mast cells. The number of granulated mast cells and the area occupied by mast cell granules was determined. There were significantly fewer mast cells (p < 0.05) in either HD exposure group than in sham-exposed animals, with significantly fewer mast cells in the 7-minute than the 5-minute HD group. There were also significantly smaller areas occupied by granules in either HD exposure group than in sham-exposed animals. HD-induced lesions in the hairless guinea pig have shown signs of an inflammatory response, and with their granules of vasoactive histamine, mast cells might be expected to play a role in HD-induced injury. Changes in mast cells exposed to low sulfur mustard levels, as detected by an IAS, may serve as an early marker for cutaneous damage, which might not be as easily determined with routine light microscopy.

  18. Toxicology and pharmacology of the chemical warfare agent sulfur mustard - a review. Final technical report, 29 September 1994-31 January 1995

    SciTech Connect

    Dacre, J.C.; Beers, R.; Goldman, M.

    1995-04-05

    Sulfur mustard is a poisonous chemical agent which exerts a local action on the eyes, skin and respiratory tissue with subsequent systemic action on the nervous, cardiac, and digestive and endocrine systems in man and laboratory animals causing lacrimation, malaise, anorexia, salivation, respiratory distress, vomiting, hyperexcitability, cardiac distress, and death. Sulfur mustard is a cell poison which causes disumption and impairment of a variety of cellular activities which are dependent upon a very specific integral relationship. These cytotoxic effects are manifested in widespread metabolic disturbances whose variable characteristics are observed in enzymatic deficiencies, vesicant action, abnormal mitotic activity and cell division, bone marrow disruption, disturbances in hematopoietic activity and systemic poisoning. Indeed, mustard gas readily combines with various components of the cell such as amino acids, amines and proteins. Sulfur mustard has been shown to be mainly a lung carcinogen in various test animal species; this effect is highly dependent of size of the dose and the route of exposure. In the human, there is evidence of cancers of the respiratory tract in men exposed to mustard gas. Mutagenicity of sulfur mustard, due to the strong alkylating activity, has been reported to occur in many different species of animals, plants, bacteria, and fungi. There is no strong evidence that sulfur mustard is a teratogen but much further research, with particular emphasis on maternal and fetal toxicity, is needed and recommended.

  19. Mustard meal weed control

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Weed control in organic production systems can be a labor intensive and expensive process. Mustard meal (MM) is phytotoxic and a potential pre-emergent and preplant-incorporated organic herbicide for controlling germinating and emerging weed seedlings. Unfortunately, MM may also adversely impact s...

  20. Response of 9L rat brain tumor multicellular spheroids to single and fractionated doses of 1,3-bis(2-chloroethyl)-1-nitrosourea.

    PubMed

    Sano, Y; Hoshino, T; Barker, M; Deen, D F

    1984-02-01

    This study was designed to examine the relative effect of each of four fractions of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) against 9L rat brain tumor multicellular spheroids and to compare the results of the cell survival and growth delay assays. Similar levels of cell kill resulted when BCNU was administered either as single fractions of 1.5, 3.0, 4.5, or 6.0 micrograms/ml for 1 hr or as one to four fractions of 1.5 micrograms/ml that were administered sequentially for 1 hr each. Survival was increased if the assay was delayed until 24 hr after drug treatment, which indicates that 9L cells in spheroids recover from BCNU-induced potentially lethal damage. When BCNU was administered in 1.5-micrograms/ml fractions, plating efficiencies depended markedly on the interval between the fractions. The 12-hr protocol produced an overall higher cell kill. Fractionation schedules of 24 and 36 hr produced less cell kill than did the other schedules. Survival plateaued for the last three treatments with BCNU in the 36-hr schedule. Cells in S phase at the time of administration of the initial 1.5-micrograms/ml fraction of BCNU moved into G1- and G2-M phases by 12 hr after treatment. For time periods longer than 12 hr, cells began to appear in the BCNU-resistant S phase. Thus, the movement of cells into the drug-sensitive and -resistant phases after the first fraction correlates well with the corresponding overall cytotoxic effect produced by treatment with the combined BCNU (1.5 micrograms/ml) fractions. For a higher concentration (3.0 micrograms/ml for 1 hr), maximum cell kill was reached within the 12- to 18-hr interval, after which cell kill plateaued. Cells were not found in the S-phase fraction 12 to 36 hr after the first treatment with 3.0 micrograms/ml; maximum cell kill for the fractionated protocols resulted at these times. Therefore, BCNU, which is classified as a cell cycle-nonspecific drug, can induce a partial synchrony in 9L spheroid cells, which determines

  1. Mass spectral studies on vinylic degradation products of sulfur mustards under gas chromatography/mass spectrometry conditions.

    PubMed

    Sai Sachin, L; Karthikraj, R; Kalyan Kumar, K; Sony, T; Prasada Raju, N; Prabhakar, S

    2015-01-01

    Sulfur mustards are a class of vesicant chemical warfare agents that rapidly degrade in environmental samples. The most feasible degradation products of sulfur mustards are chloroethyl vinylic compounds and divinylic compounds, which are formed by the elimination of one and two HCl molecules from sulfur mustards, respectively. The detection and characterization of these degradation products in environmental samples are an important proof for the verification of sulfur mustard usage. In this study, we synthesized a set of sulfur mustard degradation products, i.e., divinylic compounds (1-7) and chloroethyl vinylic compounds (8-14), and characterized using gas chromatography/mass spectrometry (GC/MS) under electron ionization (EI) and chemical ionization (CI) (methane) conditions. The EI mass spectra of the studied compounds mainly included the fragment ions that resulted from homolytic cleavages with or without hydrogen migrations. The divinylic compounds (1-7) showed [M-SH](+) ions, whereas the chloroethylvinyl compounds (8-14) showed [M-Cl](+) and [M-CH2CH2Cl](+) ions. Methane/CI mass spectra showed [M+H](+) ions and provided molecular weight information. The GC retention index (RI) values were also calculated for the studied compounds. The EI and CI mass spectral data together with RI values are extremely useful for off-site analysis for the verification of the chemical weapons convention and also to participate in official Organization for the Prohibition of Chemical Weapons proficiency tests. PMID:26764309

  2. Intratracheal Heparin Improves Plastic Bronchitis Due to Sulfur Mustard Analog

    PubMed Central

    Houin, Paul R.; Veress, Livia A.; Rancourt, Raymond C.; Hendry-Hofer, Tara B.; Loader, Joan E.; Rioux, Jacqueline S.; Garlick, Rhonda B.; White, Carl W.

    2014-01-01

    Summary Background Inhalation of sulfur mustard (SM) and SM analog, 2-chloroethyl ethyl sulfide (CEES), cause fibrinous cast formation that occludes the conducting airways, similar to children with Fontan physiology-induced plastic bronchitis. These airway casts cause significant mortality and morbidity, including hypoxemia and respiratory distress. Our hypothesis was that intratracheal heparin, a highly cost effective and easily preserved rescue therapy, could reverse morbidity and mortality induced by bronchial cast formation. Methods Sprague-Dawley rats were exposed to 7.5% CEES via nose-only aerosol inhalation to produce extensive cast formation and mortality. The rats were distributed into three groups: non-treated, phosphate-buffered saline (PBS)-treated, and heparin-treated groups. Morbidity was assessed with oxygen saturations and clinical distress. Blood and bronchoalveolar lavage fluid (BALF) were obtained for analysis, and lungs were fixed for airway microdissection to quantify the extent of airway cast formation. Results Heparin, given intratracheally improved survival (100%) when compared to non-treated (75%) and PBS-treated (90%) controls. Heparin-treated rats also had improved oxygen saturations, clinical distress and airway cast scores. Heparin-treated rats had increased thrombin clotting times, factor Xa inhibition and activated partial thromboplastin times, indicating systemic absorption of heparin. There were also increased red blood cells (RBCs) in the BALF in 2/6 heparin-treated rats compared to PBS-treated control rats. Conclusions Intratracheal heparin 1 hr after CEES inhalation improved survival, oxygenation, airway obstruction, and clinical distress. There was systemic absorption of heparin in rats treated intratracheally. Some rats had increased RBCs in BALF, suggesting a potential for intrapulmonary bleeding if used chronically after SM inhalation. PMID:24692161

  3. The synthesis and biological evaluation of new DNA-directed alkylating agents, phenyl N-mustard-4-anilinoquinoline conjugates containing a urea linker.

    PubMed

    Marvania, Bhavin; Kakadiya, Rajesh; Christian, Wilson; Chen, Tai-Lin; Wu, Ming-Hsi; Suman, Sharda; Tala, Kiran; Lee, Te-Chang; Shah, Anamik; Su, Tsann-Long

    2014-08-18

    We synthesized a series of phenyl N-mustard-4-anilinoquinoline conjugates to study their antitumorigenic effects. These agents were prepared by the condensation of 4-[N,N-bis(2-chloroethyl)amino]phenyl isocyanate with 6-amino-4-methylamino or 4-anilinoquinolines. The structure-activity relationship (SAR) studies revealed that the C2-methylquinoline derivatives (18a-o) were generally more cytotoxic than the C2-phenylquinoline conjugates (23a-d) in inhibiting the cell growth of various human tumor cell lines in vitro. However, the methylamino or aniline substituents at C4 of quinoline did not influence the cytotoxic effects. The title conjugates were capable of inducing DNA cross-linking and promoting cell-cycle arrest at the G2/M phase. This study demonstrates that phenyl N-mustard-4-anilinoquinoline conjugates are generally more potent than phenyl N-mustard-4-anilinoquinazoline conjugates against the cell growth of various tumor cell-lines. PMID:25014640

  4. Biochemical manipulation of intracellular glutathione levels influences cytotoxicity to isolated human lymphocytes by sulfur mustard

    SciTech Connect

    Gross, C.L.; Innace, J.K.; Hovatter, R.C.; Meier, H.L.; Smith, W.J.

    1993-12-31

    Glutathione (GSH) is the major nonprotein thiol that can protect cells from damage due to electrophilic alkylating agents by forming conjugates with the agent. Sulfur mustard (HD) is an electrophilic alkylating agent that has potent mutagenic, carcinogenic, cytotoxic, and vesicant properties. Compounds that elevate or reduce intracellular levels of GSH may produce changes in cytotoxicity induced by sulfur mustard. Pretreatment of human peripheral blood lymphocytes (PBL) for 72 hr with 1 mM buthionine sulfoximine (BSO), which reduces intracellular GSH content to approximately 26% of control, appears to sensitize these in vitro cells to the cytotoxic effects of 10 AM HD but not to higher HD concentrations. Pretreatment of PBL for 48 hr with 10 mM N-acetyl cysteine (NA C), which elevates intracellular glutathione levels to 122% of control, appears to partially protect these in vitro cells from the cytotoxic effects of 10 LAIHD but not to higher HD concentrations. Augmentation of intracellular levels of glutathione may provide partial protection against cytotoxicity of sulfur mustard.

  5. Giant Vesical Calculus Formation as a Complication of Augmentation Cystoplasty.

    PubMed

    Kumar, Manoj; Singh, Ranjeet Kumar; Kapoor, Rakesh

    2016-02-01

    A 44-year-old female presented with the history of recurrent UTI and intermittent hematuria. She underwent augmentation ileocystoplasty for small capacity bladder 19 years back. Patient was on clean intermittent catheterization (CIC) since then. Abdominal radiograph and ultrasonography showed the large vesical calculus. Open cystolithotomy was done, and a yellowish brown hard stone weighing 1025 g was removed. Chemical analysis revealed struvite stone. Postoperative period was uneventful. Regular bladder wash, lifelong surveillance and follow-up is advisable. PMID:27186046

  6. Toxicological profile for mustard gas. Final report

    SciTech Connect

    Not Available

    1992-09-01

    The Statement was prepared to give information about mustard gas (sulfur mustard) and to emphasize the human health effects that may result from exposure to it. The Environmental Protection Agency (EPA) has identified 1,177 sites on its National Priorities List (NPL). Mustard gas has been found at 4 of these sites. As EPA evaluates more sites, the number of sites at which mustard gas is found may change. The information is important because these sites are potential or actual sources of human exposure to mustard gas. Mustard gas may cause harmful health effects.

  7. Photoassisted and photocatalytic degradation of sulfur mustard using TiO2 nanoparticles and polyoxometalates.

    PubMed

    Naseri, Mohammad Taghi; Sarabadani, Mansour; Ashrafi, Davood; Saeidian, Hamdollah; Babri, Mehran

    2013-02-01

    The decomposition of highly toxic chemical warfare agent, sulfur mustard (bis(2-chloroethyl) sulfide or HD), has been studied by homogeneous photolysis and heterogeneous photocatalytic degradation on titania nanoparticles. Direct photolysis degradation of HD with irradiation system was investigated. The photocatalytic degradation of HD was investigated in the presence of TiO(2) nanoparticles and polyoxometalates embedded in titania nanoparticles in liquid phase at room temperature (33 ± 2 °C). Degradation products during the treatment were identified by gas chromatography-mass spectrometry. Whereas apparent first-order kinetics of ultraviolet (UV) photolysis were slow (0.0091 min(-1)), the highest degradation rate is obtained in the presence of TiO(2) nanoparticles as nanophotocatalyst. Simultaneous photolysis and photocatalysis under the full UV radiation leads to HD complete destruction in 3 h. No degradation products observed in the presence of nanophotocatalyst without irradiation in 3 h. It was found that up to 90 % of agent was decomposed under of UV irradiation without TiO(2), in 6 h. The decontamination mechanisms are often quite complex and multiple mechanisms can be operable such as hydrolysis, oxidation, and elimination. By simultaneously carrying out photolysis and photocatalysis in hexane, we have succeeded in achieving faster HD decontamination after 90 min with low catalyst loading. TiO(2) nanoparticles proved to be a superior photocatalyst under UV irradiation for HD decontamination. PMID:22707206

  8. N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) has differential efficacy for causing central noradrenergic lesions in two different rat strains: comparison between Long-Evans and Sprague-Dawley rats.

    PubMed

    Schuerger, R J; Balaban, C D

    1995-05-01

    We tested the hypothesis that Long-Evans (LE) and Sprague-Dawley (SD) rat strains were equally sensitive to the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) with respect to central lesions of locus coeruleus (LC) terminals as measured by immunohistochemical localization of dopamine-beta-hydroxylase (D beta H). Analysis of D beta H immunoreactivity was made by both qualitative and quantitative methods. Intraperitoneal injections of 50 mg/kg DSP-4 caused a dramatic reduction of noradrenergic terminals in the neocortex, hippocampus and cerebellum of SD, but not LE rats as compared to saline-injected controls. This finding indicates that LE rats are less sensitive than SD rats to the neurotoxic effects of DSP-4 in the central nervous system. PMID:7475238

  9. Tissue factor pathway inhibitor prevents airway obstruction, respiratory failure and death due to sulfur mustard analog inhalation

    SciTech Connect

    Rancourt, Raymond C. Veress, Livia A. Ahmad, Aftab Hendry-Hofer, Tara B. Rioux, Jacqueline S. Garlick, Rhonda B. White, Carl W.

    2013-10-01

    Sulfur mustard (SM) inhalation causes airway injury, with enhanced vascular permeability, coagulation, and airway obstruction. The objective of this study was to determine whether recombinant tissue factor pathway inhibitor (TFPI) could inhibit this pathogenic sequence. Methods: Rats were exposed to the SM analog 2-chloroethyl ethyl sulfide (CEES) via nose-only aerosol inhalation. One hour later, TFPI (1.5 mg/kg) in vehicle, or vehicle alone, was instilled into the trachea. Arterial O{sub 2} saturation was monitored using pulse oximetry. Twelve hours after exposure, animals were euthanized and bronchoalveolar lavage fluid (BALF) and plasma were analyzed for prothrombin, thrombin–antithrombin complex (TAT), active plasminogen activator inhibitor-1 (PAI-1) levels, and fluid fibrinolytic capacity. Lung steady-state PAI-1 mRNA was measured by RT-PCR analysis. Airway-capillary leak was estimated by BALF protein and IgM, and by pleural fluid measurement. In additional animals, airway cast formation was assessed by microdissection and immunohistochemical detection of airway fibrin. Results: Airway obstruction in the form of fibrin-containing casts was evident in central conducting airways of rats receiving CEES. TFPI decreased cast formation, and limited severe hypoxemia. Findings of reduced prothrombin consumption, and lower TAT complexes in BALF, demonstrated that TFPI acted to limit thrombin activation in airways. TFPI, however, did not appreciably affect CEES-induced airway protein leak, PAI-1 mRNA induction, or inhibition of the fibrinolytic activity present in airway surface liquid. Conclusions: Intratracheal administration of TFPI limits airway obstruction, improves gas exchange, and prevents mortality in rats with sulfur mustard-analog-induced acute lung injury. - Highlights: • TFPI administration to rats after mustard inhalation reduces airway cast formation. • Inhibition of thrombin activation is the likely mechanism for limiting casts. • Rats given TFPI

  10. Imaging sulfur mustard lesions in human epidermal tissues and keratinocytes by confocal and multiphoton microscopy

    NASA Astrophysics Data System (ADS)

    Werrlein, Robert; Madren-Whalley, Janna S.

    2002-06-01

    Topical exposure to sulfur mustard (HD), a known theat agent, produces persistent and debilitating cutaneous blisters. The blisters occur at the dermal-epidermal junction following a dose-dependent latent period of 8-24 h, however, the primary lesions causing vesication remain uncertain. Immunofluorescent images reveal that a 5-min exposure to 400 (mu) M HD disrupts molecules that are also disrupted by epidermolysis bullosa-type blistering diseases of the skin. Using keratinocyte cultures and fluorochomes conjugated to two different keratin-14 (K14) antibodies (clones CKB1 and LL002), results have shown a statistically significant (p<0.1) 1-h decrease of 29.2% in expression of the CKB1 epitope, a nearly complete loss of CKB1 expression within 2 h, and progressive cytoskeletal (K14) collapse without loss in expression of the LL002 epitope. With human epidermal tissues, multi-photon images of (alpha) 6 integrin and laminin 5 showed disruptive changes in the cell-surface organization and integrity of these adhesion molecules. At 1 H postexposure, analyses showed a statistically significant (p<0.1) decrease of 27.3% in (alpha) 6 integrin emissions, and a 32% decrease in laminin 5 volume. Multi-photon imaging indicates that molecules essential for epidermal-dermal attachment are early targets in the alkylating events leading to HD-induced vesication.

  11. Argon laser treatment of urethral stricture and vesical neck contracture.

    PubMed

    Adkins, W C

    1988-01-01

    The physical characteristics of the argon laser wavelength allow a precise incision with excellent hemostasis and negligible heating of adjacent tissues resulting in less scarring. These qualities are used to advantage in the treatment of strictures. The argon laser was used to perform 13 internal urethrotomies and ten vesical neck incisions. The operative method used is similar to optical internal urethrotomy. The argon probe incises hemostatically, reducing the need for extensive fulguration of tissues at the operative site and thereby reducing the tendency for more scar tissue to form and compromise the operation. The same hemostasis reduces the need for postoperative indwelling urethral catheterization. Utility of the argon device in most instances allows treatment to be conducted on an outpatient basis without general anesthesia and without use of postoperative urethral catheters, yielding an effective, cost-saving therapy. PMID:3210887

  12. Vesical Artery Embolization in Haemorrhagic Cystitis in Children.

    PubMed

    García-Gámez, Andrés; Bermúdez Bencerrey, Patricia; Brio-Sanagustin, Sonia; Guerrero Vara, Rubén; Sisinni, Luisa; Stuart, Sam; Roebuck, Derek; Gómez Muñoz, Fernando

    2016-07-01

    Haemorrhagic cystitis is an uncommon and, in its severe form, potentially life-threatening complication of haematopoietic stem cell transplantation or cancer therapy in children. The severe form involves macroscopic haematuria with blood clots, urinary obstruction and/or renal impairment. There are many therapeutic options to treat acute haemorrhage, but only recombinant factor VII has a high level of clinical evidence in children. Supraselective vesical artery embolization (SVAE) is an increasingly used therapeutic procedure for controlling haemorrhage in adults, but is less commonly used in children. This might be due to several factors, such as the invasive nature of the procedure, lack of appropriate medical experience and possible long-term side effects. We present three cases of children successfully treated by means of effective SVAE. PMID:26850734

  13. Toxicology Studies on Lewisite and Sulfur Mustard Agents: Modified Dominant Lethal Study of Sulfur Mustard in Rats Final Report

    SciTech Connect

    Sasser, L. B.; Cushing, J. A.; Kalkwarf, D. R.; Buschbom, R. L.

    1989-05-01

    Occupational health standards have not been established for sulfur mustard (HD) [bis{2-chloroethyl)-sulfide) ' a strong alkylating agent with known mutagenic properties. Little, however, is known about the mutagenic activity of HD in mammalian species and data regarding the dominant lethal effects of HD are ambiguous. The purpose of this study was to determine the dominant lethal effect in male and female rats orally exposed to HD. The study was conducted in two phases; a female dominant lethal phase and a male dominant lethal phase. Sprague-Dawley rats of each sex were administered 0.08, 0.20, or 0.50 mg/kg HD in sesame oil 5 days/week for 10 weeks. For the female phase, treated or untreated males were mated with treated females and their fetuses were evaluated at approximately 14 days after copulation. For the male dominant lethal phase, treated males cohabited with untreated femal (during 5 days of each week for 10 weeks) and females were sacrificed for fetal evaluation 14 days after the midweek of cohabitation during each of the 10 weeks. The appearance and behavior of the rats were unremarkable throughout the experiment and there were no treatment-related deaths. Growth rates were reduced in both female and male rats treated with 0.50 mg/kg HD. Indicators of reproductive performance did not demonstrate significant female dominant lethal effects, although significant male dominant lethal effects were observed at 2 and 3 week post-exposure. These effects included increases of early fetal resorptions and preimplantation losses and decreases of total live embryo implants. These effects were most consistently observed at a dose of 0.50 mg/kg, but frequently occurred at the lower doses. Although no treatment-related effects on male reproductive organ weights or sperm motility were found, a significant increase in the percentage of abnormal sperm was detected in males exposed to 0. 50 mg/kg HD. The timing of these effects is consistent with an effect during the

  14. Mutagenicity and antimutagenicity studies of DRDE-07 and its analogs against sulfur mustard in the in vitro Ames Salmonella/microsome assay.

    PubMed

    Vijayan, Vinod; Pathak, Uma; Meshram, Ghansham Pundilikji

    2014-10-01

    Sulfur mustard (bis(2-chloroethyl) sulfide, SM), a chemical warfare agent, is classified as a class I human carcinogen by IARC. No effective antidote against this agent is available. The synthetic aminothiol, amifostine, earlier known as WR-2721, has been extensively used as a chemical radioprotector for normal tissues in cancer radiotherapy and chemotherapy. SM is a radiomimetic agent; this prompted us to evaluate the protective efficacy of amifostine and three of its analogs, DRDE-07 [S-2(2-aminoethylamino) ethyl phenyl sulphide], DRDE-30 [S-2(2-aminoethyl amino) ethyl propyl sulphide] and DRDE-35 [S-2(2-aminoethyl amino) ethyl butyl sulphide], against sulfur mustard-induced mutagenicity in the Ames Salmonella/microsome assay. The antidotes were also evaluated for possible mutagenic activity. DRDE-07 was mutagenic in strain TA104 in the absence of S9; DRDE-30 was mutagenic in strain TA100; amifostine and DRDE-35 did not show mutagenic activity in any of the five tester strains used. SM is mutagenic in strains TA97a and TA102, with or without S9 activation. In the antimutagenicity studies, DRDE-07 and DRDE-35 showed promising antimutagenic activity against SM in the absence of S9, in comparison to amifostine. DRDE-07 and DRDE-35 are promising protective agents against SM-induced mutagenicity. PMID:25308705

  15. Macromolecular metabolism of a differentiated rat keratinocyte culture system following exposure to sulfur mustard

    SciTech Connect

    Vaughan, F.L.; Zaman, S.; Scavarelli, R.; Bernstein, I.A.

    1988-01-01

    A method for producing a stratified, squamous epithelium in vitro by cultivating rat keratinocytes on nylon membranes has been developed in this laboratory. This epidermal-like culture is being used to obtain a better understanding of the mechanism of skin vesication after topical exposure to the sulfur mustard bis(beta-chloroethyl) sulfide (BCES) dissolved in a selected solvent. Radiolabeled macromolecular precursors (thymidine, uridine, and leucine) have been used to study the effect of BCES on the synthesis of DNA, RNA, and protein, respectively, after topical exposure to the mustard at concentrations of 0.01-500 nmol/cm2 dissolved in 70% dimethyl sulfoxide (DMSO). From these and other studies it has been determined that exposure to even the low concentration of 0.01 nmol BCES/cm2 for 30 min results in significant inhibition of (/sup 3/H)thymidine incorporation, although complete recovery occurs by 24 h. Significant inhibition of (/sup 3/H)uridine and (/sup 14/C)leucine incorporation is observed only after exposure to much higher concentrations of BCES (10-500 nmol/cm2). This suggests a very early lesion in macromolecular metabolism with DNA being the primary target.

  16. Development of a liquid chromatography-multiple reaction monitoring procedure for concurrent verification of exposure to different forms of mustard agents.

    PubMed

    Yeo, Thong-Hiang; Ho, Mer-Lin; Loke, Weng-Keong

    2008-01-01

    A novel liquid chromatography-multiple reaction monitoring (LC-MRM) procedure has been developed for retrospective diagnosis of exposure to different forms of mustard agents. This concise method is able to validate prior exposure to nitrogen mustards (HN-1, HN-2, and HN-3) or sulfur mustard (HD) in a single run, which significantly reduces analysis time compared to separate runs to screen for different mustards' biomarkers based on tandem mass spectrometry. Belonging to one of the more toxic classes of chemical warfare agents, these potent vesicants bind covalently to the cysteine-34 residue of human serum albumin. This results in the formation of stable adducts whose identities were confirmed by a de novo sequencing bioinformatics software package. Our developed technique tracks these albumin-derived adduct biomarkers in blood samples which persist in vitro following exposure, enabling a detection limit of 200 nM of HN-1, 100 nM of HN-2, 200 nM of HN-3, or 50 nM of HD in human blood. The CWA-adducts formed in blood samples can be conveniently and sensitively analyzed by this MRM technique to allow rapid and reliable screening. PMID:18269793

  17. In-Line Ozonation for Sensitive Air-Monitoring of a Mustard-Gas Simulant by Atmospheric Pressure Chemical Ionization Mass Spectrometry

    NASA Astrophysics Data System (ADS)

    Okumura, Akihiko

    2015-09-01

    A highly sensitive method for real-time air-monitoring of mustard gas (bis(2-chloroethyl) sulfide, HD), which is a lethal blister agent, is proposed. Humidified air containing a HD simulant, 2-chloroethyl ethyl sulfide (2CEES), was mixed with ozone and then analyzed by using an atmospheric pressure chemical ionization ion trap tandem mass spectrometer. Mass-spectral ion peaks attributable to protonated molecules of intact, monooxygenated, and dioxygenated 2CEES (MH+, MOH+, and MO2H+, respectively) were observed. As ozone concentration was increased from zero to 30 ppm, the signal intensity of MH+ sharply decreased, that of MOH+ increased once and then decreased, and that of MO2H+ sharply increased until reaching a plateau. The signal intensity of MO2H+ at the plateau was 40 times higher than that of MH+ and 100 times higher than that of MOH+ in the case without in-line ozonation. Twenty-ppm ozone gas was adequate to give a linear calibration curve for 2CEES obtained by detecting the MO2H+ signal in the concentration range up to 60 μg/m3, which is high enough for hygiene management. In the low concentration range lower than 3 μg/m3, which is equal to the short-term exposure limit for HD, calibration plots unexpectedly fell off the linear calibration curve, but 0.6-μg/m3 vapor was actually detected with the signal-to-noise ratio of nine. Ozone was generated from instrumentation air by using a simple and inexpensive home-made generator. 2CEES was ozonated in 1-m extended sampling tube in only 1 s.

  18. Synthesis, characterization, crystal structure determination and computational study of a new Cu(II) complex of bis [2-{(E)-[2-chloroethyl)imino]methyl}phenolato)] copper(II) Schiff base complex

    NASA Astrophysics Data System (ADS)

    Grivani, Gholamhossein; Vakili, Mohammad; Khalaji, Aliakbar Dehno; Bruno, Giuseppe; Rudbari, Hadi Amiri; Taghavi, Maedeh

    2016-07-01

    The copper (II) Schiff base complex of [CuL2] (1), HL = 2-{(E)-[2-chloroethyl) imino]methyl}phenol, has been synthesized and characterized by elemental (CHN) analysis, UV-Vis and FT-IR spectroscopy. The molecular structure of 1 was determined by single crystal X-ray diffraction technique. The conformational analysis and molecular structures of CuL2 were investigated by means of density functional theory (DFT) calculations at B3LYP/6-311G* level. An excellent agreement was observed between theoretical and experimental results. The Schiff base ligand of HL acts as a chelating ligand and coordinates via one nitrogen atom and one oxygen atom to the metal center. The copper (II) center is coordinated by two nitrogen atoms and two oxygen atoms from two Schiff base ligands in an approximately square planar trans-[MN2O2] coordination geometry. Thermogravimetric analysis of CuL2 showed that it was decomposed in five stages. In addition, the CuL2 complex thermally decomposed in air at 660 °C and the XRD pattern of the obtained solid showed the formation of CuO nanoparticles with an average size of 34 nm.

  19. Neurotoxic compound N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP4) depletes endogenous norepinephrine and enhances release of (/sup 3/H)norepinephrine from rat cortical slices

    SciTech Connect

    Landa, M.E.; Rubio, M.C.; Jaim-Etcheverry, G.

    1984-10-01

    The alkylating compound N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP4) injected to rodents blocks norepinephrine (NE) uptake and reduces endogenous NE levels in the central nervous system and in the periphery. To investigate the processes leading to these alterations, rat cortical slices were incubated in the presence of DSP4. Cortical NE was depleted by 40% after incubation of slices in 10(-5) M DSP4 for 60 min and this was blocked by desipramine. The spontaneous outflow of radioactivity from cortical slices labeled previously with (/sup 3/H)NE was enhanced markedly both during exposure to DSP4 and during the subsequent washings, suggesting that NE depletion could be due to this stimulation of NE release. The radioactivity released by DSP4 was accounted for mainly by NE and its deaminated metabolite 3,4-dihydroxyphenylglycol. The enhanced release, independent of external Ca++, apparently originated from the vesicular pool as it was absent after reserpine pretreatment. Activities of the enzymes related to NE synthesis were not altered by DSP4 in vitro and only monoamine oxidase activity was inhibited at high concentrations. Thus, the depletion of endogenous NE produced by DSP4 is probably due to a persistent enhancement of its release from the vesicular pool. Fixation of DSP4 to the NE transport system is necessary but not sufficient to produce the acute NE depletion and the characteristic long-term actions of the compound.

  20. Silibinin as a potential therapeutic for sulfur mustard injuries.

    PubMed

    Balszuweit, Frank; John, Harald; Schmidt, Annette; Kehe, Kai; Thiermann, Horst; Steinritz, Dirk

    2013-12-01

    Sulfur mustard (SM) is a vesicating chemical warfare agent causing skin blistering, ulceration, impaired wound healing, prolonged hospitalization and permanent lesions. Silibinin, the lead compound from Silybum marianum, has also been discussed as a potential antidote to SM poisoning. However, its efficacy has been demonstrated only with regard to nitrogen mustards. Moreover, there are no data on the efficacy of the water-soluble prodrug silibinin-bis-succinat (silibinin-BS). We investigated the effect of SIL-BS treatment against SM toxicity in HaCaT cells with regard to potential reduction of necrosis, apoptosis and inflammation including dose-dependency of any protective effects. We also demonstrated the biotransformation of the prodrug into free silibinin. HaCaT cells were exposed to SM (30, 100, and 300μM) for 30min and treated thereafter with SIL-BS (10, 50, and 100μM) for 24h. Necrosis and apoptosis were quantified using the ToxiLight BioAssay and the nucleosome ELISA (CDDE). Pro-inflammatory interleukins-6 and -8 were determined by ELISA. HaCaT cells, incubated with silibinin-BS were lysed and investigated by LC-ESI MS/MS. LC-ESI MS/MS results suggest that SIL-BS is absorbed by HaCaT cells and biotransformed into free silibinin. SIL-BS dose-dependently reduced SM cytotoxicity, even after 300μM exposure. Doses of 50-100μM silibinin-BS were required for significant protection. Apoptosis and interleukin production remained largely unchanged by 10-50μM silibinin-BS but increased after 100μM treatment. Observed reductions of SM cytotoxicity by post-exposure treatment with SIL-BS suggest this as a promising approach for treatment of SM injuries. While 100μM SIL-BS is most effective to reduce necrosis, 50μM may be safer to avoid pro-inflammatory effects. Pro-apoptotic effects after high doses of SIL-BS are in agreement with findings in literature and might even be useful to eliminate cells irreversibly damaged by SM. Further investigations will focus on the

  1. Tissue factor pathway inhibitor prevents airway obstruction, respiratory failure and death due to sulfur mustard analog inhalation

    PubMed Central

    Rancourt, Raymond C.; Veress, Livia A.; Ahmad, Aftab; Hendry-Hofer, Tara B.; Rioux, Jacqueline S.; Garlick, Rhonda B.; White, Carl W.

    2013-01-01

    Sulfur mustard (SM) inhalation causes airway injury, with enhanced vascular permeability, coagulation, and airway obstruction. The objective of this study was to determine whether recombinant tissue factor pathway inhibitor (TFPI) could inhibit this pathogenic sequence. Methods Rats were exposed to the SM analog 2-chloroethyl ethyl sulfide (CEES) via nose-only aerosol inhalation. One hour later, TFPI (1.5 mg/kg) in vehicle, or vehicle alone, were instilled into the trachea. Arterial O2 saturation was monitored using pulse oximetry. Twelve hours after exposure, animals were euthanized and bronchoalveolar lavage fluid (BALF) and plasma analyzed for prothrombin, thrombin-antithrombin complex (TAT), active plasminogen activator inhibitor-1 (PAI-1) levels, and fluid fibrinolytic capacity. Lung steady-state PAI-1 mRNA was measured by RT-PCR analysis. Airway-capillary leak was estimated by BALF protein and IgM, and by pleural fluid measurement. In additional animals, airway cast formation was assessed by microdissection and immunohistochemical detection of airway fibrin. Results Airway obstruction in the form of fibrin-containing casts were evident in central conducting airways of rats receiving CEES. TFPI decreased cast formation, and limited severe hypoxemia. Findings of reduced prothrombin consumption, and lower TAT complexes in BALF, demonstrated that TFPI acted to limit thrombin activation in airways. TFPI, however, did not appreciably affect CEES-induced airway protein leak, PAI-1 mRNA induction, or inhibition of the fibrinolytic activity present in airway surface liquid. Conclusions Intratracheal administration of TFPI limits airway obstruction, improves gas exchange, and prevents mortality in rats with sulfur mustard-analog-induced acute lung injury. PMID:23727623

  2. Inflammatory effects of inhaled sulfur mustard in rat lung

    SciTech Connect

    Malaviya, Rama; Sunil, Vasanthi R.; Cervelli, Jessica; Anderson, Dana R.; Holmes, Wesley W.; Conti, Michele L.; Gordon, Ronald E.; Laskin, Jeffrey D.; Laskin, Debra L.

    2010-10-15

    Inhalation of sulfur mustard (SM), a bifunctional alkylating agent that causes severe lung damage, is a significant threat to both military and civilian populations. The mechanisms mediating its cytotoxic effects are unknown and were investigated in the present studies. Male rats Crl:CD(SD) were anesthetized, and then intratracheally intubated and exposed to 0.7-1.4 mg/kg SM by vapor inhalation. Animals were euthanized 6, 24, 48 h or 7 days post-exposure and bronchoalveolar lavage fluid (BAL) and lung tissue collected. Exposure of rats to SM resulted in rapid pulmonary toxicity, including focal ulceration and detachment of the trachea and bronchial epithelia from underlying mucosa, thickening of alveolar septal walls and increased numbers of inflammatory cells in the tissue. There was also evidence of autophagy and apoptosis in the tissue. This was correlated with increased BAL protein content, a marker of injury to the alveolar epithelial lining. SM exposure also resulted in increased expression of markers of inflammation including cyclooxygenase-2 (COX-2), tumor necrosis factor-{alpha} (TNF{alpha}), inducible nitric oxide synthase (iNOS), and matrix metalloproteinase-9 (MMP-9), each of which has been implicated in pulmonary toxicity. Whereas COX-2, TNF{alpha} and iNOS were mainly localized in alveolar regions, MMP-9 was prominent in bronchial epithelium. In contrast, expression of the anti-oxidant hemeoxygenase, and the anti-inflammatory collectin, surfactant protein-D, decreased in the lung after SM exposure. These data demonstrate that SM-induced oxidative stress and injury are associated with the generation of cytotoxic inflammatory proteins which may contribute to the pathogenic response to this vesicant.

  3. Historical perspective on effects and treatment of sulfur mustard injuries.

    PubMed

    Graham, John S; Schoneboom, Bruce A

    2013-12-01

    Sulfur mustard (2,2'-dichlorodiethyl sulfide; SM) is a potent vesicating chemical warfare agent that poses a continuing threat to both military and civilian populations. Significant SM injuries can take several months to heal, necessitate lengthy hospitalizations, and result in long-term complications affecting the skin, eyes, and lungs. This report summarizes initial and ongoing (chronic) clinical findings from SM casualties from the Iran-Iraq War (1980-1988), with an emphasis on cutaneous injury. In addition, we describe the cutaneous manifestations and treatment of several men recently and accidentally exposed to SM in the United States. Common, chronic cutaneous problems being reported in the Iranian casualties include pruritis (the primary complaint), burning, pain, redness, desquamation, hyperpigmentation, hypopigmentation, erythematous papular rash, xerosis, multiple cherry angiomas, atrophy, dermal scarring, hypertrophy, and sensitivity to mechanical injury with recurrent blistering and ulceration. Chronic ocular problems include keratitis, photophobia, persistent tearing, sensation of foreign body, corneal thinning and ulceration, vasculitis of the cornea and conjunctiva, and limbal stem cell deficiency. Chronic pulmonary problems include decreases in lung function, bronchitis with hyper-reactive airways, bronchiolitis, bronchiectasis, stenosis of the trachea and other large airways, emphysema, pulmonary fibrosis, decreased total lung capacity, and increased incidences of lung cancer, pulmonary infections, and tuberculosis. There are currently no standardized or optimized methods of casualty management; current treatment strategy consists of symptomatic management and is designed to relieve symptoms, prevent infections, and promote healing. New strategies are needed to provide for optimal and rapid healing, with the goals of (a) returning damaged tissue to optimal appearance and normal function in the shortest period of time, and (b) ameliorating chronic

  4. Noninvasive methods for determining lesion depth from vesicant exposure.

    PubMed

    Braue, Ernest H; Graham, John S; Doxzon, Bryce F; Hanssen, Kelly A; Lumpkin, Horace L; Stevenson, Robert S; Deckert, Robin R; Dalal, Stephen J; Mitcheltree, Larry W

    2007-01-01

    Before sulfur mustard (HD) injuries can be effectively treated, assessment of lesion depth must occur. Accurate depth assessment is important because it dictates how aggressive treatment needs to be to minimize or prevent cosmetic and functional deficits. Depth of injury typically is assessed by physical examination. Diagnosing very superficial and very deep lesions is relatively easy for the experienced burn surgeon. Lesions of intermediate depth, however, are often problematic in determining the need for grafting. This study was a preliminary evaluation of two noninvasive bioengineering methodologies, laser Doppler perfusion imaging (LDPI) and indocyanine green fluorescence imaging (ICGFI), to determine their ability to accurately diagnose depth of sulfur mustard lesions in a weanling swine model. Histological evaluation was used to assess the accuracy of the imaging techniques in determining burn depth. Six female weanling swine (8-12 kg) were exposed to 400 microl of neat sulfur mustard on six ventral sites for 2, 8, 30, or 60 minutes. This exposure regimen produced lesions of varying depths from superficial to deep dermal. Evaluations of lesion depth using the bioengineering techniques were conducted at 24, 48, and 72 hours after exposure. After euthanasia at 72 hours after exposure, skin biopsies were taken from each site and processed for routine hematoxylin and eosin histological evaluation to determine the true depth of the lesion. Results demonstrated that LDPI and ICGFI were useful tools to characterize skin perfusion and provided a good estimate of HD lesion depth. Traditional LDPI and the novel prototype ICGFI instrumentation used in this study produced images of blood flow through skin lesions, which provided a useful assessment of burn depth. LDPI and ICGFI accurately predicted the need for aggressive treatment (30- and 60-minute HD lesions) and nonaggressive treatment (2- and 8-minute HD lesions) for the lesions generated in this study. Histological

  5. Activation of DNA damage repair pathways in response to nitrogen mustard-induced DNA damage and toxicity in skin keratinocytes.

    PubMed

    Inturi, Swetha; Tewari-Singh, Neera; Agarwal, Chapla; White, Carl W; Agarwal, Rajesh

    2014-01-01

    Nitrogen mustard (NM), a structural analog of chemical warfare agent sulfur mustard (SM), forms adducts and crosslinks with DNA, RNA and proteins. Here we studied the mechanism of NM-induced skin toxicity in response to double strand breaks (DSBs) resulting in cell cycle arrest to facilitate DNA repair, as a model for developing countermeasures against vesicant-induced skin injuries. NM exposure of mouse epidermal JB6 cells decreased cell growth and caused S-phase arrest. Consistent with these biological outcomes, NM exposure also increased comet tail extent moment and the levels of DNA DSB repair molecules phospho H2A.X Ser139 and p53 Ser15 indicating NM-induced DNA DSBs. Since DNA DSB repair occurs via non homologous end joining pathway (NHEJ) or homologous recombination repair (HRR) pathways, next we studied these two pathways and noted their activation as defined by an increase in phospho- and total DNA-PK levels, and the formation of Rad51 foci, respectively. To further analyze the role of these pathways in the cellular response to NM-induced cytotoxicity, NHEJ and HRR were inhibited by DNA-PK inhibitor NU7026 and Rad51 inhibitor BO2, respectively. Inhibition of NHEJ did not sensitize cells to NM-induced decrease in cell growth and cell cycle arrest. However, inhibition of the HRR pathway caused a significant increase in cell death, and prolonged G2M arrest following NM exposure. Together, our findings, indicating that HRR is the key pathway involved in the repair of NM-induced DNA DSBs, could be useful in developing new therapeutic strategies against vesicant-induced skin injury. PMID:24732344

  6. Activation of DNA damage repair pathways in response to nitrogen mustard-induced DNA damage and toxicity in skin keratinocytes

    PubMed Central

    Inturi, Swetha; Tewari-Singh, Neera; Agarwal, Chapla; White, Carl W.; Agarwal, Rajesh

    2014-01-01

    Nitrogen mustard (NM), a structural analog of chemical warfare agent sulfur mustard (SM), forms adducts and crosslinks with DNA, RNA and proteins. Here we studied the mechanism of NM-induced skin toxicity in response to double strand breaks (DSBs) resulting in cell cycle arrest to facilitate DNA repair, as a model for developing countermeasures against vesicant-induced skin injuries. NM exposure of mouse epidermal JB6 cells decreased cell growth and caused S-phase arrest. Consistent with these biological outcomes, NM exposure also increased comet tail extent moment and the levels of DNA DSB repair molecules phospho H2A.X Ser139 and p53 Ser15 indicating NM-induced DNA DSBs. Since DNA DSB repair occurs via non homologous end joining pathway (NHEJ) or homologous recombination repair (HRR) pathways, next we studied these two pathways and noted their activation as defined by an increase in phospho- and total DNA-PK levels, and the formation of Rad51 foci, respectively. To further analyze the role of these pathways in the cellular response to NM-induced cytotoxicity, NHEJ and HRR were inhibited by DNA-PK inhibitor NU7026 and Rad51 inhibitor BO2, respectively. Inhibition of NHEJ did not sensitize cells to NM-induced decrease in cell growth and cell cycle arrest. However, inhibition of the HRR pathway caused a significant increase in cell death, and prolonged G2M arrest following NM exposure. Together, our findings, indicating that HRR is the key pathway involved in the repair of NM-induced DNA DSBs, could be useful in developing new therapeutic strategies against vesicant-induced skin injury. PMID:24732344

  7. Nrf2 Regulates the Sensitivity of Mouse Keratinocytes to Nitrogen Mustard via Multidrug Resistance-Associated Protein 1 (Mrp1).

    PubMed

    Udasin, Ronald G; Wen, Xia; Bircsak, Kristin M; Aleksunes, Lauren M; Shakarjian, Michael P; Kong, Ah-Ng Tony; Heck, Diane E; Laskin, Debra L; Laskin, Jeffrey D

    2016-01-01

    Sulfur mustard and nitrogen mustard (mechlorethamine, HN2) are potent vesicants developed as chemical warfare agents. These electrophilic, bifunctional alkylating agents cause skin injury, including inflammation, edema, and blistering. HN2 covalently modifies macromolecules such as DNA, RNA, and proteins or is scavenged by glutathione, forming adducts that can contribute to toxicity. Multidrug resistance-associated protein 1 (Mrp1/MRP1) is a transmembrane ATPase known to efflux glutathione-conjugated electrophiles. In the present studies, we examined the effects of modulating Mrp1-mediated transport activity on the sensitivity of primary and PAM212 mouse keratinocytes to HN2. Primary keratinocytes, and to a lesser extent, PAM212 cells, express Mrp1 mRNA and protein and possess Mrp1 functional activity, as measured by calcein efflux. Sulforaphane, an activator of Nrf2, increased Mrp1 mRNA, protein, and functional activity in primary keratinocytes and PAM212 cells and decreased their sensitivity to HN2-induced growth inhibition (IC(50) = 1.4 and 4.8 µM in primary keratinocytes and 1 and 13 µM in PAM212 cells, in the absence and presence of sulforaphane, respectively). The Mrp1 inhibitor, MK-571, reversed the effects of sulforaphane on HN2-induced growth inhibition in both primary keratinocytes and PAM212 cells. In primary keratinocytes from Nrf2(-/-) mice, sulforaphane had no impact on Mrp1 expression or activity, or on sensitivity to HN2, demonstrating that its effects depend on Nrf2. These data suggest that Mrp1-mediated efflux is important in regulating HN2-induced keratinocyte growth inhibition. Enhancing HN2 efflux from keratinocytes may represent a novel strategy for mitigating vesicant-induced cytotoxicity. PMID:26454883

  8. Pretreatment of primary rat cutaneous epidermal keratinocyte culture with a low concentration of MNNG: Effect on DNA cross-linking measured in situ after challenge with bis-2-chloroethyl sulfide

    SciTech Connect

    Sorsher, D.H.; Conolly, R.B. )

    1989-01-01

    Bis-2-chloroethyl sulfide- (BCES-) induced DNA cross-links in confluent, primary cultures of newborn rat cutaneous epidermal keratinocytes were detected using an assay that includes in situ unwinding of the DNA followed by separation of single-stranded DNA and double-stranded DNA (DSDNA) with hydroxylapatite. DNA cross-links in BCES-challenged cultures were inferred form increases in the percentage of DNA the remained double-stranded, compared with control cultures, after a 60-min alkaline unwinding incubation. The amount of DNA cross-linking after 5 or 10 {mu}M BCES was increased when keratinocytes were first pretreated with 0.05 {mu}M MNNG for 1 h at 8 a.m., 2 p.m., and 8 p.m. for two consecutive days and challenged with BCES the following morning. This increase was statistically significant. For example, after 5{mu}M BCES challenge, cultures not pretreated with MNNG had 114.14% control DSDNA, whereas MNNG pretreated cultures had 122.78% control DSDNA. The level of BCES-induced cross-linking was maximal immediately after 30-min challenge and decreased during postchallenge incubation. At 24 and 48 h post 5, 10, or 20 {mu}M BCES challenge, the level of DSDNA was actually depressed below unchallenged levels. This postchallenge decreased in the level of DSDNA, indicative of SSB in DNA, suggests repair activity by glycosylases and endonucleases. However completion of repair (i.e., a return to control levels of DSDNA) was not seen in these experiments. The activity that resulted in decreases in the level of DSDNA during postchallenge incubation response was unaffected by MNNG pretreatment.

  9. Airway Tissue Plasminogen Activator Prevents Acute Mortality Due to Lethal Sulfur Mustard Inhalation

    PubMed Central

    Veress, Livia A.; Anderson, Dana R.; Hendry-Hofer, Tara B.; Houin, Paul R.; Rioux, Jacqueline S.; Garlick, Rhonda B.; Loader, Joan E.; Paradiso, Danielle C.; Smith, Russell W.; Rancourt, Raymond C.; Holmes, Wesley W.; White, Carl W.

    2015-01-01

    Rationale: Sulfur mustard (SM) is a chemical weapon stockpiled today in volatile regions of the world. SM inhalation causes a life-threatening airway injury characterized by airway obstruction from fibrin casts, which can lead to respiratory failure and death. Mortality in those requiring intubation is more than 80%. No therapy exists to prevent mortality after SM exposure. Our previous work using the less toxic analog of SM, 2-chloroethyl ethyl sulfide, identified tissue plasminogen activator (tPA) an effective rescue therapy for airway cast obstruction (Veress, L. A., Hendry-Hofer, T. B., Loader, J. E., Rioux, J. S., Garlick, R. B., and White, C. W. (2013). Tissue plasminogen activator prevents mortality from sulfur mustard analog-induced airway obstruction. Am. J. Respir. Cell Mol. Biol. 48, 439–447). It is not known if exposure to neat SM vapor, the primary agent used in chemical warfare, will also cause death due to airway casts, and if tPA could be used to improve outcome. Methods: Adult rats were exposed to SM, and when oxygen saturation reached less than 85% (median: 6.5 h), intratracheal tPA or placebo was given under isoflurane anesthesia every 4 h for 48 h. Oxygen saturation, clinical distress, and arterial blood gases were assessed. Microdissection was done to assess airway obstruction by casts. Results: Intratracheal tPA treatment eliminated mortality (0% at 48 h) and greatly improved morbidity after lethal SM inhalation (100% death in controls). tPA normalized SM-associated hypoxemia, hypercarbia, and lactic acidosis, and improved respiratory distress. Moreover, tPA treatment resulted in greatly diminished airway casts, preventing respiratory failure from airway obstruction. Conclusions: tPA given via airway more than 6 h after exposure prevented death from lethal SM inhalation, and normalized oxygenation and ventilation defects, thereby rescuing from respiratory distress and failure. Intra-airway tPA should be considered as a life

  10. Sulfur mustard induced nuclear translocation of glyceraldehyde-3-phosphate-dehydrogenase (GAPDH).

    PubMed

    Steinritz, Dirk; Weber, Jana; Balszuweit, Frank; Thiermann, Horst; Schmidt, Annette

    2013-12-01

    Sulfur Mustard (SM) is a vesicant chemical warfare agent, which is acutely toxic to a variety of organ systems including skin, eyes, respiratory system and bone marrow. The underlying molecular pathomechanism was mainly attributed to the alkylating properties of SM. However, recent studies have revealed that cellular responses to SM exposure are of more complex nature and include increased protein expression and protein modifications that can be used as biomarkers. In order to confirm already known biomarkers, to detect potential new ones and to further elucidate the pathomechanism of SM, we conducted large-scale proteomic experiments based on a human keratinocyte cell line (HaCaT) exposed to SM. Surprisingly, our analysis identified glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) as one of the up-regulated proteins after exposure of HaCaT cells to SM. In this paper we demonstrate the sulfur mustard induced nuclear translocation of GAPDH in HaCaT cells by 2D gel-electrophoresis (2D GE), immunocytochemistry (ICC), Western Blot (WB) and a combination thereof. 2D GE in combination with MALDI-TOF MS/MS analysis identified GAPDH as an up-regulated protein after SM exposure. Immunocytochemistry revealed a distinct nuclear translocation of GAPDH after exposure to 300μM SM. This finding was confirmed by fractionated WB analysis. 2D GE and subsequent immunoblot staining of GAPDH demonstrated two different spot locations of GAPH (pI 7.0 and pI 8.5) that are related to cytosolic or nuclear GAPDH respectively. After exposure to 300μM SM a significant increase of nuclear GAPDH at pI 8.5 occurred. Nuclear GAPDH has been associated with apoptosis, detection of structural DNA alterations, DNA repair and regulation of genomic integrity and telomere structure. The results of our study add new aspects to the pathophysiology of sulfur mustard toxicity, yet further studies will be necessary to reveal the specific function of nuclear GAPDH in the pathomechanism of sulfur mustard

  11. Natural occurrence of bisphenol F in mustard

    PubMed Central

    Zoller, Otmar; Brüschweiler, Beat J.; Magnin, Roxane; Reinhard, Hans; Rhyn, Peter; Rupp, Heinz; Zeltner, Silvia; Felleisen, Richard

    2016-01-01

    ABSTRACT Bisphenol F (BPF) was found in mustard up to a concentration of around 8 mg kg−1. Contamination of the raw products or caused by the packaging could be ruled out. Also, the fact that only the 4,4ʹ-isomer of BPF was detected spoke against contamination from epoxy resin or other sources where technical BPF is used. Only mild mustard made of the seeds of Sinapis alba contained BPF. In all probability BPF is a reaction product from the breakdown of the glucosinolate glucosinalbin with 4-hydroxybenzyl alcohol as an important intermediate. Hot mustard made only from brown mustard seeds (Brassica juncea) or black mustard seeds (Brassica nigra) contained no BPF. BPF is structurally very similar to bisphenol A and has a similar weak estrogenic activity. The consumption of a portion of 20 g of mustard can lead to an intake of 100–200 µg of BPF. According to a preliminary risk assessment, the risk of BPF in mustard for the health of consumers is considered to be low, but available toxicological data are insufficient for a conclusive evaluation. It is a new and surprising finding that BPF is a natural food ingredient and that this is the main uptake route. This insight sheds new light on the risk linked to the family of bisphenols. PMID:26555822

  12. Natural occurrence of bisphenol F in mustard.

    PubMed

    Zoller, Otmar; Brüschweiler, Beat J; Magnin, Roxane; Reinhard, Hans; Rhyn, Peter; Rupp, Heinz; Zeltner, Silvia; Felleisen, Richard

    2016-01-01

    Bisphenol F (BPF) was found in mustard up to a concentration of around 8 mg kg(-1). Contamination of the raw products or caused by the packaging could be ruled out. Also, the fact that only the 4,4'-isomer of BPF was detected spoke against contamination from epoxy resin or other sources where technical BPF is used. Only mild mustard made of the seeds of Sinapis alba contained BPF. In all probability BPF is a reaction product from the breakdown of the glucosinolate glucosinalbin with 4-hydroxybenzyl alcohol as an important intermediate. Hot mustard made only from brown mustard seeds (Brassica juncea) or black mustard seeds (Brassica nigra) contained no BPF. BPF is structurally very similar to bisphenol A and has a similar weak estrogenic activity. The consumption of a portion of 20 g of mustard can lead to an intake of 100-200 µg of BPF. According to a preliminary risk assessment, the risk of BPF in mustard for the health of consumers is considered to be low, but available toxicological data are insufficient for a conclusive evaluation. It is a new and surprising finding that BPF is a natural food ingredient and that this is the main uptake route. This insight sheds new light on the risk linked to the family of bisphenols. PMID:26555822

  13. Hair analysis as a useful procedure for detection of vapour exposure to chemical warfare agents: simulation of sulphur mustard with methyl salicylate.

    PubMed

    Spiandore, Marie; Piram, Anne; Lacoste, Alexandre; Josse, Denis; Doumenq, Pierre

    2014-06-01

    Chemical warfare agents (CWA) are highly toxic compounds which have been produced to kill or hurt people during conflicts or terrorist attacks. Despite the fact that their use is strictly prohibited according to international convention, populations' exposure still recently occurred. Development of markers of exposure to CWA is necessary to distinguish exposed victims from unexposed ones. We present the first study of hair usage as passive sampler to assess contamination by chemicals in vapour form. This work presents more particularly the hair adsorption capacity for methyl salicylate used as a surrogate of the vesicant sulphur mustard. Chemical vapours toxicity through the respiratory route has historically been defined through Haber's law's concentration-time (Ct) product, and vapour exposure of hair to methyl salicylate was conducted with various times or doses of exposure in the range of incapacitating and lethal Ct products corresponding to sulphur mustard. Following exposure, extraction of methyl salicylate from hair was conducted by simple soaking in dichloromethane. Methyl salicylate could be detected on hair for vapour concentration corresponding to about one fifth of the sulphur mustard concentration that would kill 50% of exposed individuals (LCt50). The amount of methyl salicylate recovered from hair increased with time or dose of exposure. It showed a good correlation with the concentration-time product, suggesting that hair could be used like a passive sampler to assess vapour exposure to chemical compounds. It introduces great perspectives concerning the use of hair as a marker of exposure to CWA. PMID:24817050

  14. Acute and chronic effects of sulfur mustard on the skin: a comprehensive review.

    PubMed

    Ghanei, Mostafa; Poursaleh, Zohreh; Harandi, Ali Amini; Emadi, Seyed Emad; Emadi, Seyed Naser

    2010-12-01

    Sulfur mustard (2,2-dichlorodiethyl sulfide, SM) is one of the vesicant classes of chemical warfare agents that causes blistering in the skin and mucous membranes, where it can have lingering long-term effects for up to ten years (1). SM was employed extensively by the Iraqi army against not only Iranian soldiers but also civilians between 1983 and 1988, resulting in over 100,000 chemical casualties. Approximately 45,000 victims are still suffering from long-term effects of exposure (2,3). More than 90% of the patients exposed to SM exhibit various cutaneous lesions in the affected area. The human skin can absorb approximately 20% of the SM through exposure. Up to 70% of the chemical is concentrated in the epidermis and the remainder in the basement membrane and in the dermis (4).Sulfur mustard exists in different physical states. The liquid form of SM evaporates slowly in cold weather and can penetrate through the clothing, thereby increasing exposure. However, the gas form readily diffuses in the air and it can be inhaled, leading to systemic absorption. In addition, warm temperatures are ideal conditions that liquid SM present in the clothing of the exposed individual could be converted to gas form. SM-induced clinical cutaneous symptoms include itching and burning. Other clinical findings include erythema or painless sunburn, bulla, hypo- and hyper pigmentation in both exposed and unexposed areas (5,6) The mechanism and biochemical cascade of SM-induced cutaneous manifestations are not completely understood but several published pathways support many of the know facts. Our current understanding fails to explain the time interval between the acute chemical exposure and the late-onset and delayed tissue damage (7,8). The aim of this article is to review the acute and long-term cutaneous findings resulting from SM exposure. Also, cellular and molecular mechanism involved in SM-induced skin pathology have been discussed. PMID:20868209

  15. Neutralization and biodegradation of sulfur mustard

    SciTech Connect

    Harvey, S.P.; Beaudry, W.T.; Szafraniec, L.L.

    1995-12-31

    One technology recommended for consideration for the disposal of the U.S. Chemical Stockpile is chemical neutralization followed by biodegradation. In the case of sulfur mustard ({open_quotes}mustard gas{close_quotes}, 2,2{prime}-dichlorodiethyl sulfide), alkaline hydrolysis yields a detoxified and biodegradable product. The hydrolysis reaction was studied with respect to the effects of temperature and sulfur mustard concentration on the rate and products of the reaction. A 28-fold overall rate enhancement was observed at 70{degrees}C vs. 30{degrees}C corresponding to an enthalpy of activation value of 17.9 Kcal/mole. Material balance studies conducted by {sup 1}H Nuclear Magnetic Resonance analysis showed that the products of the reaction consisted of thiodiglycol was relatively greater at lower sulfur mustard concentrations and higher temperatures. As temperatures were decreased or sulfur mustard concentrations was increased, the proportion of ether-type compounds increased accordingly. Conditions of 1% (vol//vol) sulfur mustard, 5% stoichiometric excess of NaOH and 90{degrees}C were selected for generation of the hydrolyzed bioreactor influent material. The bioreactor was seeded with activated sludge and was initially operated as 5 liter sequencing batch reactor with a hydraulic residence time of approximately days. Early results show total organic carbon removal of greater than 90%.

  16. Checkpoint kinase 1 is activated and promotes cell survival after exposure to sulphur mustard.

    PubMed

    Jowsey, Paul A; Blain, Peter G

    2015-01-22

    Sulphur mustard (SM) is a vesicating agent that has been used several times as a weapon during military conflict and continues to pose a threat as an agent of warfare/terrorism. After exposure, SM exerts both acute and delayed long-term toxic effects principally to the skin, eyes and respiratory system. These effects are thought to be mediated, at least in part, by direct interaction of SM with DNA, forming a myriad of DNA lesions and initiating effects on cell cycle and cell death pathways. Previous studies have demonstrated that a complex network of cellular DNA damage response pathways are utilised in cells exposed to SM, consistent with SM causing multiple forms of DNA damage. The present study focused on the role of Checkpoint kinase 1 (CHK1), a protein with putative roles in homologous recombination repair, p53 activation and the initiation of cell cycle checkpoints after certain forms of DNA damage. The data showed that SM caused robust activation of CHK1, monitored by multi-site phosphorylation analysis and that this activation was dependent on the ataxia telangiectasia and Rad3-related (ATR) protein kinase. Furthermore, specific inhibition of CHK1 increased SM toxicity in multiple human cell lines, with concomitant increases in markers of apoptosis, DNA damage and mitosis. Finally, the effect of CHK1 inhibition on SM toxicity was much more marked in cells with non-functional p53. PMID:25448276

  17. Sulfur Mustard Research—Strategies for the Development of Improved Medical Therapy

    PubMed Central

    Kehe, Kai; Balszuweit, Frank; Emmler, Judith; Kreppel, Helmut; Jochum, Marianne; Thiermann, Horst

    2008-01-01

    Objective: Sulfur mustard (SM) is a bifunctional alkylating substance being used as chemical warfare agent (vesicant). It is still regarded as a significant threat in chemical warfare and terrorism. Exposure to SM produces cutaneous blisters, respiratory and gastrointestinal tract injury, eye lesions, and bone marrow depression. Victims of World War I as well as those of the Iran-Iraq war have suffered from devastating chronic health impairment. Even decades after exposure, severe long-term effects like chronic obstructive lung disease, lung fibrosis, recurrent corneal ulcer disease, chronic conjunctivitis, abnormal pigmentation of the skin, and different forms of cancer have been diagnosed. Methods: This review briefly summarizes the scientific literature and own results concerning detection, organ toxicity of SM, its proposed toxicodynamic actions, and strategies for the development of improved medical therapy. Results: Despite extensive research efforts during the last century, efficient antidotes against SM have not yet been generated because its mechanism of action is not fully understood. However, deeper insights into these mechanisms gained in the last decade and promising developments of new drugs now offer new chances to minimize SM-induced organ damage and late effects. Conclusion: Polymerase inhibitors, anti-inflammatory drugs, antioxidants, matrix metalloproteinase inhibitors, and probably regulators of DNA damage repair are identified as promising approaches to improve treatment. PMID:18615149

  18. Activation of poly(ADP-ribose) polymerase by sulfur mustard in HeLa cell cultures

    SciTech Connect

    Clark, O.E.; Smith, W.J.

    1993-05-13

    Poly(ADP-ribose) polymerase (PADPRP) E.C.2.4.2.30 has been proposed to play a key role in the NAD+ depletion following alkylation of DNA in sulfur mustard (HD) exposures. Papirmeister et al. (Fundam Appl Toxicol 5:Sl34, 1985) hypothesized that activation of PADPRP was central to the subsequent depletion of NAD+ and activation of proteolytic enzymes leading to vesication. NAD+ depletion following HD exposure has been previously documented and the results have been used to infer the effect of HD exposure on PADPRP. The present study was undertaken to demonstrate the direct effect of HD on PADPRP activity. HeLa cells culture were used as the model system. At 10 microns HD PADPRP activity was increased above the levels of controls in the first hour. The activity peaked at 4 hrs and by 6 hrs had returned to control levels. The 24-hour level of PADPRP activity was again elevated above the controls. The 100 microns HD exposures had maximal enzymatic response in HeLa cells within the first hour. The level had decreased 40% from the maximum by the second hour reaching a plateau at 30% of the maximum response after 4 hrs. Cells exposed to 100 microns HD showed enzyme levels at or below those seen with the 10 microns dose after 24 hours. The doses of HD used did not decrease viability as measured by trypan blue dye exclusion within 24 hr.

  19. Skin decontamination of mustards and organophosphates: comparative efficiency of RSDL and Fuller's earth in domestic swine.

    PubMed

    Taysse, L; Daulon, S; Delamanche, S; Bellier, B; Breton, P

    2007-02-01

    Research in skin decontamination and therapy of chemical warfare agents has been a difficult problem due to the simultaneous requirement of rapid action and non-aggressive behaviour. The aim of this study was to compare the performance of two decontaminating systems: the Canadian Reactive Skin Decontaminant Lotion (RSDL) and the Fuller's Earth (FE). The experiment was conducted with domestic swine, as a good model for extrapolation to human skin. RSDL and FE were tested against sulphur mustard (SM), a powerful vesicant, and VX, a potent and persistent cholinesterase inhibitor. When used 5 min after contamination, the results clearly showed that both systems were active against SM (10.1 mg/cm(2)) and VX (0.06 mg/cm(2)). The potency of the RSDL/sponge was statistically better than FE against skin injury induced by SM, observed 3 days post-exposure. RSDL was rather more efficient than FE in reducing the formation of perinuclear vacuoles and inflammation processes in the epidermis and dermis. Against a severe inhibition (67%) of plasmatic cholinesterases induced by VX poisoning, the potencies of the RSDL/sponge and FE were similar. Both systems completely prevented cholinesterase inhibition, which indirectly indicates a prevention of toxic absorption through the skin. PMID:17370872

  20. Quenching action of monofunctional sulfur mustard on chlorophyll fluorescence: towards an ultrasensitive biosensor.

    PubMed

    Kaur, Simerjit; Singh, Minni; Flora, Swaran Jeet Singh

    2013-11-01

    An ultrasensitive fluorimetric biosensor for the detection of chemical warfare agent sulfur mustard (SM) was developed using its monofunctional analogue. SM is a vesicant and a potent chemical threat owing to its direct toxic effects on eyes, lungs, skin and DNA. This work investigates the quenching action of the analyte on chlorophyll fluorescence as elucidated by nuclear magnetic resonance, Fourier transform infrared spectroscopy and mass spectrometry studies suggesting the electrophilic attack of carbonium ion on nitrogens of the porphyrin moiety of chlorophyll. The properties of immobilisation matrix were optimised and scanning electron microscope observations confirmed improvement in pore size of sol-gels by addition of 32 % (v/v) glycerol, a feature enabling enhanced sensitivity towards the analyte. Chlorophyll embedded sol-gel was treated with increasing concentrations of monofunctional SM and the corresponding drop in maximum fluorescence intensity as measured by emission at 673 nm was observed, which varied linearly and had a detection limit of 7.68 × 10(-16) M. The biosensor was found to be 6 orders of magnitude more sensitive than the glass microfibre-based disc biosensor previously reported by us. PMID:23955347

  1. Early indicators of survival following exposure to mustard gas: Protective role of 25(OH)D.

    PubMed

    Das, Lopa M; Binko, Amy M; Traylor, Zachary P; Duesler, Lori R; Dynda, Scott M; Debanne, Sara; Lu, Kurt Q

    2016-04-25

    The use of sulfur mustard (SM) as a chemical weapon for warfare has once again assumed center stage, endangering civilian and the military safety. SM causes rapid local skin vesication and late-onset systemic toxicity. Most studies on SM rely on obtaining tissue and blood for characterizing burn pathogenesis and assessment of systemic pathology, respectively. However the present study focuses on developing a non-invasive method to predict mortality from high dose skin SM exposure. We demonstrate that exposure to SM leads to a dose dependent increase in wound area size on the dorsal surface of mice that is accompanied by a progressive loss in body weight loss, blood cytopenia, bone marrow destruction, and death. Thus our model utilizes local skin destruction and systemic outcome measures as variables to predict mortality in a novel skin-based model of tissue injury. Based on our recent work using vitamin D (25(OH)D) as an intervention to treat toxicity from SM-related compounds, we explored the use of 25(OH)D in mitigating the toxic effects of SM. Here we show that 25(OH)D offers protection against SM and is the first known demonstration of an intervention that prevents SM-induced mortality. Furthermore, 25(OH)D represents a safe, novel, and readily translatable potential countermeasure following mass toxic exposure. PMID:26940683

  2. Thioredoxin Cross-Linking by Nitrogen Mustard in Lung Epithelial Cells: Formation of Multimeric Thioredoxin/Thioredoxin Reductase Complexes and Inhibition of Disulfide Reduction.

    PubMed

    Jan, Yi-Hua; Heck, Diane E; Casillas, Robert P; Laskin, Debra L; Laskin, Jeffrey D

    2015-11-16

    The thioredoxin (Trx) system, which consists of Trx and thioredoxin reductase (TrxR), is a major cellular disulfide reduction system important in antioxidant defense. TrxR is a target of mechlorethamine (methylbis(2-chloroethyl)amine; HN2), a bifunctional alkylating agent that covalently binds to selenocysteine/cysteine residues in the redox centers of the enzyme, leading to inactivation and toxicity. Mammalian Trx contains two catalytic cysteines; herein, we determined if HN2 also targets Trx. HN2 caused a time- and concentration-dependent inhibition of purified Trx and Trx in A549 lung epithelial cells. Three Trx cross-linked protein complexes were identified in both cytosolic and nuclear fractions of HN2-treated cells. LC-MS/MS of these complexes identified both Trx and TrxR, indicating that HN2 cross-linked TrxR and Trx. This is supported by our findings of a significant decrease of Trx/TrxR complexes in cytosolic TrxR knockdown cells after HN2 treatment. Using purified recombinant enzymes, the formation of protein cross-links and enzyme inhibition were found to be redox status-dependent; reduced Trx was more sensitive to HN2 inactivation than the oxidized enzyme, and Trx/TrxR cross-links were only observed using reduced enzyme. These data suggest that HN2 directly targets catalytic cysteine residues in Trx resulting in enzyme inactivation and protein complex formation. LC-MS/MS confirmed that HN2 directly alkylated cysteine residues on Trx, including Cys32 and Cys35 in the redox center of the enzyme. Inhibition of the Trx system by HN2 can disrupt cellular thiol-disulfide balance, contributing to vesicant-induced lung toxicity. PMID:26451472

  3. Determination and prevention of cytotoxic effects induced in human lymphocytes by the alkylating agent 2,2`-dichlorodiethyl sulfide (sulfur mustard, HD). (Reannouncement with new availability information)

    SciTech Connect

    Meier, H.L.; Johnson, J.B.

    1992-12-31

    2,2`-Dichlorodiethyl sulfide (sulfur mustard), HD, 1,1`thiobis(2-chloroethane) is a potent vesicant which can cause severe lesions to skin, lung, and eyes. There is no convenient in vitro or in vivo method(s) to objectively measure the damage induced by HD; therefore, a simple in vitro method was developed using human peripheral lymphocytes to study HD-induced cytotoxicity. The cytotoxicity of HD was measured using dye exclusion as an indicator of human lymphocyte viability. Exposure to HD resulted in both a time- and a concentration-dependent cytotoxic effect on human lymphocytes. Using this in vitro assay, the effectiveness of various therapeutics (niacin, niacinamide, and 3-aminobenzamide) in preventing HD-induced cytotoxicity was studied. Niacinamide and 3-aminobenzamide prevented the cytotoxic effects of HD for up to 2 days.

  4. Mustard Gas: Its Pre-World War I History

    ERIC Educational Resources Information Center

    Duchovic, Ronald J.; Vilensky, Joel A.

    2007-01-01

    The Meyer-Clarke synthetic method was used in the German process for large scale production of mustard gas during World War I, which clearly shows the historical connection of synthesis of mustard gas.

  5. Histopathological and immunohistochemical evaluation of nitrogen mustard-induced cutaneous effects in SKH-1 hairless and C57BL/6 mice.

    PubMed

    Jain, Anil K; Tewari-Singh, Neera; Inturi, Swetha; Orlicky, David J; White, Carl W; Agarwal, Rajesh

    2014-03-01

    Sulfur mustard (SM) is a vesicant warfare agent which causes severe skin injuries. Currently, we lack effective antidotes against SM-induced skin injuries, in part due to lack of appropriate animal model(s) that can be used for efficacy studies in laboratory settings to identify effective therapies. Therefore, to develop a relevant mouse skin injury model, we examined the effects of nitrogen mustard (NM), a primary vesicant and a bifunctional alkylating agent that induces toxic effects comparable to SM. Specifically, we conducted histopathological and immunohistochemical evaluation of several applicable cutaneous pathological lesions following skin NM (3.2mg) exposure for 12-120h in SKH-1 and C57BL/6 mice. NM caused a significant increase in epidermal thickness, incidence of microvesication, cell proliferation, apoptotic cell death, inflammatory cells (neutrophils, macrophages and mast cells) and myleoperoxidase activity in the skin of both mouse strains. However, there was a more prominent NM-induced increase in epidermal thickness, and macrophages and mast cell infiltration, in SKH-1 mice relative to what was seen in C57BL/6 mice. NM also caused collagen degradation and edema at early time points (12-24h); however, at later time points (72 and 120h), dense collagen staining was observed, indicating either water loss or start of integument repair in both the mouse strains. This study provides quantitative measurement of NM-induced histopathological and immunohistochemical cutaneous lesions in both hairless and haired mouse strains that could serve as useful tools for screening and identification of effective therapies for treatment of skin injuries due to NM and SM. PMID:24373750

  6. Sulfur mustard-induced increase in intracellular free calcium level and arachidonic acid release from cell membrane

    SciTech Connect

    Ray, R.; Legere, R.H.; Majerus, B.J.; Petrali, J.P.

    1995-12-31

    The mechanism of action of the alkylating agent bis-(2-chloroethyl)sulfide (sulfur mustard, SM) was studied using the in thai vitro mouse neuroblastoma-rat glioma hybrid NG 108-1 S clonal p cell line model. Following 0.3 mM SM exposure, cell viability remained high (>80% of untreated control) up to 9 hr and then declined steadily to about 40% of control after 20-24 hr. During the early period of SM exposure, when there was no significant cell viability loss, the following effects were observed. The cellular glutathione level decreased 20% after 1 hr and 34% after 6 hr. Between 2 and 6 hr, there was a time-dependent increase (about 10 to 30%) in intracellular free calcium (Ca2+), which was localized to the limiting membrane of swollen endoplasmic reticula and mitochondria, to euchromatin areas of the nucleus, and to areas of the cytosol and plasma membrane. Moreover,there was also a time-dependent increase in the release of isotopically labeled arachidonic acid ((3H)AA) from cellular membranes. Increase in (3H)AA release was 28% at 3 hr and about 60-80% between 6 and 9 hr. This increase in I3HIAA release was inhibited by quinacrine (20 uM), which is a phospholipase (PLA2) inhibitor. At 16 hr after SM exposure, there was a large increase (about 200% of control) in I3HIAA release, which was coincident with a 50% loss of cell viability. These results suggest a Ca2+-mediated toxic mechanism of SM via PLA2 activation and arachidonate release.

  7. Sulfur and nitrogen mustards induce characteristic poly(ADP-ribosyl)ation responses in HaCaT keratinocytes with distinctive cellular consequences.

    PubMed

    Mangerich, Aswin; Debiak, Malgorzata; Birtel, Matthias; Ponath, Viviane; Balszuweit, Frank; Lex, Kirsten; Martello, Rita; Burckhardt-Boer, Waltraud; Strobelt, Romano; Siegert, Markus; Thiermann, Horst; Steinritz, Dirk; Schmidt, Annette; Bürkle, Alexander

    2016-02-26

    Mustard agents are potent DNA alkylating agents with mutagenic, cytotoxic and vesicant properties. They include bi-functional agents, such as sulfur mustard (SM) or nitrogen mustard (mustine, HN2), as well as mono-functional agents, such as "half mustard" (CEES). Whereas SM has been used as a chemical warfare agent, several nitrogen mustard derivatives, such as chlorambucil and cyclophosphamide, are being used as established chemotherapeutics. Upon induction of specific forms of genotoxic stimuli, several poly(ADP-ribose) polymerases (PARPs) synthesize the nucleic acid-like biopolymer poly(ADP-ribose) (PAR) by using NAD(+) as a substrate. Previously, it was shown that SM triggers cellular poly(ADP-ribosyl) ation (PARylation), but so far this phenomenon is poorly characterized. In view of the protective effects of PARP inhibitors, the latter have been proposed as a treatment option of SM-exposed victims. In an accompanying article (Debiak et al., 2016), we have provided an optimized protocol for the analysis of the CEES-induced PARylation response in HaCaT keratinocytes, which forms an experimental basis to further analyze mustard-induced PARylation and its functional consequences, in general. Thus, in the present study, we performed a comprehensive characterization of the PARylation response in HaCaT cells after treatment with four different mustard agents, i.e., SM, CEES, HN2, and chlorambucil, on a qualitative, quantitative and functional level. In particular, we recorded substance-specific as well as dose- and time-dependent PARylation responses using independent bioanalytical methods based on single-cell immuno-fluorescence microscopy and quantitative isotope dilution mass spectrometry. Furthermore, we analyzed if and how PARylation contributes to mustard-induced toxicity by treating HaCaT cells with CEES, SM, and HN2 in combination with the clinically relevant PARP inhibitor ABT888. As evaluated by a novel immunofluorescence-based protocol for the detection of

  8. Sulfur mustard and respiratory diseases.

    PubMed

    Tang, Feng Ru; Loke, Weng Keong

    2012-09-01

    Victims exposed to sulfur mustard (HD) in World War I and Iran-Iraq war, and those suffered occupational or accidental exposure have endured discomfort in the respiratory system at early stages after exposure, and marked general physical deterioration at late stages due to pulmonary fibrosis, bronchiolitis obliterans or lung cancer. At molecule levels, significant changes of cytokines and chemokines in bronchoalveolar lavage and serum, and of selectins (in particular sE-selectin) and soluble Fas ligand in the serum have been reported in recent studies of patients exposed to HD in Iran-Iraq war, suggesting that these molecules may be associated with the pathophysiological development of pulmonary diseases. Experimental studies in rodents have revealed that reactive oxygen and nitrogen species, their product peroxynitrite (ONOO(-)), nitric oxide synthase, glutathione, poly (adenosine diphosphate-ribose) polymerase, activating protein-1 signaling pathway are promising drug targets for preventing HD-induced toxicity, whereas N-acetyl cysteine, tocopherols, melatonin, aprotinin and many other molecules have been proved to be effective in prevention of HD-induced damage to the respiratory system in different animal models. In this paper, we will systemically review clinical and pathophysiological changes of respiratory system in victims exposed to HD in the last century, update clinicians and researchers on the mechanism of HD-induced acute and chronic lung damages, and on the relevant drug targets for future development of antidotes for HD. Further research directions will also be proposed. PMID:22742653

  9. Protective role of spleen-derived macrophages in lung inflammation, injury, and fibrosis induced by nitrogen mustard.

    PubMed

    Venosa, Alessandro; Malaviya, Rama; Gow, Andrew J; Hall, Leroy; Laskin, Jeffrey D; Laskin, Debra L

    2015-12-15

    Nitrogen mustard (NM) is a vesicant that causes lung injury and fibrosis, accompanied by a persistent macrophage inflammatory response. In these studies we analyzed the spleen as a source of these cells. Splenectomized (SPX) and sham control rats were treated intratracheally with NM (0.125 mg/kg) or PBS control. Macrophage responses were analyzed 1-7 days later. Splenectomy resulted in an increase in lung macrophages expressing CCR2, but a decrease in ATR-1α(+) cells, receptors important in bone marrow and spleen monocyte trafficking, respectively. Splenectomy was also associated with an increase in proinflammatory M1 (iNOS(+), CD11b(+)CD43(+)) macrophages in lungs of NM-treated rats, as well as greater upregulation of iNOS and COX-2 mRNA expression. Conversely, a decrease in CD11b(+)CD43(-) M2 macrophages was observed in SPX rats, with no changes in CD68(+), CD163(+), CD206(+), or YM-1(+) M2 macrophages, suggesting distinct origins of M2 subpopulations responding to NM. Macrophage expression of M2 genes including IL-10, ApoE, PTX-2, PTX-3, 5-HT2α, and 5-HT7 was also reduced in NM-treated SPX rats compared with shams, indicating impaired M2 activity. Changes in lung macrophages responding to NM as a consequence of splenectomy were correlated with exacerbated tissue injury and more rapid fibrogenesis. These data demonstrate that the spleen is a source of a subset of M2 macrophages with anti-inflammatory activity; moreover, in their absence, proinflammatory/cytotoxic M1 macrophages predominate in the lung, resulting in heightened pathology. Understanding the origin of macrophages and characterizing their phenotype after vesicant exposure may lead to more targeted therapeutics aimed at reducing toxicity and disease pathogenesis. PMID:26475734

  10. MUSTARD GAS EXPOSURE AND CARCINOGENESIS OF LUNG

    PubMed Central

    Hosseini-khalili, Alireza; Haines, David D; Modirian, Ehsan; Soroush, Mohammadreza; Khateri, Shahriar; Joshi, Rashmi; Zendehdel, Kazem; Ghanei, Mostafa; Giardina, Charles

    2009-01-01

    Sulfur mustard (SM), also known as mustard gas, is an alkylating compound used as a chemical weapon in World War I and by Iraqi forces against Iranians and indigenous Iraqi Kurds during the Iran-Iraq War of the 1980s. Although SM is a proven carcinogen there are conflicting views regarding the carcinogenicity of a single exposure. The present study characterizes lung cancers formed in mustard gas victims from the Iran-Iraq War. Methods and Materials Demographic information and tumor specimens were collected from 20 Iranian male lung cancer patients with single high-dose SM exposures during the Iran-Iraq war. Formalin fixed, paraffin-embedded lung cancers were analyzed by immunohistochemistry for p53 protein. In addition, DNA was extracted from the tissues, PCR amplified and sequenced to identify mutations in the p53 and KRAS genes associated with SM exposure. Results A relatively early age of lung cancer onset (ranging from 28 to 73 with a mean of 48) in mustard gas victims, particularly those in the non-smoking population (mean age of 40.7), may be an indication of a unique etiology for these cancers. Seven of the 20 patients developed lung cancer before the age of 40. Five of 16 cancers from which DNA sequence data was obtainable provided information on eight p53 mutations (within exons 5–8). These mutations were predominately G to A transitions; a mutation consistent with the DNA lesion caused by SM. Two of the lung cancers had multiple p53 point mutations, similar to results obtained from factory workers chronically exposed to mustard agent. No mutations were detected in the KRAS gene. Discussion The distinguishing characteristics of lung carcinogenesis in these mustard gas victims suggest that a single exposure may increase the risk of lung cancer development in some individuals. PMID:19559099

  11. The sources, fate, and toxicity of chemical warfare agent degradation products.

    PubMed

    Munro, N B; Talmage, S S; Griffin, G D; Waters, L C; Watson, A P; King, J F; Hauschild, V

    1999-12-01

    We include in this review an assessment of the formation, environmental fate, and mammalian and ecotoxicity of CW agent degradation products relevant to environmental and occupational health. These parent CW agents include several vesicants: sulfur mustards [undistilled sulfur mustard (H), sulfur mustard (HD), and an HD/agent T mixture (HT)]; nitrogen mustards [ethylbis(2-chloroethyl)amine (HN1), methylbis(2-chloroethyl)amine (HN2), tris(2-chloroethyl)amine (HN3)], and Lewisite; four nerve agents (O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate (VX), tabun (GA), sarin (GB), and soman (GD)); and the blood agent cyanogen chloride. The degradation processes considered here include hydrolysis, microbial degradation, oxidation, and photolysis. We also briefly address decontamination but not combustion processes. Because CW agents are generally not considered very persistent, certain degradation products of significant persistence, even those that are not particularly toxic, may indicate previous CW agent presence or that degradation has occurred. Of those products for which there are data on both environmental fate and toxicity, only a few are both environmentally persistent and highly toxic. Major degradation products estimated to be of significant persistence (weeks to years) include thiodiglycol for HD; Lewisite oxide for Lewisite; and ethyl methyl phosphonic acid, methyl phosphonic acid, and possibly S-(2-diisopropylaminoethyl) methylphosphonothioic acid (EA 2192) for VX. Methyl phosphonic acid is also the ultimate hydrolysis product of both GB and GD. The GB product, isopropyl methylphosphonic acid, and a closely related contaminant of GB, diisopropyl methylphosphonate, are also persistent. Of all of these compounds, only Lewisite oxide and EA 2192 possess high mammalian toxicity. Unlike other CW agents, sulfur mustard agents (e.g., HD) are somewhat persistent; therefore, sites or conditions involving potential HD contamination should include an

  12. The sources, fate, and toxicity of chemical warfare agent degradation products.

    PubMed Central

    Munro, N B; Talmage, S S; Griffin, G D; Waters, L C; Watson, A P; King, J F; Hauschild, V

    1999-01-01

    We include in this review an assessment of the formation, environmental fate, and mammalian and ecotoxicity of CW agent degradation products relevant to environmental and occupational health. These parent CW agents include several vesicants: sulfur mustards [undistilled sulfur mustard (H), sulfur mustard (HD), and an HD/agent T mixture (HT)]; nitrogen mustards [ethylbis(2-chloroethyl)amine (HN1), methylbis(2-chloroethyl)amine (HN2), tris(2-chloroethyl)amine (HN3)], and Lewisite; four nerve agents (O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate (VX), tabun (GA), sarin (GB), and soman (GD)); and the blood agent cyanogen chloride. The degradation processes considered here include hydrolysis, microbial degradation, oxidation, and photolysis. We also briefly address decontamination but not combustion processes. Because CW agents are generally not considered very persistent, certain degradation products of significant persistence, even those that are not particularly toxic, may indicate previous CW agent presence or that degradation has occurred. Of those products for which there are data on both environmental fate and toxicity, only a few are both environmentally persistent and highly toxic. Major degradation products estimated to be of significant persistence (weeks to years) include thiodiglycol for HD; Lewisite oxide for Lewisite; and ethyl methyl phosphonic acid, methyl phosphonic acid, and possibly S-(2-diisopropylaminoethyl) methylphosphonothioic acid (EA 2192) for VX. Methyl phosphonic acid is also the ultimate hydrolysis product of both GB and GD. The GB product, isopropyl methylphosphonic acid, and a closely related contaminant of GB, diisopropyl methylphosphonate, are also persistent. Of all of these compounds, only Lewisite oxide and EA 2192 possess high mammalian toxicity. Unlike other CW agents, sulfur mustard agents (e.g., HD) are somewhat persistent; therefore, sites or conditions involving potential HD contamination should include an

  13. Mustard (Sinapis alba) Seed Meal Suppresses Weeds in Container Grown Ornamentals

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Mustard seed meal is a byproduct of mustard (Sinapis alba L.) grown and oil production. Developing new uses for mustard seed meal could increase the profitability of growing mustard. Seed meal of mustard, var. ‘IdaGold’ was applied to the soil surface to evaluate its effect on several common weeds...

  14. Mustard meal as an organic herbicide

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Mustard meal (MM) is phytotoxic and a potential pre-emergent and preplant-incorporated organic herbicide for controlling germinating and emerging weed seedlings: unfortunately, MM may also adversely impact seedling survival of certain direct-seeded vegetable crops. Field research was conducted in s...

  15. The influence of N-acetyl-L-cysteine on oxidative stress and nitric oxide synthesis in stimulated macrophages treated with a mustard gas analogue

    PubMed Central

    Paromov, Victor; Qui, Min; Yang, Hongsong; Smith, Milton; Stone, William L

    2008-01-01

    Background Sulphur mustard gas, 2, 2'-dichlorodiethyl sulphide (HD), is a chemical warfare agent. Both mustard gas and its monofunctional analogue, 2-chloroethyl ethyl sulphide (CEES), are alkylating agents that react with and diminish cellular thiols and are highly toxic. Previously, we reported that lipopolysaccharide (LPS) significantly enhances the cytotoxicity of CEES in murine RAW 264.7 macrophages and that CEES transiently inhibits nitric oxide (NO) production via suppression of inducible NO synthase (iNOS) protein expression. NO generation is an important factor in wound healing. In this paper, we explored the hypotheses that LPS increases CEES toxicity by increasing oxidative stress and that treatment with N-acetyl-L-cysteine (NAC) would block LPS induced oxidative stress and protect against loss of NO production. NAC stimulates glutathione (GSH) synthesis and also acts directly as a free radical scavenger. The potential therapeutic use of the antibiotic, polymyxin B, was also evaluated since it binds to LPS and could thereby block the enhancement of CEES toxicity by LPS and also inhibit the secondary infections characteristic of HD/CEES wounds. Results We found that 10 mM NAC, when administered simultaneously or prior to treatment with 500 μM CEES, increased the viability of LPS stimulated macrophages. Surprisingly, NAC failed to protect LPS stimulated macrophages from CEES induced loss of NO production. Macrophages treated with both LPS and CEES show increased oxidative stress parameters (cellular thiol depletion and increased protein carbonyl levels). NAC effectively protected RAW 264.7 cells simultaneously treated with CEES and LPS from GSH loss and oxidative stress. Polymyxin B was found to partially block nitric oxide production and diminish CEES toxicity in LPS-treated macrophages. Conclusion The present study shows that oxidative stress is an important mechanism contributing to CEES toxicity in LPS stimulated macrophages and supports the notion

  16. Characterization of acute and long-term pathologies of superficial and deep dermal sulfur mustard skin lesions in the hairless guinea pig model.

    PubMed

    Dachir, Shlomit; Cohen, Maayan; Kamus-Elimeleh, Dikla; Fishbine, Eliezer; Sahar, Rita; Gez, Rellie; Brandeis, Rachel; Horwitz, Vered; Kadar, Tamar

    2012-01-01

    Sulfur mustard induces severe acute and prolonged damage to the skin and only partially effective treatments are available. We have previously validated the use of hairless guinea pigs as an experimental model for skin lesions. The present study aimed to characterize a model of a deep dermal lesion and to compare it with the previously described superficial lesion. Clinical evaluation of the lesions was conducted using reflectance colorimetry, trans-epidermal water loss and wound area measurements. Prostaglandin E(2) content, matrix metalloproteinase-2 and 9 activity, and histopathology were conducted up to 4 weeks post-exposure. Sulfur mustard skin injury, including erythema and edema, impairment of skin barrier and wounds developed in a dose-dependent manner. Prostaglandin E(2) content and matrix metalloproteinase-2 and 9 activities were elevated during the wound development and the healing process. Histological evaluation revealed severe damage to the epidermis and deep dermis and vesications. At 4 weeks postexposure, healing was not completed: significantly impaired stratum corneum, absence of hair follicles, and epidermal hyperplasia were observed. These results confirm the use of the superficial and deep dermal skin injuries in the hairless guinea pigs as suitable models that can be utilized for the investigation of the pathological processes of acute as well as long-term injuries. These models will be further used to develop treatments to improve the healing process and prevent skin damage and long-term effects. PMID:23082902

  17. [Sonography of the uretero-vesical junction and the urinary bladder in children].

    PubMed

    Ponhold, W; Balzar, E; Zwiauer, K

    1984-03-01

    Sonography of the ureterovesical junction and of the urinary bladder is described on the basis of examinations of 41 children. This included all distended bladder walls, ureteral dilations, ureteroceles and a rhabdomyosarcoma. Sonographic imaging presents difficulties in visualising ureters less than 6 mm wide, and in case of normal uretero-vesical junctions. Sonography cannot assess a versicoureteral reflux. Sonography should not be used in the first diagnosis of nephrourological changes as an alternative to radiological methods, since this may result in overlooking relevant curable changes in children. Sonography is particularly valuable in clarifying renal insufficiency and in following up children with nephrourological disease. PMID:6713789

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

    SciTech Connect

    Watson, A.P.; Munro, N.B.; Sidell, F.R.; Leffingwell, S.S.

    1992-01-01

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

  19. Synthesis, anti-proliferative and genotoxicity studies of 6-chloro-5-(2-substituted-ethyl)-1,3-dihydro-2H-indol-2-ones and 6-chloro-5-(2-chloroethyl)-3-(alkyl/ary-2-ylidene)indolin-2-ones.

    PubMed

    Meti, Gangadhar Y; Kamble, Atulkumar A; Kamble, Ravindra R; Somagond, Shilpa M; Devarajegowda, H C; Kumari, Sandhya; Kalthur, Guruprasad; Adiga, Satish K

    2016-10-01

    A series of 6-chloro-5-(2-substituted-ethyl)-1,3-dihydro-2H-indol-2-ones (3a-h) and 6-chloro-5-(2-chloroethyl)-3-(alkyl/aryl-2-ylidene)indolin-2-ones (5i-x) were synthesized. Compounds 3a-e, 5i-l and 5q-r were selected by NIH, USA for in vitro anti-proliferative screening. Based on the impressive growth inhibitory (GI %) effect by the compounds 3a-b and 3e which showed growth inhibition in the range 1.22-76.30%, 2.85-76.03% and 10.98-82.05% respectively at 10(-5) concentration, these compounds were further analyzed for anti-proliferative activity at 5 dose concentration and genotoxicity. PMID:27240276

  20. Soil biotransformation of thiodiglycol, the hydrolysis product of mustard gas: understanding the factors governing remediation of mustard gas contaminated soil.

    PubMed

    Li, Hong; Muir, Robert; McFarlane, Neil R; Soilleux, Richard J; Yu, Xiaohong; Thompson, Ian P; Jackman, Simon A

    2013-02-01

    Thiodiglycol (TDG) is both the precursor for chemical synthesis of mustard gas and the product of mustard gas hydrolysis. TDG can also react with intermediates of mustard gas degradation to form more toxic and/or persistent aggregates, or reverse the pathway of mustard gas degradation. The persistence of TDG have been observed in soils and in the groundwater at sites contaminated by mustard gas 60 years ago. The biotransformation of TDG has been demonstrated in three soils not previously exposed to the chemical. TDG biotransformation occurred via the oxidative pathway with an optimum rate at pH 8.25. In contrast with bacteria isolated from historically contaminated soil, which could degrade TDG individually, a consortium of three bacterial strains isolated from the soil never contaminated by mustard gas was able to grow on TDG in minimal medium and in hydrolysate derived from an historical mustard gas bomb. Exposure to TDG had little impacts on the soil microbial physiology or on community structure. Therefore, the persistency of TDG in soils historically contaminated by mustard gas might be attributed to the toxicity of mustard gas to microorganisms and the impact to soil chemistry during the hydrolysis. TDG biodegradation may form part of a remediation strategy for mustard gas contaminated sites, and may be enhanced by pH adjustment and aeration. PMID:22752796

  1. Attenuation of acute nitrogen mustard-induced lung injury, inflammation and fibrogenesis by a nitric oxide synthase inhibitor

    SciTech Connect

    Malaviya, Rama; Venosa, Alessandro; Hall, LeRoy; Gow, Andrew J.; Sinko, Patrick J.; Laskin, Jeffrey D.; Laskin, Debra L.

    2012-12-15

    Nitrogen mustard (NM) is a toxic vesicant known to cause damage to the respiratory tract. Injury is associated with increased expression of inducible nitric oxide synthase (iNOS). In these studies we analyzed the effects of transient inhibition of iNOS using aminoguanidine (AG) on NM-induced pulmonary toxicity. Rats were treated intratracheally with 0.125 mg/kg NM or control. Bronchoalveolar lavage fluid (BAL) and lung tissue were collected 1 d–28 d later and lung injury, oxidative stress and fibrosis assessed. NM exposure resulted in progressive histopathological changes in the lung including multifocal lesions, perivascular and peribronchial edema, inflammatory cell accumulation, alveolar fibrin deposition, bronchiolization of alveolar septal walls, and fibrosis. This was correlated with trichrome staining and expression of proliferating cell nuclear antigen (PCNA). Expression of heme oxygenase (HO)-1 and manganese superoxide dismutase (Mn-SOD) was also increased in the lung following NM exposure, along with levels of protein and inflammatory cells in BAL, consistent with oxidative stress and alveolar-epithelial injury. Both classically activated proinflammatory (iNOS{sup +} and cyclooxygenase-2{sup +}) and alternatively activated profibrotic (YM-1{sup +} and galectin-3{sup +}) macrophages appeared in the lung following NM administration; this was evident within 1 d, and persisted for 28 d. AG administration (50 mg/kg, 2 ×/day, 1 d–3 d) abrogated NM-induced injury, oxidative stress and inflammation at 1 d and 3 d post exposure, with no effects at 7 d or 28 d. These findings indicate that nitric oxide generated via iNOS contributes to acute NM-induced lung toxicity, however, transient inhibition of iNOS is not sufficient to protect against pulmonary fibrosis. -- Highlights: ► Nitrogen mustard (NM) induces acute lung injury and fibrosis. ► Pulmonary toxicity is associated with increased expression of iNOS. ► Transient inhibition of iNOS attenuates acute

  2. Comparison of fixation and processing methods for hairless guinea pig skin following sulfur mustard exposure. (Reannouncement with new availability information)

    SciTech Connect

    Bryant, M.A.; Braue Jr, E.H.

    1992-12-31

    Ten anesthetized hairless guinea pigs Crl:IAF(HA)BR were exposed to 10 pi of neat sulfur mustard (HD) in a vapor cup on their skin for 7 min. At 24 h postexposure, the guinea pigs were euthanatized and skin sections taken for histologic evaluation. The skin was fixed using either 10% neutral buffered formalin (NBF), McDowell Trump fixative (4CF-IG), Zenker`s formol-saline (Helly`s fluid), or Zenker`s fluid. Fixed skin sections were cut in half: one half was embedded in paraffin and the other half in plastic (glycol methacrylate). Paraffin-embedded tissue was stained with hematoxylin and eosin; plastic-embedded tissue was stained with Lee`s methylene blue basic fuchsin. Skin was also frozen unfixed, sectioned by cryostat, and stained with pinacyanole. HD-exposed skin was evaluated histologically for the presence of epidermal and follicular necrosis, microblister formation, epidermitis, and intracellular edema to determine the optimal fixation and embedding method for lesion preservation. The percentage of histologic sections with lesions varied little between fixatives and was similar for both paraffin and plastic embedding material. Plastic-embedded sections were thinner, allowing better histologic evaluation, but were more difficult to stain. Plastic embedding material did not infiltrate tissue fixed in Zenker`s fluid or Zenker`s formol-saline. Frozen tissue sections were prepared in the least processing time and lesion preservation was comparable to fixed tissue. It was concluded that standard histologic processing using formalin fixation and paraffin embedding is adequate for routine histopathological evaluation of HD skin lesions in the hairless guinea pig.... Sulfur mustard, Vesicating agents, Pathology, Hairless guinea pig model, Fixation.

  3. Absence of a p53 allele delays nitrogen mustard-induced early apoptosis and inflammation of murine skin

    PubMed Central

    Inturi, Swetha; Tewari-Singh, Neera; Jain, Anil K.; Roy, Srirupa; White, Carl W.; Agarwal, Rajesh

    2013-01-01

    Bifunctional alkylating agent sulfur mustard (SM) and its analog nitrogen mustard (NM) cause DNA damage leading to cell death, and potentially activating inflammation. Transcription factor p53 plays a critical role in DNA damage by regulating cell cycle progression and apoptosis. Earlier studies by our laboratory demonstrated phosphorylation of p53 at Ser15 and an increase in total p53 in epidermal cells both in vitro and in vivo following NM exposure. To elucidate the role of p53 in NM-induced skin toxicity, we employed SKH-1 hairless mice harboring wild type (WT) or heterozygous p53 (p53+/−). Exposure to NM (3.2 mg) caused a more profound increase in epidermal thickness and apoptotic cell death in WT relative to p53+/− mice at 24 h. However, by 72 h after exposure, there was a comparable increase in NM-induced epidermal cell death in both WT and p53+/− mice. Myeloperoxidase activity data showed that neutrophil infiltration was strongly enhanced in NM-exposed WT mice at 24 h persisting through 72 h of exposure. Conversely, robust NM-induced neutrophil infiltration (comparable to WT mice) was seen only at 72 h after exposure in p53+/− mice. Similarly, NM-exposure strongly induced macrophage and mast cell infiltration in WT, but not p53+/− mice. Together, these data indicate that early apoptosis and inflammation induced by NM in mouse skin are p53-dependent. Thus, targeting this pathway could be a novel strategy for developing countermeasures against vesicants-induced skin injury. PMID:23845566

  4. Simultaneous determination of sulfur mustard and related oxidation products by isotope-dilution LC-MS/MS method coupled with a chemical conversion.

    PubMed

    Qi, Meiling; Xu, Bin; Wu, Jianfeng; Zhang, Yajiao; Zong, Cheng; Chen, Jia; Guo, Lei; Xie, Jianwei

    2016-08-15

    Sulfur mustard (SM) is a highly reactive alkylating vesicant with high toxicity and complicated metabolism, the in vivo profile of its oxidation metabolism is not still fully known and urgently needs to be clarified well. In this work, an isotope-dilution high performance liquid chromatography-tandem mass spectrometric method coupled with chemical conversion was developed for the simultaneous quantification of SM and its oxidation products, i.e., mustard sulfoxide (SMO) and mustard sulfone (SMO2). The accurate measurement of SM and its oxidation products with high reaction activity was achived via the method of chemical conversion of 2-(3,5-bis(mercaptomethyl)phenoxy) acetic acid into stable derivative products. Method validation was performed in whole blood matrix, the linear range of the method was between 0.2 and 1000μg/L with correlation coefficients (r(2))>0.99, and the lower limits of quantification for SM, SMO and SMO2 were 1, 1, 0.2μg/L, respectively. The validated method was successfully applied to a toxicokinetics research of SM and its oxidation products after SM dermal exposed rats in a single dose. All three target analytes were found in whole blood samples from poisoned rats, and significant time-dependent responses were also observed. Among them, SMO2 with relatively high toxicity was identified and quantified in vivo for the first time, while SMO was the major product in whole blood and some of them continued to be oxidized to SMO2in vivo. These results give a direct experimental evidence to support that a large amount of SM is converted into the corresponding SMO and SMO2, and these oxidation products might cause potential combined toxic effects. PMID:27322628

  5. Vesical calculus formation on non-absorbable sutures used for open inguinal hernia repair

    PubMed Central

    Almarzouq, Ahmad; Mahmoud, Akram H.; Ashebu, Samuel D.; Kehinde, Elijah O.

    2014-01-01

    INTRODUCTION Iatrogenic injuries to the urogenital tract are rare, with the bladder being the organ most affected. We describe a case of a vesical calculus that formed on non-absorbable sutures that were used to repair an inguinal hernia. PRESENTATION OF CASE A 45-year-old male presented with frank haematuria and dysuria 2 years following an open left inguinal hernia repair. A CT urography showed a vesical calculus adherent to the left anterio-lateral wall of the bladder. Cystoscopy revealed that the calculus formed on non-absorbable sutures. Cystolapaxy was performed followed by cystoscopic excision of the sutures. The patient's post-operative course was uneventful. DISCUSSION Foreign bodies in the urinary bladder always act as a nidus for formation of a calculus. Iatrogenic bladder injuries are common during hernia repair. It is however rare for sutures used to repair an inguinal hernia to involve the urinary bladder wall. The patient most likely had a full bladder at the time of hernia repair or the bladder was part of the contents of the hernia sac. CONCLUSION This case illustrates the need to ensure that the bladder is empty prior to pelvic surgery and for surgeons to have a good understanding of inguinal anatomy to avoid injuring the contents of the hernia sac. PMID:25308188

  6. Modeling the spinal pudendo-vesical reflex for bladder control by pudendal afferent stimulation.

    PubMed

    McGee, Meredith J; Grill, Warren M

    2016-06-01

    Electrical stimulation of the pudendal nerve (PN) is a promising approach to restore continence and micturition following bladder dysfunction resulting from neurological disease or injury. Although the pudendo-vesical reflex and its physiological properties are well established, there is limited understanding of the specific neural mechanisms that mediate this reflex. We sought to develop a computational model of the spinal neural network that governs the reflex bladder response to PN stimulation. We implemented and validated a neural network architecture based on previous neuroanatomical and electrophysiological studies. Using synaptically-connected integrate and fire model neurons, we created a network model with realistic spiking behavior. The model produced expected sacral parasympathetic nucleus (SPN) neuron firing rates from prescribed neural inputs and predicted bladder activation and inhibition with different frequencies of pudendal afferent stimulation. In addition, the model matched experimental results from previous studies of temporal patterns of pudendal afferent stimulation and selective pharmacological blockade of inhibitory neurons. The frequency- and pattern-dependent effects of pudendal afferent stimulation were determined by changes in firing rate of spinal interneurons, suggesting that neural network interactions at the lumbosacral level can mediate the bladder response to different frequencies or temporal patterns of pudendal afferent stimulation. Further, the anatomical structure of excitatory and inhibitory interneurons in the network model was necessary and sufficient to reproduce the critical features of the pudendo-vesical reflex, and this model may prove useful to guide development of novel, more effective electrical stimulation techniques for bladder control. PMID:26968615

  7. Putting Some Mustard into Economic Growth

    PubMed Central

    Evans, Robert G.

    2012-01-01

    On September 27, 2012, the University of Toronto launched the Fraser Mustard Institute for Human Development – an appropriate recognition of an extraordinary individual. Fraser was a keen student of the science of human development and, most particularly, of early child development (ECD). He was also a powerful and tireless advocate for translating science into action. His institute must do both. Action is needed also because 25% of Canadians lack the competencies to function effectively in a modern economy. Other countries do much better. Facing a low-growth future, we cannot afford to waste this untapped potential. Although Prime Minister Harper's personal ideology has no place for ECD, the Mustard Institute can help keep the flame alive. PMID:23968611

  8. Pentoxifylline attenuates nitrogen mustard-induced acute lung injury, oxidative stress and inflammation.

    PubMed

    Sunil, Vasanthi R; Vayas, Kinal N; Cervelli, Jessica A; Malaviya, Rama; Hall, LeRoy; Massa, Christopher B; Gow, Andrew J; Laskin, Jeffrey D; Laskin, Debra L

    2014-08-01

    Nitrogen mustard (NM) is a toxic alkylating agent that causes damage to the respiratory tract. Evidence suggests that macrophages and inflammatory mediators including tumor necrosis factor (TNF)α contribute to pulmonary injury. Pentoxifylline is a TNFα inhibitor known to suppress inflammation. In these studies, we analyzed the ability of pentoxifylline to mitigate NM-induced lung injury and inflammation. Exposure of male Wistar rats (150-174 g; 8-10 weeks) to NM (0.125 mg/kg, i.t.) resulted in severe histopathological changes in the lung within 3d of exposure, along with increases in bronchoalveolar lavage (BAL) cell number and protein, indicating inflammation and alveolar-epithelial barrier dysfunction. This was associated with increases in oxidative stress proteins including lipocalin (Lcn)2 and heme oxygenase (HO)-1 in the lung, along with pro-inflammatory/cytotoxic (COX-2(+) and MMP-9(+)), and anti-inflammatory/wound repair (CD163+ and Gal-3(+)) macrophages. Treatment of rats with pentoxifylline (46.7 mg/kg, i.p.) daily for 3d beginning 15 min after NM significantly reduced NM-induced lung injury, inflammation, and oxidative stress, as measured histologically and by decreases in BAL cell and protein content, and levels of HO-1 and Lcn2. Macrophages expressing COX-2 and MMP-9 also decreased after pentoxifylline, while CD163+ and Gal-3(+) macrophages increased. This was correlated with persistent upregulation of markers of wound repair including pro-surfactant protein-C and proliferating nuclear cell antigen by Type II cells. NM-induced lung injury and inflammation were associated with alterations in the elastic properties of the lung, however these were largely unaltered by pentoxifylline. These data suggest that pentoxifylline may be useful in treating acute lung injury, inflammation and oxidative stress induced by vesicants. PMID:24886962

  9. Proteomic assessment of sulfur mustard-induced protein adducts and other protein modifications in human epidermal keratinocytes

    SciTech Connect

    Mol, Marijke A.E. Berg, Roland M. van den; Benschop, Henk P.

    2008-07-01

    Although some toxicological mechanisms of sulfur mustard (HD) have been uncovered, new knowledge will allow for advanced insight in the pathways that lead towards epidermal-dermal separation in skin. In the present investigation, we aimed to survey events that occur at the protein level in human epidermal keratinocytes (HEK) during 24 h after exposure to HD. By using radiolabeled {sup 14}C-HD, it was found that proteins in cultured HEK are significant targets for alkylation by HD. HD-adducted proteins were visualized by two-dimensional gel electrophoresis and analyzed by mass spectrometry. Several type I and II cytokeratins, actin, stratifin (14-3-3{sigma}) and galectin-7 were identified. These proteins are involved in the maintenance of the cellular cytoskeleton. Their alkylation may cause changes in the cellular architecture and, in direct line with that, be determinative for the onset of vesication. Furthermore, differential proteomic analysis was applied to search for novel features of the cellular response to HD. Partial breakdown of type I cytokeratins K14, K16 and K17 as well as the emergence of new charge variants of the proteins heat shock protein 27 and ribosomal protein P0 were observed. Studies with caspase inhibitors showed that caspase-6 is probably responsible for the breakdown of type I cytokeratins in HEK. The significance of the results is discussed in terms of toxicological relevance and possible clues for therapeutic intervention.

  10. Mustard bran in lactating dairy cow diets.

    PubMed

    Maiga, H A; Bauer, M L; Dahlen, C R; Badaruddin, M; Scholljegerdes, E J

    2011-06-01

    Two trials using lactating Holstein cows were conducted to evaluate effects of a diet containing oriental mustard bran on dry matter intake (DMI), milk production, milk components, and organoleptic properties. In experiment 1, 34 lactating cows (24 multiparous and 10 primiparous; days in milk ≥ 50 d) were used in a switchback design to determine the lactational response and organoleptic quality of milk when the diet contained 8% oriental mustard bran (MB) versus a control diet (CON). Mustard bran replaced a portion of soybean meal and all the beet pulp in the CON diet. Milk yields were greater for cows fed the MB diet; however, no differences were found in DMI, 3.5% fat- (FCM) or solids-corrected milk. Milk components and components production were not affected by treatment. Milk organoleptic qualities were not affected by diet. In experiment 2, 22 lactating cows (16 multiparous and 6 primiparous; days in milk ≥ 21 d) were assigned randomly within parity to receive MB or CON from wk 4 to 19 postpartum in a randomized complete block design. Cows were fed CON wk 1 to 3 postpartum. The MB diet contained the same ingredients as the CON, except sunflower seed and a portion of soybean meal were replaced with mustard bran. Milk and components data were collected during wk 3 postpartum and used as covariates to adjust treatment means. Intake was greater for cows fed the MB diet; however, daily milk, 3.5% FCM, and solids-corrected milk yields were not different between diets. Milk components and component yields were not affected by treatment. Milk urea concentration was less for cows fed the MB diet. Although cows fed the MB diet had greater DMI, this was not translated into a higher milk 3.5% FCM/DMI production efficiency ratio. During experiment 2, many cows fed MB experienced minor to severe hemolysis with bloody urine. This hemolysis believed to be caused by the S-methyl-cysteine sulfoxide contained in mustard bran could have affected milk production efficiency

  11. Therapeutic potential of a non-steroidal bifunctional anti-inflammatory and anti-cholinergic agent against skin injury induced by sulfur mustard

    SciTech Connect

    Chang, Yoke-Chen; Wang, James D.; Hahn, Rita A.; Gordon, Marion K.; Joseph, Laurie B.; Heck, Diane E.; Heindel, Ned D.; Young, Sherri C.; Sinko, Patrick J.; Casillas, Robert P.; Laskin, Jeffrey D.; Laskin, Debra L.; Gerecke, Donald R.

    2014-10-15

    Sulfur mustard (bis(2-chloroethyl) sulfide, SM) is a highly reactive bifunctional alkylating agent inducing edema, inflammation, and the formation of fluid-filled blisters in the skin. Medical countermeasures against SM-induced cutaneous injury have yet to be established. In the present studies, we tested a novel, bifunctional anti-inflammatory prodrug (NDH 4338) designed to target cyclooxygenase 2 (COX2), an enzyme that generates inflammatory eicosanoids, and acetylcholinesterase, an enzyme mediating activation of cholinergic inflammatory pathways in a model of SM-induced skin injury. Adult SKH-1 hairless male mice were exposed to SM using a dorsal skin vapor cup model. NDH 4338 was applied topically to the skin 24, 48, and 72 h post-SM exposure. After 96 h, SM was found to induce skin injury characterized by edema, epidermal hyperplasia, loss of the differentiation marker, keratin 10 (K10), upregulation of the skin wound marker keratin 6 (K6), disruption of the basement membrane anchoring protein laminin 322, and increased expression of epidermal COX2. NDH 4338 post-treatment reduced SM-induced dermal edema and enhanced skin re-epithelialization. This was associated with a reduction in COX2 expression, increased K10 expression in the suprabasal epidermis, and reduced expression of K6. NDH 4338 also restored basement membrane integrity, as evidenced by continuous expression of laminin 332 at the dermal–epidermal junction. Taken together, these data indicate that a bifunctional anti-inflammatory prodrug stimulates repair of SM induced skin injury and may be useful as a medical countermeasure. - Highlights: • Bifunctional anti-inflammatory prodrug (NDH4338) tested on SM exposed mouse skin • The prodrug NDH4338 was designed to target COX2 and acetylcholinesterase. • The application of NDH4338 improved cutaneous wound repair after SM induced injury. • NDH4338 treatment demonstrated a reduction in COX2 expression on SM injured skin. • Changes of skin repair

  12. Therapeutic Potential of a Non-Steroidal Bifunctional Anti-Inflammatory and Anti-Cholinergic Agent against Skin Injury Induced by Sulfur Mustard

    PubMed Central

    Chang, Yoke-Chen; Wang, James D.; Hahn, Rita A.; Gordon, Marion K.; Joseph, Laurie B.; Heck, Diane E.; Heindel, Ned D.; Young, Sherri C.; Sinko, Patrick J.; Casillas, Robert P.; Laskin, Jeffrey D.; Laskin, Debra L.; Gerecke, Donald R.

    2014-01-01

    Sulfur mustard (bis(2-chloroethyl) sulfide, SM) is a highly reactive bifunctional alkylating agent inducing edema, inflammation, and the formation of fluid-filled blisters in the skin. Medical countermeasures against SM-induced cutaneous injury have yet to be established. In the present studies, we tested a novel, bifunctional anti-inflammatory prodrug (NDH 4338) designed to target cyclooxygenase 2 (COX2), an enzyme that generates inflammatory eicosanoids, and acetylcholinesterase, an enzyme mediating activation of cholinergic inflammatory pathways in a model of SM-induced skin injury. Adult SKH-1 hairless male mice were exposed to SM using a dorsal skin vapor cup model. NDH 4338 was applied topically to the skin 24, 48, and 72 hr post-SM exposure. After 96 hr, SM was found to induce skin injury characterized by edema, epidermal hyperplasia, loss of the differentiation marker, keratin 10 (K10), upregulation of the skin wound marker keratin 6 (K6), disruption of the basement membrane anchoring protein laminin 322, and increased expression of epidermal COX2. NDH 4338 post-treatment reduced SM-induced dermal edema and enhanced skin re-epithelialization. This was associated with a reduction in COX2 expression, increased K10 expression in the suprabasal epidermis, and reduced expression of K6. NDH 4338 also restored basement membrane integrity, as evidenced by continuous expression of laminin 332 at the dermalepidermal junction. Taken together, these data indicate that a bifunctional anti-inflammatory prodrug stimulates repair of SM induced skin injury and may be useful as a medical countermeasure. PMID:25127551

  13. Enhancement of radiosensitivity in human glioblastoma cells by the DNA N-mustard alkylating agent BO-1051 through augmented and sustained DNA damage response

    PubMed Central

    2011-01-01

    Background 1-{4-[Bis(2-chloroethyl)amino]phenyl}-3-[2-methyl-5-(4-methylacridin-9-ylamino)phenyl]urea (BO-1051) is an N-mustard DNA alkylating agent reported to exhibit antitumor activity. Here we further investigate the effects of this compound on radiation responses of human gliomas, which are notorious for the high resistance to radiotherapy. Methods The clonogenic assay was used to determine the IC50 and radiosensitivity of human glioma cell lines (U87MG, U251MG and GBM-3) following BO-1051. DNA histogram and propidium iodide-Annexin V staining were used to determine the cell cycle distribution and the apoptosis, respectively. DNA damage and repair state were determined by γ-H2AX foci, and mitotic catastrophe was measure using nuclear fragmentation. Xenograft tumors were measured with a caliper, and the survival rate was determined using Kaplan-Meier method. Results BO-1051 inhibited growth of human gliomas in a dose- and time-dependent manner. Using the dosage at IC50, BO-1051 significantly enhanced radiosensitivity to different extents [The sensitizer enhancement ratio was between 1.24 and 1.50 at 10% of survival fraction]. The radiosensitive G2/M population was raised by BO-1051, whereas apoptosis and mitotic catastrophe were not affected. γ-H2AX foci was greatly increased and sustained by combined BO-1051 and γ-rays, suggested that DNA damage or repair capacity was impaired during treatment. In vivo studies further demonstrated that BO-1051 enhanced the radiotherapeutic effects on GBM-3-beared xenograft tumors, by which the sensitizer enhancement ratio was 1.97. The survival rate of treated mice was also increased accordingly. Conclusions These results indicate that BO-1051 can effectively enhance glioma cell radiosensitivity in vitro and in vivo. It suggests that BO-1051 is a potent radiosensitizer for treating human glioma cells. PMID:21244709

  14. Effects of Exposure to Sulfur Mustard on Speech Aerodynamics

    ERIC Educational Resources Information Center

    Heydari, Fatemeh; Ghanei, Mostafa

    2011-01-01

    Sulfur mustard is an alkylating agent with highly cytotoxic properties even at low exposure. It was used widely against both military and civilian population by Iraqi forces in the Iraq-Iran war (1983-1988). Although various aspects of mustard gas effects on patients with chemical injury have been relatively well characterized, its effects on…

  15. Harmful Effects of Mustard Bio-fumigants on Entomopathogenic Nematodes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Green manures, particularly mustards tilled into the soil preceding potato crops act as bio-fumigants that are toxic to plant parasitic nematodes, providing an alternative to synthetic soil fumigants. It is not known if mustard green manures also kill beneficial entomopathogenic nematodes (EPNs) tha...

  16. Symptomatic treatment of ascites with a peritoneo-vesical automated fluid shunt system in a dog.

    PubMed

    Venzin, C; Kook, P; Jenni, S; Wilhelm, S; Degen, T; Braun, A; Rütten, M; Glaus, T M

    2012-02-01

    A six-year-old Rottweiler with chronic ascites and moderate panhypoproteinaemia that had been treated with large volume paracentesis over several months duration was diagnosed with a large bi-atrial mass and hepatic fibrosis. For palliative treatment, a peritoneo-vesical automated fluid shunt system with an integrated chargeable battery and an integrated computer to control pump function and to transmit data transcutaneously was implanted by coeliotomy. The pump was left in place for 10 weeks, eliminating the need for further paracentesis during this time. At the end of this period, no ascites was discernible and serum protein concentrations had returned to their respective reference intervals. As a complication, decubitus with skin perforation had developed above the pump. Besides palliative treatment of chronic refractory ascites, this pump may have application in other conditions characterised by chronic cavity effusion or in peritoneal dialysis. PMID:22106956

  17. The role of climate on prevalence or eradication of vesical schistosomiasis in Khuzestan Province of Iran.

    PubMed

    Hamidinia, Dariush; Maraghi, Sharif; Azimi, Farideh; Ai, Armin; Shirian, Sadegh

    2016-06-01

    Climate is defined as the combination of climate and air elements of a given region which is usually measured for a period of decades. De-marton climate classification has been established based on many factors, including elements such as temperature and rainfall. Vesicle schistosomiasis is a parasitic disease caused by Schistosoma haematobium. This parasite lives in the blood vessels of the bladder. The parasite can cause hematuria in human and if not treated properly can lead to vesicale carcinoma. The parasite is distributed only in certain parts of the province and it is highly dispersed along the rivers of Dez, Karkheh and Karun with high emissions. In 1970, the prevalence of infection in infected foci was 23.8 %. Campaign against the parasite began in 1958 but it did not encompass all centers of infection. Preventive measures include diagnosis and treatment of patients, public health promotion, health education, drying swamps and ponds, improving the environment, cementing the irrigation canals, and the use of moluscocide eventually leads to changing the ecological and conditions of parasite and snail inhabits. Application of preventive measures resulted in the reduction of infection level to 0.7 % in 1979. By continuing struggle and intensifying preventive measures and changing ecological and climatic environment, in 2008, the examination of 3400 urine samples of students in Andimeshk district revealed no cases of the vesical schistosomiasis. It is concluded that S. haematobium and vesical schistosomiasis is eliminated from Khuzestan province southwest Iran, but the disease is still prevalent in neighboring Iran's western border country (Iraq) and due to the special conditions of its facilities and the traffic between the two countries, it is necessary to control and eradicate the disease in Iraq by using the experiences of Iran in eliminating the disease. PMID:27413310

  18. Neutralization and biodegradation of sulfur mustard. Final report, October 1995-June 1996

    SciTech Connect

    Harvey, S.P.; Szafraniec, L.L.; Beaudry, W.T.; Earley, J.T.; Irvine, R.L.

    1997-02-01

    The chemical warfare agent sulfur mustard was hydrolyzed to products that were biologically mineralized in sequencing batch reactors seeded with activated sludge. Greater than 90% carbon removal was achieved using laboratory scale bioreactors processing hydrolyzed munitions grade sulfur mustard obtained directly from the U.S. Chemical Stockpile. The bioreactor effluent was nontoxic and contained no detectable sulfur mustard or priority pollutants. The sulfur mustard hydrolysis biodegradation process has potential application to the congressionally mandated disposal of sulfur mustard stockpiles.

  19. Inhibition of sulfur mustard-induced cytotoxicity and inflammation by the macrolide antibiotic roxithromycin in human respiratory epithelial cells

    PubMed Central

    Gao, Xiugong; Ray, Radharaman; Xiao, Yan; Barker, Peter E; Ray, Prabhati

    2007-01-01

    Background Sulfur mustard (SM) is a potent chemical vesicant warfare agent that remains a significant military and civilian threat. Inhalation of SM gas causes airway inflammation and injury. In recent years, there has been increasing evidence of the effectiveness of macrolide antibiotics in treating chronic airway inflammatory diseases. In this study, the anti-cytotoxic and anti-inflammatory effects of a representative macrolide antibiotic, roxithromycin, were tested in vitro using SM-exposed normal human small airway epithelial (SAE) cells and bronchial/tracheal epithelial (BTE) cells. Cell viability, expression of proinflammatory cytokines including interleukin (IL)-1β, IL-6, IL-8 and tumor necrosis factor (TNF), and expression of inducible nitric oxide synthase (iNOS) were examined, since these proinflammatory cytokines/mediators are import indicators of tissue inflammatory responses. We suggest that the influence of roxithromycin on SM-induced inflammatory reaction could play an important therapeutic role in the cytotoxicity exerted by this toxicant. Results MTS assay and Calcein AM/ethidium homodimer (EthD-1) fluorescence staining showed that roxithromycin decreased SM cytotoxicity in both SAE and BTE cells. Also, roxithromycin inhibited the SM-stimulated overproduction of the proinflammatory cytokines IL-1β, IL-6, IL-8 and TNF at both the protein level and the mRNA level, as measured by either enzyme-linked immunosorbent assay (ELISA) or real-time RT-PCR. In addition, roxithromycin inhibited the SM-induced overexpression of iNOS, as revealed by immunocytochemical analysis using quantum dots as the fluorophore. Conclusion The present study demonstrates that roxithromycin has inhibitory effects on the cytotoxicity and inflammation provoked by SM in human respiratory epithelial cells. The decreased cytotoxicity in roxithromycin-treated cells likely depends on the ability of the macrolide to down-regulate the production of proinflammatory cytokines and

  20. Models of invasion and establishment of African Mustard (Brassica tournefortii)

    USGS Publications Warehouse

    Berry, Kristin H.; Gowan, Timothy A.; Miller, David M.; Brooks, Matthew L.

    2015-01-01

    Introduced exotic plants can drive ecosystem change. We studied invasion and establishment ofBrassica tournefortii (African mustard), a noxious weed, in the Chemehuevi Valley, western Sonoran Desert, California. We used long-term data sets of photographs, transects for biomass of annual plants, and densities of African mustard collected at irregular intervals between 1979 and 2009. We suggest that African mustard may have been present in low numbers along the main route of travel, a highway, in the late 1970s; invaded the valley along a major axial valley ephemeral stream channel and the highway; and by 2009, colonized 22 km into the eastern part of the valley. We developed predictive models for invasibility and establishment of African mustard. Both during the initial invasion and after establishment, significant predictor variables of African mustard densities were surficial geology, proximity to the highway and axial valley ephemeral stream channel, and number of small ephemeral stream channels. The axial valley ephemeral stream channel was the most vulnerable of the variables to invasions. Overall, African mustard rapidly colonized and quickly became established in naturally disturbed areas, such as stream channels, where geological surfaces were young and soils were weakly developed. Older geological surfaces (e.g., desert pavements with soils 140,000 to 300,000 years old) were less vulnerable. Microhabitats also influenced densities of African mustard, with densities higher under shrubs than in the interspaces. As African mustard became established, the proportional biomass of native winter annual plants declined. Early control is important because African mustard can colonize and become well established across a valley in 20 yr.

  1. Pityriasis rosea-like eruptions due to mustard oil application.

    PubMed

    Zawar, Vijay

    2005-01-01

    A young man employed in a construction company, presented with cutaneous lesions clinically simulating pityriasis rosea. Satisfactory and complete response to corticosteroids and antihistamines was followed by recurrence. Multiple recurrences within a short span of time arose a suspicion of alternative diagnosis. Site visit helped us to rule out occupational contact dermatitis. Further history taking revealed that he was recently using mustard oil for body massage. Subsequent patch testing confirmed contact hypersensitivity to mustard oil. Avoidance of the contact with mustard oil arrested appearance of further skin lesions. We stress the importance of taking a good history in clinical practice in disclosing a possible contactant. PMID:16394442

  2. Nd:YAG laser incision of the vesical neck in obstructive BPH

    NASA Astrophysics Data System (ADS)

    Gilbert, Peter T. O.

    2003-06-01

    From February, 1995 through June, 2002, 68 patients underwent laser incision of the prostate at our clinic. By means of a 23 F cytoscope and a 600 micrometer lateral firing quartz fiber the vesical neck was incised at the 5 and 7 o'clock position at 60 W power. Total energy averaged 13648 J. Operative time did not exceed 15 minutes. General anesthesia was employed in all but one patient. 38 patients remained catheter-free whereas 30 patients were catheterized for two hours. Except for three cases, all patients were discharged on the same day, usually after the first micturition. Anti-inflammatory treatment was administered for two weeks, Cotrimoxazole for 5 days. No serious complications were encountered. Minor side effects included urinary retention (1 pat.), urinary infection (3 pat.) and retrograde ejaculation (1 pat.). Considering a mean follow-up of 21 months, the average Qmax improved enormously (25.4 ml/s versus 10.9 ml/s), as did residual urine volume (35 ml versus 95 ml) and IPSS (7.1 versus 20.5). Three patients required TUR-P 2-3 years after laser surgery and one patient underwent radical retropubic prostatectomy for prostate cancer 2 years later. In conclusion, Nd:YAG laser incision of the prostate is a simple, safe, reliable and cost-effective outpatient procedure.

  3. Release of allyl isothiocyanate from mustard seed meal powder.

    PubMed

    Dai, Ruyan; Lim, Loong-Tak

    2014-01-01

    Allyl isothiocyanate (AITC) is a wide-spectrum antimicrobial compound found in mustard seeds, produced when their tissues are disrupted. The formation of AITC in mustard seed is mediated by the myrosinase enzyme which catalyzes the release of volatile AITC from a glucosinolate-sinigrin. Since water is a substrate in the reaction, humidity from the air can be used to activate the release of AITC from mustard seed. In this study, defatted and partially defatted mustard seed meals were ground into powders with particle size ranging from 5 to 300 μm. The mustard seed meal powder (MSMP) samples were enclosed within hermetically sealed glass jars wherein the headspace air was adjusted to 85% or 100% relative humidity at 5, 20, or 35 °C. Data from gas chromatography analysis showed that AITC release rate and amount increased with increasing relative humidity and temperature. Moreover, the release rate can be manipulated by particle size and lipid content of the MSMP samples. The amount of AITC released ranged from 2 to 17 mg/g MSMP within 24 h under the experimental conditions tested. In view of the antimicrobial properties of AITC, the mustard meal powder may be used as a natural antimicrobial material for extending the shelf life of food products. PMID:24313968

  4. Development and validation of a real-time PCR method for the simultaneous detection of black mustard (Brassica nigra) and brown mustard (Brassica juncea) in food.

    PubMed

    Palle-Reisch, Monika; Wolny, Martina; Cichna-Markl, Margit; Hochegger, Rupert

    2013-05-01

    The paper presents a real-time PCR method allowing the simultaneous detection of traces of black mustard (Brassica nigra) and brown mustard (Brassica juncea) in food. The primers and the probe target the B. nigra partial RT gene for reverse transcriptase from gypsy-like retroelement 13G42-26. The real-time PCR method does not show any cross-reactivity with other Brassicaceae species with the exception of white mustard. Low cross-reactivities with cinnamon, cumin, fenugreek, ginger, rye and turmeric can be ignored because in common mustard containing foodstuffs these biological species are present in very low amounts. By analysing serially diluted DNA extracts from black and brown mustard, the DNA of both mustard species could be detected down to 0.1 pg. With 10 ng DNA per PCR tube the real-time PCR method allows the detection of 5 ppm black and brown mustard in brewed sausages. PMID:23265498

  5. Comparison of cake compositions, pepsin digestibility and amino acids concentration of proteins isolated from black mustard and yellow mustard cakes.

    PubMed

    Sarker, Ashish Kumar; Saha, Dipti; Begum, Hasina; Zaman, Asaduz; Rahman, Md Mashiar

    2015-01-01

    As a byproduct of oil production, black and yellow mustard cakes protein are considered as potential source of plant protein for feed applications to poultry, fish and swine industries. The protein contents in black and yellow mustard cakes were 38.17% and 28.80% and their pepsin digestibility was 80.33% and 77.43%, respectively. The proteins were extracted at different pH and maximum proteins (89.13% of 38.17% and 87.76% of 28.80% respectively) isolated from black and yellow mustard cakes at pH 12. The purity of isolated proteins of black and yellow mustard cakes was 89.83% and 91.12% respectively and their pepsin digestibility was 89.67% and 90.17% respectively which assigned the absence of antinutritional compounds. It was found that essential amino acids isoleucine, lysine, methionine, threonine and tryptophan and non essential amino acids arginine and tyrosine were present in greater concentration in black mustard cake protein whereas other amino acids were higher in yellow mustard cake protein. PMID:25859422

  6. The Mixture of Salvianolic Acids from Salvia miltiorrhiza and Total Flavonoids from Anemarrhena asphodeloides Attenuate Sulfur Mustard-Induced Injury

    PubMed Central

    Li, Jianzhong; Chen, Linlin; Wu, Hongyuan; Lu, Yiming; Hu, Zhenlin; Lu, Bin; Zhang, Liming; Chai, Yifeng; Zhang, Junping

    2015-01-01

    Sulfur mustard (SM) is a vesicating chemical warfare agent used in numerous military conflicts and remains a potential chemical threat to the present day. Exposure to SM causes the depletion of cellular antioxidant thiols, mainly glutathione (GSH), which may lead to a series of SM-associated toxic responses. MSTF is the mixture of salvianolic acids (SA) of Salvia miltiorrhiza and total flavonoids (TFA) of Anemarrhena asphodeloides. SA is the main water-soluble phenolic compound in Salvia miltiorrhiza. TFA mainly includes mangiferin, isomangiferin and neomangiferin. SA and TFA possess diverse activities, including antioxidant and anti-inflammation activities. In this study, we mainly investigated the therapeutic effects of MSTF on SM toxicity in Sprague Dawley rats. Treatment with MSTF 1 h after subcutaneous injection with 3.5 mg/kg (equivalent to 0.7 LD50) SM significantly increased the survival levels of rats and attenuated the SM-induced morphological changes in the testis, small intestine and liver tissues. Treatment with MSTF at doses of 60 and 120 mg/kg caused a significant (p < 0.05) reversal in SM-induced GSH depletion. Gene expression profiles revealed that treatment with MSTF had a dramatic effect on gene expression changes caused by SM. Treatment with MSTF prevented SM-induced differential expression of 93.8% (973 genes) of 1037 genes. Pathway enrichment analysis indicated that these genes were mainly involved in a total of 36 pathways, such as the MAPK signaling pathway, pathways in cancer, antigen processing and presentation. These data suggest that MSTF attenuates SM-induced injury by increasing GSH and targeting multiple pathways, including the MAPK signaling pathway, as well as antigen processing and presentation. These results suggest that MSTF has the potential to be used as a potential therapeutic agent against SM injuries. PMID:26501264

  7. The Mixture of Salvianolic Acids from Salvia miltiorrhiza and Total Flavonoids from Anemarrhena asphodeloides Attenuate Sulfur Mustard-Induced Injury.

    PubMed

    Li, Jianzhong; Chen, Linlin; Wu, Hongyuan; Lu, Yiming; Hu, Zhenlin; Lu, Bin; Zhang, Liming; Chai, Yifeng; Zhang, Junping

    2015-01-01

    Sulfur mustard (SM) is a vesicating chemical warfare agent used in numerous military conflicts and remains a potential chemical threat to the present day. Exposure to SM causes the depletion of cellular antioxidant thiols, mainly glutathione (GSH), which may lead to a series of SM-associated toxic responses. MSTF is the mixture of salvianolic acids (SA) of Salvia miltiorrhiza and total flavonoids (TFA) of Anemarrhena asphodeloides. SA is the main water-soluble phenolic compound in Salvia miltiorrhiza. TFA mainly includes mangiferin, isomangiferin and neomangiferin. SA and TFA possess diverse activities, including antioxidant and anti-inflammation activities. In this study, we mainly investigated the therapeutic effects of MSTF on SM toxicity in Sprague Dawley rats. Treatment with MSTF 1 h after subcutaneous injection with 3.5 mg/kg (equivalent to 0.7 LD50) SM significantly increased the survival levels of rats and attenuated the SM-induced morphological changes in the testis, small intestine and liver tissues. Treatment with MSTF at doses of 60 and 120 mg/kg caused a significant (p<0.05) reversal in SM-induced GSH depletion. Gene expression profiles revealed that treatment with MSTF had a dramatic effect on gene expression changes caused by SM. Treatment with MSTF prevented SM-induced differential expression of 93.8% (973 genes) of 1037 genes. Pathway enrichment analysis indicated that these genes were mainly involved in a total of 36 pathways, such as the MAPK signaling pathway, pathways in cancer, antigen processing and presentation. These data suggest that MSTF attenuates SM-induced injury by increasing GSH and targeting multiple pathways, including the MAPK signaling pathway, as well as antigen processing and presentation. These results suggest that MSTF has the potential to be used as a potential therapeutic agent against SM injuries. PMID:26501264

  8. Synthesis and antitumor evaluation of novel sulfonylcycloureas derived from nitrogen mustard.

    PubMed

    Cheloufi, H; Belhani, B; Ouk, T S; Zerrouki, R; Aouf, N-E; Berredjem, M

    2016-05-01

    A new series of sulfonylcycloureas derivatives have been synthesized and evaluated in vitro for their antitumor activity against four cancer cell lines (A431, Jurkat, U266, and K562). These compounds were prepared by the condensation of several sulfonamides (2a-m) with ethyl bis(2-chloroethyl)carbamate (1a). The relative cytotoxicity of these new derivatives in comparison to chlorambucil is reported. PMID:26597910

  9. Sandwich enzyme-linked immunosorbent assay (ELISA) for detection of mustard in foods.

    PubMed

    Lee, P-W; Hefle, S L; Taylor, S L

    2008-05-01

    Undeclared mustard residues in food products could trigger allergic reactions in mustard-allergic consumers. Our objective was to develop and validate a sandwich-type ELISA for the detection of mustard residues in foods. A mixture of yellow, brown, and oriental mustard seeds was used to immunize 3 rabbits and 1 sheep. Two mustard ELISAs were developed by utilizing the reciprocal combination of rabbit and sheep polyclonal antimustard sera as the capture and detector reagents. Binding was visualized by addition of rabbit antisheep or goat antirabbit IgG antibody labeled with alkaline phosphatase and subsequent addition of substrate. The optimized ELISAs have limits of quantification (LOQ) of 1 and 3 ppm (mug of ground, whole mustard seeds/mL) for the sheep capture and rabbit capture formats, respectively. Only rapeseed cross-reacted in the rabbit and sheep capture mustard ELISAs at a level equivalent to 12300 and 16900 ppm of mustard. The mean percent recovery for cooked frankfurters spiked with 0 to 1000 ppm mustard flour was 95.3%+/- 10.7%. A limited retail survey of 29 foods revealed that, of 15 samples having mustard declared on the ingredient list, 2 baked bean products contained no detectable mustard, possibly owing to a decrease in extractability and detectability of mustard proteins after subjecting to thermal processing. For the remaining 14 samples without mustard declared on the label, 3 samples contained detectable mustard, presumably due to the labeling of mustard as "spice" or inadvertent cross-contamination. This sandwich-type ELISA can serve as a powerful tool for food manufacturers and regulatory agencies to detect and quantify mustard residues in processed foods. PMID:18460147

  10. [Mustard gas bombs found astray in the Faxaflói bay. Mustard gas: usage and poisonings].

    PubMed

    Kristinsson, Jakop; Jóhannesson, Thorkell

    2009-05-01

    The finding in 1972 of two World War II mustard gas artillery shells in crushed shell sediment dredged in the Faxaflói Bay and transported as raw material for cement production at Akranes (Western Iceland) is reported. One of the shells was wedged in a stone crusher in the raw material processing line and was ruptured. As a result dark fluid with a garlic like smell seeped out from the metal canister. The attending employees believed the metal object to be inert and tried to cut it out with a blow torch. This resulted in the explosion of the shell charge and in the exposure of four employees to mustard gas. All suffered burns on their hands and two of them in the eyes also. The second shell was detonated in the open at a distance from the factory. Emphasis is given to the fact that instant, or at least as soon as possible, cleansing and washing is the most efficient measure to be taken against the debilitating effects of mustard gas. It is also pointed out that the active principle in mustard gas (dichlorodiethyl sulphide) can easily be synthesized and none of the precursor substances are subjected to any restrictions of use. The authors conclude that mustard gas bombs may still be found in the arsenals of some military powers in spite of an international convention that prohibits the production, stockpiling and the use of chemical weapons. Terrorist groups have also seemingly tried to aquire mustard gas bombs and other chemical weapons. Therefore cases of mustard gas poisoning might still occur. PMID:19430031

  11. Mustard seed meal for management of root-knot nematode and weeds in tomato production

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Mustard seed meals of indian mustard [InM (Brassica juncea)] and yellow mustard [YeM (Sinapis alba)], alone and combined, were tested for effects on tomato (Solanum lycopersicum) plants and for suppression of southern root-knot nematode [RKN (Meloidogyne incognita)] and weed populations. In the gree...

  12. Pacific Northwest Condiment Yellow Mustard (Sinapis alba L.) Grower Guide: 2000-2002

    SciTech Connect

    Brown, J.; Davis, J. B.; Esser, A.

    2005-07-01

    This report is a grower guide for yellow mustard. Yellow mustard (Sinapis alba L.), synonymous with white mustard, is a spring annual crop and well adapted to hot, dry growing conditions. It has shown potential as an alternative crop in rotations with small grain cereals and has fewer limitations compared to other traditional alternative crops.

  13. Lipid Biosynthesis in Developing Mustard Seed

    PubMed Central

    Mukherjee, Kumar D.

    1983-01-01

    Cotyledons of developing mustard (Sinapis alba L.) seed have been found to synthesize lipids containing the common plant fatty acids and very long-chain monounsaturated (icosenoic, erucic, and tetracosenic) and saturated (icosanoic, docosanoic, and tetracosanoic) fatty acids from various radioactive precursors. The in vivo pattern of labeling of acyl lipids, either from fatty acids synthesized `endogenously' from radioactive acetate or malonate, or from radioactive fatty acids added `exogenously', indicates the involvement of the following pathways in the biosynthesis of triacylglycerols. Palmitic, stearic, and oleic acid, synthesized in the acyl carrier protein-track, are channeled to the Coenzyme A (CoA)-track and converted to triacylglycerols via the glycerol-3-phosphate pathway. Pools of stearoyl-CoA and oleoyl-CoA are elongated to very long-chain saturated and monounsaturated acyl-CoA, respectively. Most of the very long-chain saturated acyl-CoAs acylate preformed diacylglycerols. Very long-chain monounsaturated acyl-CoAs are converted to triacylglycerols, partly via phosphatidic acids and diacylglycerols, and partly by acylation of preformed diacylglycerols. PMID:16663345

  14. Nitrogen mustard hydrochloride-induced acute respiratory failure and myelosuppression: A case report

    PubMed Central

    ZHANG, XIAOJUAN; ZHANG, ZHIDAN; CHEN, SONG; ZHAO, DONGMEI; ZHANG, FANGXIAO; HU, ZIWEI; XIAO, FENG; MA, XIAOCHUN

    2015-01-01

    Nitrogen mustards are chemical agents that are similar to sulfur mustards, with similar toxicities. The present study describes a case of nitrogen mustard-induced acute respiratory failure and myelosuppression in a 33-year-old man. The patient, who was accidentally exposed to nitrogen mustard hydrochloride in a pharmaceutical factory, exhibited severe inhalation injury and respiratory symptoms. Laboratory tests revealed reduced white blood cell counts and lowered platelet levels during the first 6 days after the skin exposure to nitrogen mustard. Following treatment with mechanical ventilation, immunity-enhancing agents and nutritional supplements for 1 month, the patient successfully recovered and was released from hospital. PMID:26622480

  15. Novel liquid chromatography-mass spectrometry method for sensitive determination of the mustard allergen Sin a 1 in food.

    PubMed

    Posada-Ayala, Maria; Alvarez-Llamas, Gloria; Maroto, Aroa S; Maes, Xavier; Muñoz-Garcia, Esther; Villalba, Mayte; Rodríguez, Rosalía; Perez-Gordo, Marina; Vivanco, Fernando; Pastor-Vargas, Carlos; Cuesta-Herranz, Javier

    2015-09-15

    Mustard is a condiment added to a variety of foodstuffs and a frequent cause of food allergy. A new strategy for the detection of mustard allergen in food products is presented. The methodology is based on liquid chromatography analysis coupled to mass spectrometry. Mustard allergen Sin a 1 was purified from yellow mustard seeds. Sin a 1 was detected with a total of five peptides showing a linear response (lowest LOD was 5ng). Sin a 1 was detected in mustard sauces and salty biscuit (19±3mg/kg) where mustard content is not specified. Sin a 1, used as an internal standard, allowed quantification of this mustard allergen in foods. A novel LC/MS/MS SRM-based method has been developed to detect and quantify the presence of mustard. This method could help to detect mustard allergen Sin a 1 in processed foods and protect mustard-allergic consumers. PMID:25863610

  16. Mugwort-Mustard Allergy Syndrome due to Broccoli Consumption

    PubMed Central

    2016-01-01

    Pollen-food allergy syndrome (PFAS) is a relatively rare form of food allergy which develops in individuals who are sensitized to pollen. Tree pollens, especially birch pollen, frequently induce PFAS; however, the incidence of PFAS due to grass or weed pollens such as ragweed or mugwort is relatively rare. Mugwort-mustard allergy syndrome (MMAS) is an example of a PFAS in which individuals sensitized to mugwort may develop an allergy to mustard and experience severe reactions. We herein describe a case of MMAS due to broccoli consumption. PMID:27478657

  17. Mugwort-Mustard Allergy Syndrome due to Broccoli Consumption.

    PubMed

    Sugita, Yuri; Makino, Teruhiko; Mizawa, Megumi; Shimizu, Tadamichi

    2016-01-01

    Pollen-food allergy syndrome (PFAS) is a relatively rare form of food allergy which develops in individuals who are sensitized to pollen. Tree pollens, especially birch pollen, frequently induce PFAS; however, the incidence of PFAS due to grass or weed pollens such as ragweed or mugwort is relatively rare. Mugwort-mustard allergy syndrome (MMAS) is an example of a PFAS in which individuals sensitized to mugwort may develop an allergy to mustard and experience severe reactions. We herein describe a case of MMAS due to broccoli consumption. PMID:27478657

  18. An improved method for retrospective quantification of sulfur mustard exposure by detection of its albumin adduct using ultra-high pressure liquid chromatography-tandem mass spectrometry.

    PubMed

    Liu, ChangCai; Liang, LongHui; Xiang, Yu; Yu, HuiLan; Zhou, ShiKun; Xi, HaiLing; Liu, ShiLei; Liu, JingQuan

    2015-09-01

    Sulfur mustard (HD) adduct to human serum albumin (ALB) at Cys-34 residue has become an important and long-term retrospective biomarker of HD exposure. Here, a novel, sensitive, and convenient approach for retrospective quantification of HD concentration exposed to plasma was established by detection of the HD-ALB adduct using ultra-high pressure liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) with a novel non-isotope internal standard (IS). The HD-ALB adduct was isolated from HD-exposed plasma with blue Sepharose. The adduct was digested with proteinase K to form sulfur-hydroxyethylthioethyl ([S-HETE])-Cys-Pro-Phe tripeptide biomarker. The tripeptide adduct could be directly analyzed by UHPLC-MS/MS without an additional solid phase extraction (SPE), which was considered as a critical procedure in previous methods. The easily available 2-chloroethyl ethylsulfide (2-CEES) as HD surrogate was first reported to be used as IS in place of traditional d8-HD for quantification of HD exposure. Furthermore, 2-CEES was also confirmed to be a good IS alternative for quantification of HD exposure by investigation of product ion spectra for their corresponding tripeptide adducts which exhibited identical MS/MS fragmentation behaviors. The method was found to be linear between 1.00 and 250 ng•mL(-1) HD exposure (R(2)>0.9989) with precision of <4.50% relative standard deviation (%RSD), accuracy range between 96.5% and 114%, and a calculated limit of detection (LOD) of 0.532 ng•mL(-1). The lowest reportable limit (LRL) is 1.00 ng•mL(-1), over seven times lower than that of the previous method. The entire method required only 0.1 mL of plasma sample and took under 7 h without special sample preparation equipment. It is proven to be a sensitive, simple, and rugged method, which is easily applied in international laboratories to improve the capabilities for the analysis of biomedical samples related to verification of the Chemical Weapon Convention (CWC). PMID

  19. Characterization of mustard seeds and paste by DART ionization with time-of-flight mass spectrometry.

    PubMed

    Prchalová, Jana; Kovařík, František; Ševčík, Rudolf; Čížková, Helena; Rajchl, Aleš

    2014-09-01

    Direct analysis in real time (DART) is a novel technique with great potential for rapid screening analysis. The DART ionization method coupled with high-resolution time-of-flight mass spectrometry (TOF-MS) has been used for characterization of mustard seeds and table mustard. The possibility to use DART to analyse glucosinolates was confirmed on determination of sinalbin (4-hydroxybenzyl glucosinolate). The DART-TOF-MS method was optimized and validated. A set of samples of mustard seeds and mustard products was analyzed. High-performance liquid chromatography and DART-TOF-MS were used to determine glucosinolates in mustard seeds and compared. The correlation equation between these methods was DART = 0.797*HPLC + 6.987, R(2)  = 0.972. The DART technique seems to be a suitable method for evaluation of the quality of mustard seeds and mustard products. PMID:25230177

  20. [Clinical effect of LM-001, prostaglandin synthetic inhibitor, on pain from urinary tract stone and vesical urgency after operation of the bladder or prostate].

    PubMed

    Nakano, E; Yoshioka, T; Matsuda, M; Sonoda, T; Yano, H; Ihara, Y; Kuroda, H; Kishimoto, T; Sakurai, T; Uchida, K

    1990-05-01

    Clinical effect of LM-001, a prostaglandin synthetic inhibitor developed from a drug delivery system, was evaluated in 54 patients with pain from urinary tract stones (stone pain) and 32 with vesical urgency after an operation on bladder or prostate. LM-001, felbinac ethyl incorporated in lipid microsphere, wes intravenously administered at the onset of stone pain or vesical urgency. Of 54 with stones and 32 with urgency, 53 and 29 were eligible for response, respectively. The symptoms improved or disappeared in some cases just after the administration and in the majority of patients within 15 minutes, in 49 of 53 patients with stone pain. Further, the effectiveness lasted over 24 hours in 26 of the 49 responding to this agent. On one hand, improvement or disappearance of vesical urgency was recognized in 25 of 29 patients, and the effectiveness was observed shortly after injection in 16 and lasted over 24 hours in 13 cases. Toxicities of this drug were investigated in 54 patients with stone pain and 32 with urinary urgency. Side effects consisted of pain at the injection site in 4, a slight fall of blood pressure in 1, slight visual disturbance in 1, body heat sensation in 1, leukocytosis in 3 and elevation of alkaline phosphatase in 1. These symptoms were transient and disappeared without use of any agent. LM-001 is concluded to be a useful drug for controlling stone pain and vesical urgency since an immediate effect, long durability and high response rates were obtained without severe side PMID:2399865

  1. functional analysis of nonlinearity in garlic mustard demographic parameters

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Garlic mustard (Alliaria petiolata (M. Bieb.) Cavara and Grande) invades and degrades woodland habitats in North America. Coupled-plant herbivore population models will be helpful in the design and implementation of effective biological control strategies for this species. Such models will be most u...

  2. 14. SOUTH PLANT MUSTARD FILLING BUILDING (BUILDING 728) AND WAREHOUSE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    14. SOUTH PLANT MUSTARD FILLING BUILDING (BUILDING 728) AND WAREHOUSE (BUILDING 729) FROM CHEMICAL STORAGE TANK. VIEW TO NORTHEAST. - Rocky Mountain Arsenal, Bounded by Ninety-sixth Avenue & Fifty-sixth Avenue, Buckley Road, Quebec Street & Colorado Highway 2, Commerce City, Adams County, CO

  3. 87. EAST SECTION OF SOUTH PLANT, SHOWING MUSTARD FILLING BUILDING ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    87. EAST SECTION OF SOUTH PLANT, SHOWING MUSTARD FILLING BUILDING (BUILDING 728) AT LEFT AND INCINERATOR/PRECIPITATOR (BUILDING 724) AT CENTER, FROM CHEMICAL STORAGE TANK. VIEW TO SOUTHWEST. - Rocky Mountain Arsenal, Bounded by Ninety-sixth Avenue & Fifty-sixth Avenue, Buckley Road, Quebec Street & Colorado Highway 2, Commerce City, Adams County, CO

  4. Onion and weed response to mustard (Sinapis alba) seed meal

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Onion and weed response to mustard seed meal (MSM) were tested in greenhouse and field trials in 2007-2009. MSM was applied to the soil surface at rates of 1.1, 2.2, and 4.4 MT/ha. In greenhouse trials, onions were severely injured and stands reduced with all rates of MSM applied prior to onion emer...

  5. Onion and weed response to mustard (Sinapis alba) seed meal

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Weed control in organic onion production is often difficult and expensive, requiring numerous cultivations and extensive hand-weeding. Onion safety and weed control with mustard seed meal (MSM) derived from Sinapis alba was evaluated in greenhouse and field trials. MSM applied at 110, 220, and 440 g...

  6. 7 CFR 457.168 - Mustard crop insurance provisions.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... have limited or additional levels of coverage, as specified in 7 CFR part 400, subpart T, and pay an... 7 Agriculture 6 2013-01-01 2013-01-01 false Mustard crop insurance provisions. 457.168 Section 457.168 Agriculture Regulations of the Department of Agriculture (Continued) FEDERAL CROP...

  7. Pulmonary complications of mustard gas exposure: a study on cadavers.

    PubMed

    Taghaddosinejad, Fakhreddin; Fayyaz, Amir Farshid; Behnoush, Behnam

    2011-01-01

    Sulfur mustard gas is one of the chemical warfare gases that roughly about 45000 soldiers continue to suffer long-lasting consequences of exposure during the Iran-Iraq war between 1980 and 1988. According to the common pulmonary lesions due to this gas exposure, we studied gross and microscopic pulmonary lesions in cadavers and also assessed the main causes of mortality caused by mustard gas exposure. A case-series study was performed on hospital record files of 100 cadavers that were exposed with documented sulfur mustard gas during the Iran-Iraq war from 1979 to 1988 and autopsied in legal medicine organization In Tehran between 2005 and 2007 and gross and microscopic pathological findings of autopsied organs such as hematological, pulmonary, hepatic, and renal changes were evaluated. All cases were male with the mean age of 43 years. The time interval between the gas exposure and death was almost 20years. The most frequent pulmonary complication was chronic bronchitis in 81% of autopsied cadavers. Other pulmonary findings were progressive pulmonary fibrosis (9%), pulmonary infections and tuberculosis (29%), malignant cellular infiltration (4%), and aspergilloma (1%). According to the chronic progressive lesions caused by mustard gas exposure such as pulmonary lesions and also its high mortality rate, suitable programming for protection of the gas exposed persons and prohibiting chemical warfare are recommended. PMID:21713733

  8. 7 CFR 201.56-3 - Mustard family, Brassicaceae (Cruciferae).

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ...) FEDERAL SEED ACT FEDERAL SEED ACT REGULATIONS Germination Tests in the Administration of the Act § 201.56-3 Mustard family, Brassicaceae (Cruciferae). Kinds of seed: Broccoli, brussels sprouts, cabbage...) Germination habit: Epigeal dicot. (2) Food reserves: Cotyledons which expand and become thin, leaf-like...

  9. 7 CFR 201.56-3 - Mustard family, Brassicaceae (Cruciferae).

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ...) FEDERAL SEED ACT FEDERAL SEED ACT REGULATIONS Germination Tests in the Administration of the Act § 201.56-3 Mustard family, Brassicaceae (Cruciferae). Kinds of seed: Broccoli, brussels sprouts, cabbage...) Germination habit: Epigeal dicot. (2) Food reserves: Cotyledons which expand and become thin, leaf-like...

  10. 7 CFR 201.56-3 - Mustard family, Brassicaceae (Cruciferae).

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ...) FEDERAL SEED ACT FEDERAL SEED ACT REGULATIONS Germination Tests in the Administration of the Act § 201.56-3 Mustard family, Brassicaceae (Cruciferae). Kinds of seed: Broccoli, brussels sprouts, cabbage...) Germination habit: Epigeal dicot. (2) Food reserves: Cotyledons which expand and become thin, leaf-like...

  11. 7 CFR 201.56-3 - Mustard family, Brassicaceae (Cruciferae).

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ...) FEDERAL SEED ACT FEDERAL SEED ACT REGULATIONS Germination Tests in the Administration of the Act § 201.56-3 Mustard family, Brassicaceae (Cruciferae). Kinds of seed: Broccoli, brussels sprouts, cabbage...) Germination habit: Epigeal dicot. (2) Food reserves: Cotyledons which expand and become thin, leaf-like...

  12. 7 CFR 201.56-3 - Mustard family, Brassicaceae (Cruciferae).

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ...) FEDERAL SEED ACT FEDERAL SEED ACT REGULATIONS Germination Tests in the Administration of the Act § 201.56-3 Mustard family, Brassicaceae (Cruciferae). Kinds of seed: Broccoli, brussels sprouts, cabbage...) Germination habit: Epigeal dicot. (2) Food reserves: Cotyledons which expand and become thin, leaf-like...

  13. Mustard Seed Meal suppresses Weeds in Potato and Peppermint

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Seed meal is a co-product remaining after pressing mustard seed to remove the oil. Seed meals containing high glucosinolates have been reported to have herbicidal activity. Weed suppression with seed meal of Sinapis alba, variety Ida Gold was evaluated in field trials on potatoes and peppermint in ...

  14. 23. SOUTH PLANT MUSTARD FILLING BUILDING (BUILDING 728) AND WAREHOUSE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    23. SOUTH PLANT MUSTARD FILLING BUILDING (BUILDING 728) AND WAREHOUSE (BUILDING 729) FROM ROOF OF TON CONTAINER RECONDITIONING BUILDING, SHOWING FACILITIES MAINTENANCE BUILDING AT FOREGROUND AND BUILDING 741, 742 AND 743 AT CENTER BACKGROUND. VIEW TO SOUTHEAST. - Rocky Mountain Arsenal, Bounded by Ninety-sixth Avenue & Fifty-sixth Avenue, Buckley Road, Quebec Street & Colorado Highway 2, Commerce City, Adams County, CO

  15. Task 89-07: Evaluation of the in vitro efficacy of candidate pretreatment and treatment (pt) compounds against vesicants and nerve agents. Final report, January 1990-January 1993

    SciTech Connect

    Hobson, D.W.; Blank, J.A.; Starner, R.A.

    1993-10-01

    MREF Task 89-07 encompassed four vesicant assays and four nerve agent assays. The four vesicant assays evaluated the candidate P and T compound solubility limitations, direct cytotoxic effects, efficacy against HD-induced cellular nicotinamide adenine dinucleotide (NAD+) depletion, and efficacy against HD-induced cytotoxicity. Normal human epidermal cells (NHEKs) were used to evaluate candidate PT compound efficacy against HD-induced NAD+ depletion, and peripheral blood mononuclear leukocytes (PBMC) were used in direct cytotoxicity and HD-induced cytotoxicity assays. The four nerve agent assays assessed candidate PT compound direct inhibitory effects on acetylcholinesterase (AChE) activity, candidate PT compound efficacy in reactivating Tabun (GA) - and O-ethyl S-(2-diisopropylaminoethyl) methylphosphonothiolate (VX)-inhibited A ThE, and candidate PT compound efficacy in slowing the aging rate of Soman (GD) inhibited AChE. All nerve agent and vesicant assays with the exception of the direct cytotoxicity and HD-induced cytotoxicity assays were initially established under MREF Task 88-36. The direct cytotoxicity and HD-induced cytotoxicity assays were transitioned to the MREF from USAMRICD and validated for use in routine screening procedures, including the generation of control database values, under Task 89-07. Solubility data were obtained for 37 compounds submitted for evaluation in the vesicant assays. Thirty-five of these compounds were evaluated for direct cytotoxicity, and their effect against HD-induced cytotoxicity, while 13 compound is were evaluated for efficacy against HD-induced NAD+ depletion. AChE reactivation, ACHE aging, ACHE inhibition, In vitro, Cytotoxicity , Vesicant assays, Nerve ag.

  16. Effects of native herbs and light on garlic mustard (Alliaria petiolata) invasion

    USGS Publications Warehouse

    Phillips-Mao, Laura; Larson, Diane L.; Jordan, Nicholas R.

    2014-01-01

    The degree to which invasive species drive or respond to environmental change has important implications for conservation and invasion management. Often characterized as a driver of change in North American woodlands, the invasive herb garlic mustard may instead respond to declines in native plant cover and diversity. We tested effects of native herb cover, richness, and light availability on garlic mustard invasion in a Minnesota oak woodland. We planted 50 garlic mustard seeds into plots previously planted with 0 to 10 native herb species. We measured garlic mustard seedling establishment, survival to rosette and adult stages, and average (per plant) and total (per plot) biomass and silique production. With the use of structural equation models, we analyzed direct, indirect, and net effects of native cover, richness, and light on successive garlic mustard life stages. Native plant cover had a significant negative effect on all life stages. Species richness had a significant positive effect on native cover, resulting in indirect negative effects on all garlic mustard stages, and net negative effects on adult numbers, total biomass, and silique production. Light had a strong negative effect on garlic mustard seedling establishment and a positive effect on native herb cover, resulting in significant negative net effects on garlic mustard rosette and adult numbers. However, light's net effect on total garlic mustard biomass and silique production was positive; reproductive output was high even in low-light/high-cover conditions. Combined effects of cover, richness, and light suggest that native herbs provide biotic resistance to invasion by responding to increased light availability and suppressing garlic mustard responses, although this resistance may be overwhelmed by high propagule pressure. Garlic mustard invasion may occur, in part, in response to native plant decline. Restoring native herbs and controlling garlic mustard seed production may effectively reduce

  17. Competitive Interactions of Garlic Mustard (Alliaria petiolata) and Damesrocket (Hesperis matronalis)

    USGS Publications Warehouse

    Leicht-Young, Stacey A.; Pavlovic, Noel B.; Adams, Jean V.

    2012-01-01

    Competitive interactions between native plants and nonnative, invasive plant species have been extensively studied; however, within degraded landscapes, the effect of interspecific interactions among invasive plants is less explored. We investigated a competitive interaction between two sympatric, invasive mustard species that have similar life history strategies and growth forms: garlic mustard and damesrocket. Greenhouse experiments using a full range of reciprocal density ratios were conducted to investigate interspecific competition. Garlic mustard had a negative effect on the final biomass, number of leaves, and relative growth rate in height of damesrocket. Survival of damesrocket was not negatively affected by interspecific competition with garlic mustard; however, garlic mustard showed higher mortality because of intraspecific competition. These results indicated that although garlic mustard has been observed to be the dominant species in this landscape, it may not completely outcompete damesrocket in all situations. Studies of invasive species in competition are important in degraded landscapes because this is the common situation in many natural areas.

  18. Teratology Studies on Lewisite and Sulfur Mustard Agents: Effects of Sulfur Mustard in Rats and Rabbits

    SciTech Connect

    Hackett, P. L.; Rommereim, R. L.; Burton, F. G.; Buschbom, R. L.; Sasser, L . B.

    1987-09-30

    Sulfur mustard (HD) was administered to rats and rabbits by intragastric intubation. Rats were dosed daily from 6 through 15 days of gestation (dg) with 0. 0.5, 1.0 or 2.0 mg of HD/kg; rabbits were dosed with 0, 0.4, 0.6 or 0.8 mg/kg on 6 through 19 dg. Maternal animals were weighed periodically and, at necropsy, were examined for gross lesions of major organs and reproductive performance; live fetuses were weighed and examined for external, internal and skeletal defects. In rats, reductions in body weights were observed in maternal animals and their female fetuses at the lowest administered dose (0.5 mg/kg), but the incidence of fetal malformations was not increased. In rabbits the highest administered dose (0.8 mg/kg) induced maternal mortality and depressed body weight measures but did not affect fetal development. These results suggest that orally administered HD is not teratogenic in rats and rabbits since fetal effects were observed only at dose levels that induced frank maternal toxicity. Estimations of dose ranges for "no observable effects levels" in rats and rabbits, respectively, were: < 0.5 and < 0.4 mg/kg in maternal animals and < 0.5 and > 0.8 mg/kg in their fetuses.

  19. Sensory evaluation of dry-fermented sausage containing ground deodorized yellow mustard.

    PubMed

    Li, Shuliu; Aliani, Michel; Holley, Richard A

    2013-10-01

    Ground deodorized yellow mustard is used as a binder and meat protein substitute in cooked processed meat products. Recent studies have shown that it has the potential to be used in uncooked processed meat products because of its natural antimicrobial properties. In the present study, ground deodorized yellow mustard was added to uncooked dry-fermented sausage during manufacture at 1% to 4% (w/w) and analyzed for its effects on starter cultures, physico-chemical properties, and consumer acceptability. Mustard had a nondose-dependent inhibitory effect on the Staphylococcus starter culture, had no effect on water activity or instrumental texture, and tended to accelerate sausage pH reduction. At 3% and 4% mustard, consumer scores on all sensory attributes as well as overall acceptability were significantly lower. The appearance and color of 3% and 4% mustard-treated sausages were liked slightly, whereas flavor, texture, and overall acceptability scores were reduced. The control without mustard and 1% mustard-treated sausages had similar sensory properties and were the most acceptable, while 2% mustard-treated sausages were given "like moderately" and "like slightly" descriptors. Sensory results mean that at concentrations necessary for mandated regulatory control of Escherichia coli O157:H7 in dry sausages, mustard may have a negative effect on consumer acceptance. PMID:24025044

  20. Sulfur mustard toxicity: history, chemistry, pharmacokinetics, and pharmacodynamics.

    PubMed

    Ghabili, Kamyar; Agutter, Paul S; Ghanei, Mostafa; Ansarin, Khalil; Panahi, Yunes; Shoja, Mohammadali M

    2011-05-01

    Sulfur mustard (SM) and similar bifunctional agents have been used as chemical weapons for almost 100 years. Victims of high-dose exposure, both combatants and civilians, may die within hours or weeks, but low-dose exposure causes both acute injury to the eyes, skin, respiratory tract and other parts of the body, and chronic sequelae in these organs are often debilitating and have a serious impact on quality of life. Ever since they were first used in warfare in 1917, SM and other mustard agents have been the subjects of intensive research, and their chemistry, pharmacokinetics and mechanisms of toxic action are now fairly well understood. In the present article we review this knowledge and relate the molecular-biological basis of SM toxicity, as far as it has been elucidated, to the pathological effects on exposure victims. PMID:21329486

  1. Hemicholinium mustard derivatives: preliminary assessment of cholinergic neurotoxicity.

    PubMed

    Tagari, P C; Maysinger, D; Cuello, A C

    1986-07-01

    We have attempted to design novel neurotoxins based on the use of hemicholinium derivatives. Three compounds were tested for their neurochemical effects on cholinergic, gabaergic and catecholaminergic markers in the hippocampus, striatum and cortex following intracerebroventricular administration. The effects were compared with those of the non-specific alkylating agent (nitrogen mustard) and the previously reported ethylcholine mustard aziridinium ion (AF 64A). The results indicate that only one of these derivatives (HcM-9) exhibits comparable neurotoxic effects on cholinergic markers with a similar pattern of specificity to that of AF 64A. In addition, HcM-9 showed less overall toxicity, this being reflected in a higher survival rate. The present results indicate that hemicholinium derivatives could be good substrates for further molecular modifications, thus a step towards the design of a more specific cholinergic neurotoxin. PMID:3748277

  2. Optimized verification method for detection of an albumin-sulfur mustard adduct at Cys(34) using a hybrid quadrupole time-of-flight tandem mass spectrometer after direct plasma proteolysis.

    PubMed

    John, Harald; Siegert, Markus; Gandor, Felix; Gawlik, Michael; Kranawetvogl, Andreas; Karaghiosoff, Konstantin; Thiermann, Horst

    2016-02-26

    The vesicant sulfur mustard (SM) is a banned chemical warfare agent that is controlled by the Organisation for the Prohibition of Chemical Weapons (OPCW). Bioanalytical procedures are mandatory for proving an alleged use and incorporation of SM into the body. We herein present the development and application of a novel optimized procedure suitable for qualitative verification analysis of plasma targeting the SM-adduct of human serum albumin (HSA) alkylated at the cysteine(34) residue. Diluted human plasma is directly mixed with pronase in an ultrafiltration device (10kDa cut-off) for proteolysis (4h, 37°C). Following ultrafiltration the filtrate is diluted and analyzed by microbore liquid chromatography-electrospray ionization high resolution tandem-mass spectrometry (μLC-ESI HR MS/MS) targeting the alkylated dipeptide hydroxyethylthioethyl-CysPro (HETE-CP). A hybrid quadrupole time-of-flight mass spectrometer provided high mass spectrometric resolution in the MS/MS mode enabling highest selectivity and sensitivity (lower limit of detection corresponding to 9.8nM SM in plasma). Kinetics of HETE-CP formation from heparin-, citrate-, and EDTA-plasma as well as serum are presented and the influence of different EDTA and pronase concentrations was characterized. The novel procedure was applied to plasma samples provided by the OPCW as well as to patientś plasma derived from real cases of SM-poisoning. PMID:26449527

  3. Possible long-term health effects of short-term exposure to chemical agents. Volume 2. Cholinesterase reactivators, psychochemicals, and irritants and vesicants. Final report

    SciTech Connect

    Not Available

    1984-01-01

    The present report evaluates toxicologic and epidemiologic data relevant to the testing of approximately 750 subjects exposed to cholinesterase reactivators, about 260 exposed to psychochemicals, and 1,500 exposed to irritants or vesicants. A remaining group of subjects used largely in tests involving placebo or innocuous chemicals or conditions is available for comparison and will be discussed later. The report is the work of three panels of scientists--the Panel on Cholinesterase Reactivator Chemicals, the Panel on Psychochemicals, and the Panel on Irritants and Vesicants. The chairman of each panel was selected from the Committee on Toxicology, and the members were selected on the basis of their knowledge of the compounds in question or because they represented required disciplines.

  4. Arsenic and Old Mustard: Chemical Problems of Old Arsenical and 'Mustard' Munitions (Joseph F. Bunnett and Marian Mikotajczyk, Eds.)

    NASA Astrophysics Data System (ADS)

    Garrett, Benjamin

    1999-10-01

    What do Knute Rockne, Notre Dame's famed football coach, and Lewisite, a chemical warfare agent dubbed "the dew of death", have in common? Both owe their discovery to Father Julius Arthur Nieuwland.1 Rockne's legacy lives on in the Fighting Irish and their tradition of excellence on the gridiron. Lewisite, together with other arsenical- and mustard-type chemical warfare agents, provide a legacy that lives on, too, but with less cheerful consequences. The book Arsenic and Old Mustard: Chemical Problems of Old Arsenical and 'Mustard' Munitions makes clear the challenges faced in dealing with those consequences. This book documents the proceedings of a workshop devoted to arsenical- and mustard-type chemical warfare agents and their associated munitions. The workshop, held in Poland in 1996, included nine lectures, eight posters, and three discussion groups; and the contents of all these are presented. Major support for the workshop came from the Scientific Affairs Division of NATO as part of on ongoing series of meetings, cooperative research projects, and related efforts dealing with problems leftover from the Cold War and, in the case of the arsenicals and mustards, from conflicts dating to World War I. These problems can be seen in contemporary accounts, including a January 1999 news report that the U.S. Department of Defense intends to survey Washington, DC, areas near both American University and the Catholic University of America (CUA), site of the original synthesis of Lewisite, for chemical warfare agents and other materials disposed at the end of World War I.2 The first nine chapters of the book present the workshop's lectures. Of these, readers interested in chemical weapon destruction might find especially useful the first chapter, in which Ron Mansley of the Organisation for the Prohibition of Chemical Weapons presents a scholarly overview covering historical aspects of the arsenicals and mustards; their production and use; prospective destruction

  5. UPPER-BOUND QUANTITATIVE CANCER RISK ESTIMATES FOR POPULATION ADJACENT TO SULFUR MUSTARD INCINERATION FACILITIES

    EPA Science Inventory

    This document characterizes the potential cancer hazard to populations residing near sulfur mustard incineration facilities while the incineration is taking place. he carcinogenicity of sulfur mustard is reviewed briefly to show what evidence has lead to the previously-accepted c...

  6. Effect of mustard seed meal on early weed emergence in peppermint and potato

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Seed meal is the by-product remaining after pressing/crushing mustard seed to remove the majority of the oil. Trials to evaluate weed suppression were conducted at several locations on peppermint and potatoes using seed meal obtained from Sinapis alba, variety Ida Gold. White mustard seed meal appl...

  7. Suppression of bacterial blight on mustard greens with host plant resistance and Acibenzolar-S-Methyl

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bacterial blight, caused by Pseudomonas cannabina pv. alisalensis, attacks the leaves of most brassica vegetables, including mustard greens (Brassica juncea). ‘Carolina Broadleaf,’ a new mustard cultivar, is resistant to bacterial blight. Acibenzolar-S-methyl (trade name Actigard) has been used to m...

  8. Phenolic component profiles of mustard greens, yu choy and 15 other Brassica vegatables

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A liquid chromatography-mass spectrometry (LC-MS) profiling method was used to characterize the phenolic components of 17 leafy vegetables from Brassica species other than Brassica oleracea. The vegetables studied were mustard green, baby mustard green, gai choy, baby gai choy, yu choy, yu choy tip...

  9. Protection of chymotrypsin from inactivation by a N-mustard analog.

    PubMed

    Brecher, A S; Koenig, M J

    1995-02-01

    Chymotrypsin activity is rapidly inactivated by the N-mustard anti-tumor drug, chlorambucil. Since mustards react with thiols, amines, carboxyls, imidazoles, and sulfide sites on proteins, N-acetylcysteine, 2 proprietary protein hydrolyzates, beta-mercaptoethanol, ethanolamine, and sodium lactate were tested for their capacity to protect chymotrypsin from inactivation by the mustard. In each instance, protection was afforded to chymotrypsin. In as much as N-acetylcysteine protected chymotrypsin from inactivation by chlorambucil, it is suggested that this thiol compound may serve as a detoxication agent and may not require prior transformation into glutathione by cells in order to reduce mustard levels within the cells, as suggested by Smith and Gross (Proceedings of the NATO Panel VIII meeting, Grenoble, France, 1991.) It is further suggested that amino acids present as biosynthetic and degradative components of cells may detoxify mustards. PMID:7701511

  10. Veterans at risk: The health effects of mustard gas and lewisite

    SciTech Connect

    Pechura, C.M.; Rall, D.P.

    1993-01-01

    So vivid were the memories of the first use of mustard gas (sulfur mustard) by the Germans in World War I that the United States government began to prepare for chemical warfare even before the Japanese attacked Pearl Harbor in 1941. This work was also spurred by the fury of war in Europe and reports of Japanese use of sulfur mustard against the Chinese. The US preparations included the establishment of war-related research programs organized by President Roosevelt under the White House Office of Scientific Research and Development (OSRD). Two groups under the OSRD became involved in secret testing programs concerned with mustard agents (Sulfur and nitrogen mustard) and Lewisite: The Committee on Medical Research; This group studied protective ointments and other treatments through the National Research Council's Committee on Treatment of Gas Casualties, and The National Defense Research Committee; This group studied protective clothing and gas masks through military units such as the Chemical Warfare Service.