Pathology of lethal and sublethal doses of aerosolized ricin in rhesus macaques.

PubMed

Bhaskaran, Manoj; Didier, Peter J; Sivasubramani, Satheesh K; Doyle, Lara A; Holley, Jane; Roy, Chad J

2014-01-01

Ricin toxin, a type 2 ribosome-inactivating protein and a category B bioterrorism agent, is produced from the seeds of castor oil plant (Ricinus communis). Chronic pathological changes in survivors of aerosolized ricin exposure have not been reported in primates. Here we compare and contrast the pathological changes manifested between rhesus macaques (RM) that succumbed to lethal dose of ricin (group I) and survivor RM exposed to low dose of ricin (group II). All animals in group I exhibited severe diffuse, necrotizing bronchiolitis and alveolitis with fibrinopurulent bronchointerstitial pneumonia, massive alveolar, perivascular and peribronchial/bronchiolar edema with hemorrhage, and necropurulent and hemorrhagic tracheobronchial lymphadenitis. All animals from group II had multifocal, fibrosing interstitial pneumonia with prominent alveolar histiocytosis and type II pneumocyte hyperplasia. Subacute changes like infiltration by lymphocytes and plasma cells and persistence of edematous fluid were occasionally present in lung and tracheobronchial lymph nodes. The changes appear to be a continuum wherein the inflammatory response shifts from an acute to subacute/chronic reparative process if the animals can survive the initial insult.

Full recovery from a potentially lethal dose of mercuric chloride.

PubMed

Beasley, D Michael G; Schep, Leo J; Slaughter, Robin J; Temple, Wayne A; Michel, Jonathan M

2014-03-01

Mercuric chloride poisoning is rare yet potentially life-threatening. We report a case of poisoning with a potentially significant amount of mercuric chloride which responded to aggressive management. A 19-year-old female presented to the Emergency Department with nausea, abdominal discomfort, vomiting of blood-stained fluid, and diarrhea following suicidal ingestion of 2-4 g of mercuric chloride powder. An abdominal radiograph showed radio-opaque material within the gastric antrum and the patient's initial blood mercury concentration was 17.9 μmol/L (or 3.58 mg/L) at 3 h post-ingestion. Given the potential toxicity of inorganic mercury, the patient was admitted to the intensive care unit and chelation with dimercaprol was undertaken. Further clinical effects included mild hemodynamic instability, acidosis, hypokalemia, leukocytosis, and fever. The patient's symptoms began to improve 48 h after admission and resolved fully within a week. Mercuric chloride has an estimated human fatal dose of between 1 and 4 g. Despite a reported ingestion of a potentially lethal dose and a high blood concentration, this patient experienced mild to moderate poisoning only and she responded to early and appropriate intervention. Mercuric chloride can produce a range of toxic effects including corrosive injury, severe gastrointestinal disturbances, acute renal failure, circulatory collapse, and eventual death. Treatment includes close observation and aggressive supportive care along with chelation, preferably with 2,3-dimercapto-1-propane sulfonate or 2,3-meso-dimercaptosuccinic acid.

Vaccination With a Highly Attenuated Recombinant Vesicular Stomatitis Virus Vector Protects Against Challenge With a Lethal Dose of Ebola Virus

PubMed Central

Matassov, Demetrius; Marzi, Andrea; Latham, Terri; Xu, Rong; Ota-Setlik, Ayuko; Feldmann, Friederike; Geisbert, Joan B.; Mire, Chad E.; Hamm, Stefan; Nowak, Becky; Egan, Michael A.; Geisbert, Thomas W.; Eldridge, John H.; Feldmann, Heinz; Clarke, David K.

2015-01-01

Previously, recombinant vesicular stomatitis virus (rVSV) pseudotypes expressing Ebolavirus glycoproteins (GPs) in place of the VSV G protein demonstrated protection of nonhuman primates from lethal homologous Ebolavirus challenge. Those pseudotype vectors contained no additional attenuating mutations in the rVSV genome. Here we describe rVSV vectors containing a full complement of VSV genes and expressing the Ebola virus (EBOV) GP from an additional transcription unit. These rVSV vectors contain the same combination of attenuating mutations used previously in the clinical development pathway of an rVSV/human immunodeficiency virus type 1 vaccine. One of these rVSV vectors (N4CT1-EBOVGP1), which expresses membrane-anchored EBOV GP from the first position in the genome (GP1), elicited a balanced cellular and humoral GP-specific immune response in mice. Guinea pigs immunized with a single dose of this vector were protected from any signs of disease following lethal EBOV challenge, while control animals died in 7–9 days. Subsequently, N4CT1-EBOVGP1 demonstrated complete, single-dose protection of 2 macaques following lethal EBOV challenge. A single sham-vaccinated macaque died from disease due to EBOV infection. These results demonstrate that highly attenuated rVSV vectors expressing EBOV GP may provide safer alternatives to current EBOV vaccines. PMID:26109675

UV-induced lethal sectoring and pure mutant clones in yeast.

PubMed

Hannan, M A; Duck, P; Nasim, A

1976-08-01

The induction of lethal sectoring and pure mutant clones by ultraviolet light has been studied in a homogeneous G1 population of Saccharomyces cerevisiae grown in a normal growth medium. At the lowest UV dose of 250 ergs, which corresponds to a shoulder in the survival curve, all mutants appeared as pure clones. At higher doses the frequency of mosaic mutants progressively increased. These results indicate a relationship between the highest frequency of complete mutants and the maximum repair activity. In addition, the frequency of lethal sectoring at all doses tested was too low to account for the origin of pure mutant clones.

Priming dose of phenylhydrazine protects against hemolytic and lethal effects of 2-butoxyethanol

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

Palkar, Prajakta S.; Philip, Binu K.; Reddy, Ramesh N.

2007-11-15

Protection against a high dose of a toxicant by prior exposure to another toxicant is called heteroprotection. Our objective was to establish a heteroprotection model in RBCs. Female Sprague Dawley rats treated with an LD90 dose of 2-butoxyethanol (BE, 1500 mg/kg in water, 5 ml/kg po) 14 days after priming with 0.9% NaCl suffered 90% mortality by 15 days, whereas all rats receiving the LD90 dose of BE 14 days after priming with phenylhydrazine (PHZ, 125 mg/kg in 0.9% NaCl, 3 ml/kg po) survived. Hematocrit decreased from normal 45% to 24% by day 3 after PHZ priming and improved thereafter.more » Increasing the time interval between the priming and LD90 dose to 21 days abolished the heteroprotection. RBCs obtained on days 7 and 14 after PHZ priming unlike those on day 21 were resilient to the hemotoxic metabolite of BE, butoxyacetic acid (BAA). Unaltered hepatic alcohol and aldehyde dehydrogenase activities upon PHZ priming suggested that bioactivation of BE to BAA was unaffected. Lower renal (6 and 12 h) and hepatic (12 h) BAA levels and 3 fold higher excretion of BAA in PHZ-primed rat urine suggested a protective role of toxicokinetics. Higher erythropoietin, reticulocytes, and resiliency of PHZ-primed rat RBCs indicated that newly formed RBCs are resilient to hemolytic BAA. The antioxidant levels in the PHZ-primed rat RBCs did not indicate a protective role in heteroprotection. In conclusion, the resistance of PHZ-primed rats against BE-induced hemotoxicity and lethality is mediated by a combination of altered toxicokinetics, robust erythropoiesis, and resiliency of new RBCs.« less

Calculating Hematopoietic-Mode-Lethality Risk Avoidance Associated with Radionuclide Decorporation Countermeasures Related to a Radiological Terrorism Incident

PubMed Central

Scott, Bobby R.

2009-01-01

This paper provides theoretical health-risk-assessment tools that are designed to facilitate planning for and managing radiological terrorism incidents that involve ingestion exposure to bone-seeking radionuclides (e.g., radiostrontium nuclides). The focus is on evaluating lethality risk avoidance (RAV; i.e., the decrease in risk) that is associated with radionuclide decorporation countermeasures employed to remove ingested bone-seeking beta and/or gamma-emitting radionuclides from the body. To illustrate the application of tools presented, hypothetical radiostrontium decorporation scenarios were considered that involved evaluating the hematopoietic-mode-lethality RAV. For evaluating the efficacy of specific decorporation countermeasures, the lethality risk avoidance proportion (RAP; which is the RAV divided by the total lethality risk in the absence of protective countermeasures) is introduced. The lethality RAP is expected to be a useful tool for designing optimal radionuclide decorporation schemes and for identifying green, yellow and red dose-rate zones. For the green zone, essentially all of the lethality risk is expected to be avoided (RAP = 1) as a consequence of the radionuclide decorporation scheme used. For the yellow zone, some but not all of the lethality risk is expected to be avoided. For the red zone, none of the lethality risk (which equals 1) is expected to be avoided. PMID:20011652

Core body temperature as adjunct to endpoint determination in murine median lethal dose testing of rattlesnake venom.

PubMed

Cates, Charles C; McCabe, James G; Lawson, Gregory W; Couto, Marcelo A

2014-12-01

Median lethal dose (LD50) testing in mice is the 'gold standard' for evaluating the lethality of snake venoms and the effectiveness of interventions. As part of a study to determine the murine LD50 of the venom of 3 species of rattlesnake, temperature data were collected in an attempt to more precisely define humane endpoints. We used an 'up-and-down' methodology of estimating the LD50 that involved serial intraperitoneal injection of predetermined concentrations of venom. By using a rectal thermistor probe, body temperature was taken once before administration and at various times after venom exposure. All but one mouse showed a marked, immediate, dose-dependent drop in temperature of approximately 2 to 6°C at 15 to 45 min after administration. The lowest temperature sustained by any surviving mouse was 33.2°C. Surviving mice generally returned to near-baseline temperatures within 2 h after venom administration, whereas mice that did not survive continued to show a gradual decline in temperature until death or euthanasia. Logistic regression modeling controlling for the effects of baseline core body temperature and venom type showed that core body temperature was a significant predictor of survival. Linear regression of the interaction of time and survival was used to estimate temperatures predictive of death at the earliest time point and demonstrated that venom type had a significant influence on temperature values. Overall, our data suggest that core body temperature is a useful adjunct to monitoring for endpoints in LD50 studies and may be a valuable predictor of survival in venom studies.

Dose-response tests and semi-field evaluation of lethal and sub-lethal effects of slow release pyriproxyfen granules (Sumilarv®0.5G) for the control of the malaria vectors Anopheles gambiae sensu lato.

PubMed

Mbare, Oscar; Lindsay, Steven W; Fillinger, Ulrike

2013-03-14

Recently research has shown that larviciding can be an effective tool for integrated malaria vector control. Nevertheless, the uptake of this intervention has been hampered by the need to re-apply larvicides frequently. There is a need to explore persistent, environmentally friendly larvicides for malaria vector control to reduce intervention efforts and costs by reducing the frequency of application. In this study, the efficacy of a 0.5% pyriproxyfen granule (Surmilarv®0.5G, Sumitomo Chemicals) was assessed for the control of Anopheles gambiae sensu stricto and Anopheles arabiensis, the major malaria vectors in sub-Saharan Africa. Dose-response and standardized field tests were implemented following standard procedures of the World Health Organization's Pesticide Evaluation Scheme to determine: (i) the susceptibility of vectors to this formulation; (ii) the residual activity and appropriate retreatment schedule for field application; and, (iii) sub-lethal impacts on the number and viability of eggs laid by adults after exposure to Sumilarv®0.5G during larval development. Anopheles gambiae s.s. and An. arabiensis were highly susceptible to Sumilarv®0.5G. Estimated emergence inhibition (EI) values were very low and similar for both species. The minimum dosage that completely inhibited adult emergence was between 0.01-0.03 parts per million (ppm) active ingredient (ai). Compared to the untreated control, an application of 0.018 ppm ai prevented 85% (95% confidence interval (CI) 82%-88%) of adult emergence over six weeks under standardized field conditions. A fivefold increase in dosage of 0.09 ppm ai prevented 97% (95% CI 94%-98%) emergence. Significant sub-lethal effects were observed in the standardized field tests. Female An. gambiae s.s. that were exposed to 0.018 ppm ai as larvae laid 47% less eggs, and females exposed to 0.09 ppm ai laid 74% less eggs than females that were unexposed to the treatment. Furthermore, 77% of eggs laid by females exposed to 0

Lethal mobilization of DDT by cowbirds

USGS Publications Warehouse

Van Velzen, A.C.; Stiles, W.B.; Stickel, L.F.

1972-01-01

This study is an experimental demonstration of lethal mobilization of DDT by brown-headed cowbirds (Molothrus ater) and the effects of food deprivation on the distribution and loss of DDT, DDD, and DDE. The principal experimental group consisted of 20 birds fed a dietary dosage of 100 ppm of DDT for 13 days. After 2 days of full rations of untreated food, they were subjected to food restriction. Food was reduced to 43 percent of normal. Seven of the 20 birds died within 4 days. No birds died in the three control groups, treated as follows: ( 1 ) 20 birds fed 100 ppm DDT for 13 days and full rations of untreated food thereafter, (2) 20 birds fed only untreated food but subjected to food restriction, and (3) 20 birds fed full rations of untreated food throughout. In a pilot study, birds were fed 100, 200, or 300 ppm of DDT and subjected to two periods of food restriction, the first of these immediately after dosage ceased and the second 4 months later. DDT-dosed birds from all dosage levels died in each period of food restriction. Before the weight loss that accompanied food restriction, the brains of DDT-dosed birds had concentrations of DDT and DDD that were far below the lethal range. Concentrations increased rapidly to lethal levels. In these birds, DDT in carcasses decreased while DDD increased. DDT-dosed birds that died during food restriction lost 16 percent of their total body burden of DDT + DDD + DDE, 21 percent of their weight, and 81 percent of their fat. The DDT-dosed birds that were subjected to food restriction but survived lost a significantly greater proportion of their body burden of residues than similarly dosed birds not subjected to weight loss. Brain levels of DDT and DDD in birds that died during food restriction soon after dosage did not differ significantly from brain levels of birds that died in a period of food restriction 4 months after dosage. Concentrations of DDE were significantly higher in the latter group, although they were lower

Rancher-reported efficacy of lethal and non-lethal livestock predation mitigation strategies for a suite of carnivores.

PubMed

Scasta, J D; Stam, B; Windh, J L

2017-10-26

Pastoralists have dealt with livestock losses from predators for millennia, yet effective mitigation strategies that balance wildlife conservation and sustainable agriculture are still needed today. In Wyoming, USA, 274 ranchers responded to a retrospective survey, and rated the efficacy of predation mitigation strategies for foxes, dogs, coyotes, wolves, bobcats, mountain lions, bears, and birds (buzzards, eagles, hawks, ravens). Rancher reported efficacy of mitigation varied by predator species, mitigation strategy, and lethality of strategies, but not livestock type. Ranchers perceive they were most effective at mitigating predation by foxes and coyotes, moderately effective at mitigating large carnivores, and the least effective at mitigating birds. Ranchers also reported that avian predators seem to be the most challenging predator type. The general perception was lethal mitigation strategies were more effective than non-lethal strategies, with guard animals showing the most potential among the non-lethal options. In general, ranchers did not perceive non-lethal strategies as a proxy for lethal strategies. However, a few ranchers reported being successful with non-lethal options such as herding, fencing, and stalling at night but more details about such successful applications are needed. Innovation in current or novel non-lethal mitigation strategies, and examples of efficacy, are needed to justify producer adoption.

Core Body Temperature as Adjunct to Endpoint Determination in Murine Median Lethal Dose Testing of Rattlesnake Venom

PubMed Central

Cates, Charles C; McCabe, James G; Lawson, Gregory W; Couto, Marcelo A

2014-01-01

Median lethal dose (LD50) testing in mice is the ‘gold standard’ for evaluating the lethality of snake venoms and the effectiveness of interventions. As part of a study to determine the murine LD50 of the venom of 3 species of rattlesnake, temperature data were collected in an attempt to more precisely define humane endpoints. We used an ‘up-and-down’ methodology of estimating the LD50 that involved serial intraperitoneal injection of predetermined concentrations of venom. By using a rectal thermistor probe, body temperature was taken once before administration and at various times after venom exposure. All but one mouse showed a marked, immediate, dose-dependent drop in temperature of approximately 2 to 6 °C at 15 to 45 min after administration. The lowest temperature sustained by any surviving mouse was 33.2 °C. Surviving mice generally returned to near-baseline temperatures within 2 h after venom administration, whereas mice that did not survive continued to show a gradual decline in temperature until death or euthanasia. Logistic regression modeling controlling for the effects of baseline core body temperature and venom type showed that core body temperature was a significant predictor of survival. Linear regression of the interaction of time and survival was used to estimate temperatures predictive of death at the earliest time point and demonstrated that venom type had a significant influence on temperature values. Overall, our data suggest that core body temperature is a useful adjunct to monitoring for endpoints in LD50 studies and may be a valuable predictor of survival in venom studies. PMID:25527024

Chronic Exposure of Corals to Fine Sediments: Lethal and Sub-Lethal Impacts

PubMed Central

Flores, Florita; Hoogenboom, Mia O.; Smith, Luke D.; Cooper, Timothy F.; Abrego, David; Negri, Andrew P.

2012-01-01

Understanding the sedimentation and turbidity thresholds for corals is critical in assessing the potential impacts of dredging projects in tropical marine systems. In this study, we exposed two species of coral sampled from offshore locations to six levels of total suspended solids (TSS) for 16 weeks in the laboratory, including a 4 week recovery period. Dose-response relationships were developed to quantify the lethal and sub-lethal thresholds of sedimentation and turbidity for the corals. The sediment treatments affected the horizontal foliaceous species (Montipora aequituberculata) more than the upright branching species (Acropora millepora). The lowest sediment treatments that caused full colony mortality were 30 mg l−1 TSS (25 mg cm−2 day−1) for M. aequituberculata and 100 mg l−1 TSS (83 mg cm−2 day−1) for A. millepora after 12 weeks. Coral mortality generally took longer than 4 weeks and was closely related to sediment accumulation on the surface of the corals. While measurements of damage to photosystem II in the symbionts and reductions in lipid content and growth indicated sub-lethal responses in surviving corals, the most reliable predictor of coral mortality in this experiment was long-term sediment accumulation on coral tissue. PMID:22662225

Treatment of Irradiated Mice with High-Dose Ascorbic Acid Reduced Lethality

PubMed Central

Sato, Tomohito; Kinoshita, Manabu; Yamamoto, Tetsuo; Ito, Masataka; Nishida, Takafumi; Takeuchi, Masaru; Saitoh, Daizoh; Seki, Shuhji; Mukai, Yasuo

2015-01-01

Ascorbic acid is an effective antioxidant and free radical scavenger. Therefore, it is expected that ascorbic acid should act as a radioprotectant. We investigated the effects of post-radiation treatment with ascorbic acid on mouse survival. Mice received whole body irradiation (WBI) followed by intraperitoneal administration of ascorbic acid. Administration of 3 g/kg of ascorbic acid immediately after exposure significantly increased mouse survival after WBI at 7 to 8 Gy. However, administration of less than 3 g/kg of ascorbic acid was ineffective, and 4 or more g/kg was harmful to the mice. Post-exposure treatment with 3 g/kg of ascorbic acid reduced radiation-induced apoptosis in bone marrow cells and restored hematopoietic function. Treatment with ascorbic acid (3 g/kg) up to 24 h (1, 6, 12, or 24 h) after WBI at 7.5 Gy effectively improved mouse survival; however, treatments beyond 36 h were ineffective. Two treatments with ascorbic acid (1.5 g/kg × 2, immediately and 24 h after radiation, 3 g/kg in total) also improved mouse survival after WBI at 7.5 Gy, accompanied with suppression of radiation-induced free radical metabolites. In conclusion, administration of high-dose ascorbic acid might reduce radiation lethality in mice even after exposure. PMID:25651298

The Hematopoietic Syndrome of the Acute Radiation Syndrome in Rhesus Macaques: A Systematic Review of the Lethal Dose Response Relationship.

PubMed

MacVittie, Thomas J; Farese, Ann M; Jackson, William

2015-11-01

Well characterized animal models that mimic the human response to potentially lethal doses of radiation are required to assess the efficacy of medical countermeasures under the criteria of the U.S. Food and Drug Administration "animal rule." Development of a model requires the determination of the radiation dose response relationship and time course of mortality and morbidity across the hematopoietic acute radiation syndrome. The nonhuman primate, rhesus macaque, is a relevant animal model that may be used to determine the efficacy of medical countermeasures to mitigate major signs of morbidity and mortality at selected lethal doses of total body irradiation. A systematic review of relevant studies that determined the dose response relationship for the hematopoietic acute radiation syndrome in the rhesus macaque relative to radiation quality, dose rate, and exposure uniformity has never been performed. The selection of data cohorts was made from the following sources: Ovid Medline (1957-present), PubMed (1954-present), AGRICOLA (1976-present), Web of Science (1954-present), and U.S. HHS REPORT (2002 to present). The following terms were used: Rhesus, total body-irradiation, total body x irradiation, TBI, irradiation, gamma radiation, hematopoiesis, LD50/60, Macaca mulatta, whole-body irradiation, nonhuman primate, NHP, monkey, primates, hematopoietic radiation syndrome, mortality, and nuclear radiation. The reference lists of all studies, published and unpublished, were reviewed for additional studies. The total number of hits across all search sites was 3,001. There were a number of referenced, unpublished, non-peer reviewed government reports that were unavailable for review. Fifteen studies, 11 primary (n = 863) and four secondary (n = 153) studies [n = 1,016 total nonhuman primates (NHP), rhesus Macaca mulatta] were evaluated to provide an informative and consistent review. The dose response relationships (DRRs) were determined for uniform or non-uniform total

Lethality In Mice Following Localized Photodynamic Therapy

NASA Astrophysics Data System (ADS)

Ferrario, Angela; Gomer, Charles J.; Murphree, A. L.

1989-06-01

Porphyrin photodynamic therapy directed specifically to the hind leg of various strains of mice was found to induce a high percentage of lethality at dosages which would be required to achieve cures in tumor bearing mice. Toxicity was observed in both pigmented and albino mouse strains. An inverse relationship between light dose rate and lethality was documented. Anti-coagulant drugs and anti-inflammatory agents which inhibit cyclo-oxygenase had protective effects. The response induced by localized PDT appears to mimic that of a classical traumatic shock syndrome and may be limited to PDT in small animals such as mice.

Comparative toxicity and efficacy of engineered anthrax lethal toxin variants with broad anti-tumor activities.

PubMed

Peters, Diane E; Hoover, Benjamin; Cloud, Loretta Grey; Liu, Shihui; Molinolo, Alfredo A; Leppla, Stephen H; Bugge, Thomas H

2014-09-01

We have previously designed and characterized versions of anthrax lethal toxin that are selectively cytotoxic in the tumor microenvironment and which display broad and potent anti-tumor activities in vivo. Here, we have performed the first direct comparison of the safety and efficacy of three engineered anthrax lethal toxin variants requiring activation by either matrix-metalloproteinases (MMPs), urokinase plasminogen activator (uPA) or co-localized MMP/uPA activities. C57BL/6J mice were challenged with six doses of engineered toxins via intraperitoneal (I.P.) or intravenous (I.V.) dose routes to determine the maximum tolerated dose for six administrations (MTD6) and dose-limiting toxicities. Efficacy was evaluated using the B16-BL6 syngraft model of melanoma; mice bearing established tumors were treated with six I.P. doses of toxin and tumor measurements and immunohistochemistry, paired with terminal blood work, were used to elaborate upon the anti-tumor mechanism and relative efficacy of each variant. We found that MMP-, uPA- and dual MMP/uPA-activated anthrax lethal toxins exhibited the same dose-limiting toxicity; dose-dependent GI toxicity. In terms of efficacy, all three toxins significantly reduced primary B16-BL6 tumor burden, ranging from 32% to 87% reduction, and they also delayed disease progression as evidenced by dose-dependent normalization of blood work values. While target organ toxicity and effective doses were similar amongst the variants, the dual MMP/uPA-activated anthrax lethal toxin exhibited the highest I.P. MTD6 and was 1.5-3-fold better tolerated than the single MMP- and uPA-activated toxins. Overall, we demonstrate that this dual MMP/uPA-activated anthrax lethal toxin can be administered safely and is highly effective in a preclinical model of melanoma. This modified bacterial cytotoxin is thus a promising candidate for further clinical development and evaluation for use in treating human cancers. Published by Elsevier Inc.

Comparative toxicity and efficacy of engineered anthrax lethal toxin variants with broad anti-tumor activities

PubMed Central

Peters, Diane E.; Hoover, Benjamin; Cloud, Loretta Grey; Liu, Shihui; Molinolo, Alfredo A.; Leppla, Stephen H.; Bugge, Thomas H.

2014-01-01

We have previously designed and characterized versions of anthrax lethal toxin that are selectively cytotoxic in the tumor microenvironment and which display broad and potent anti-tumor activities in vivo. Here, we have performed the first direct comparison of the safety and efficacy of three engineered anthrax lethal toxin variants requiring activation by either matrix-metalloproteinases (MMPs), urokinase plasminogen activator (uPA) or co-localized MMP/uPA activities. C57BL/6J mice were challenged with six doses of engineered toxins via intraperitoneal (I.P.) or intravenous (I.V.) dose routes to determine the maximum tolerated dose for six administrations (MTD6) and dose-limiting toxicities. Efficacy was evaluated using the B16-BL6 syngraft model of melanoma; Mice bearing established tumors were treated with six I.P. doses of toxin and tumor measurements and immunohistochemistry, paired with terminal blood work, were used to elaborate upon the anti-tumor mechanism and relative efficacy of each variant. We found that MMP-, uPA- and dual MMP/uPA- activated anthrax lethal toxins exhibited the same dose-limiting toxicity; dose-dependent GI toxicity. In terms of efficacy, all three toxins significantly reduced primary B16-BL6 tumor burden, ranging from 32%–87% reduction, and they also delayed disease progression as evidenced by dose-dependent normalization of blood work values. While target organ toxicity and effective doses were similar amongst the variants, the dual MMP/uPA-activated anthrax lethal toxin exhibited the highest I.P. MTD6 and was 1.5–3-fold better tolerated than the single MMP- and uPA-activated toxins. Overall, we demonstrate that this dual MMP/uPA-activated anthrax lethal toxin can be administered safely and is highly effective in a preclinical model of melanoma. This modified bacterial cytotoxin is thus a promising candidate for further clinical development and evaluation for use in treating human cancers. PMID:24971906

Acute Lethality after Fast-Neutron and X-Irradiation of Tribolium confusum

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

Glenn, Norman D.; Ducoff, Howard S.

1976-01-01

The acute lethal effects of fast neutrons and of X-rays on adults and larvae of T. confusum are compared. The time course of mortality of adults of the Oklahoma strain was the same after midlethal doses of neutrons and X-rays, although the neutrons were about twice as effective as X-rays in producing lethality, based on LD 50(35). The neutron RBE for adults of the Ebony mutant strain was also about 2, but that for Oklahoma larvae was about 3.85. Larvae surviving midlethal doses of neutrons showed a tendency toward wing abnormalities and delayed pupation. Dose-fractionation recovery with neutron doses inmore » the midlethal range was not detectable in the adults or in the larvae. A considerable sparing effect of dose fractionation was found in X-irradiated adults. Finally, also presented are techniques for using a beam port of a Triga research reactor for fast-neutron irradiation and a method of neutron and gamma dosimetry.« less

Filgrastim Improves Survival in Lethally Irradiated Nonhuman Primates

PubMed Central

Farese, Ann M.; Cohen, Melanie V.; Katz, Barry P.; Smith, Cassandra P.; Gibbs, Allison; Cohen, Daniel M.; MacVittie, Thomas J.

2015-01-01

Treatment of individuals exposed to potentially lethal doses of radiation is of paramount concern to health professionals and government agencies. We evaluated the efficacy of filgrastim to increase survival of nonhuman primates (NHP) exposed to an approximate mid-lethal dose (LD50/60) (7.50 Gy) of LINAC-derived photon radiation. Prior to total-body irradiation (TBI), nonhuman primates were randomized to either a control (n =22) or filgrastim-treated (n =24) cohorts. Filgrastim (10 μg/kg/d) was administered beginning 1 day after TBI and continued daily until the absolute neutrophil count (ANC) was >1,000/μL for 3 consecutive days. All nonhuman primates received medical management as per protocol. The primary end point was all cause overall mortality over the 60 day in-life study. Secondary end points included mean survival time of decedents and all hematologic-related parameters. Filgrastim significantly (P < 0.004) reduced 60 day overall mortality [20.8% (5/24)] compared to the controls [59.1% (13/22)]. Filgrastim significantly decreased the duration of neutropenia, but did not affect the absolute neutrophil count nadir. Febrile neutropenia (ANC <500/μL and body temperature ≥103°F) was experienced by 90.9% (20/22) of controls compared to 79.2% (19/24) of filgrastim-treated animals (P = 0.418). Survival was significantly increased by 38.3% over controls. Filgrastim, administered at this dose and schedule, effectively mitigated the lethality of the hematopoietic subsyndrome of the acute radiation syndrome. PMID:23210705

Prophylaxis with human serum butyrylcholinesterase protects Göttingen minipigs exposed to a lethal high-dose of sarin vapor.

PubMed

Saxena, Ashima; Hastings, Nicholas B; Sun, Wei; Dabisch, Paul A; Hulet, Stanley W; Jakubowski, Edward M; Mioduszewski, Robert J; Doctor, Bhupendra P

2015-08-05

Serum-derived human butyrylcholinesterase (Hu BChE) is a stoichiometric bioscavenger that is being developed as a potential prophylactic nerve agent countermeasure. Previously, we reported the prophylactic efficacy of Hu BChE in Göttingen minipigs against a whole-body exposure to 4.1mg/m(3) of sarin (GB) vapor, which produced lethality over 60min. Since the toxicity of nerve agent is concentration-dependent, in the present study, we investigated the toxic effects of an almost 3-fold higher rate of GB vapor exposure and the ability of Hu BChE to protect minipigs against this exposure. Male minipigs were subjected to: (1) air exposure; (2) GB vapor exposure; or (3) pretreatment with 7.5mg/kg of Hu BChE by i.m. injection, 24h prior to whole-body exposure to 11.4mg/m(3) of GB vapor for 10min. Electrocardiogram, electroencephalogram, and pupil size were monitored throughout exposure. Blood drawn before and throughout exposure was analyzed for blood gases, electrolytes, metabolites, acetylcholinesterase and BChE activities, and amount of GB bound to red blood cells and plasma. A novel finding was that saline-treated animals exposed to GB vapor did not develop any seizures, but manifested a variety of cardiac and whole blood toxic signs and rapidly died due to respiratory failure. Strikingly, pre-treatment with 7.5mg/kg of Hu BChE not only prevented lethality, but also avoided all cardiac toxic signs manifested in the non-treated cohort. Thus, Hu BChE alone can serve as an effective prophylactic countermeasure versus a lethal high-dose exposure to GB vapor. Published by Elsevier Ireland Ltd.

Sub-lethal glyphosate exposure alters flowering phenology and causes transient male-sterility in Brassica spp

PubMed Central

2014-01-01

Background Herbicide resistance in weedy plant populations can develop through different mechanisms such as gene flow of herbicide resistance transgenes from crop species into compatible weedy species or by natural evolution of herbicide resistance or tolerance following selection pressure. Results from our previous studies suggest that sub-lethal levels of the herbicide glyphosate can alter the pattern of gene flow between glyphosate resistant Canola®, Brassica napus, and glyphosate sensitive varieties of B. napus and B. rapa. The objectives of this study were to examine the phenological and developmental changes that occur in Brassica crop and weed species following sub-lethal doses of the herbicides glyphosate and glufosinate. We examined several vegetative and reproductive traits of potted plants under greenhouse conditions, treated with sub-lethal herbicide sprays. Results Our results indicate that exposure of Brassica spp. to a sub-lethal dose of glyphosate results in altering flowering phenology and reproductive function. Flowering of all sensitive species was significantly delayed and reproductive function, specifically male fertility, was suppressed. Higher dosage levels typically contributed to an increase in the magnitude of phenotypic changes. Conclusions These results demonstrate that Brassica spp. plants that are exposed to sub-lethal doses of glyphosate could be subject to very different pollination patterns and an altered pattern of gene flow that would result from changes in the overlap of flowering phenology between species. Implications include the potential for increased glyphosate resistance evolution and spread in weedy communities exposed to sub-lethal glyphosate. PMID:24655547

Sub-lethal glyphosate exposure alters flowering phenology and causes transient male-sterility in Brassica spp.

PubMed

Londo, Jason Paul; McKinney, John; Schwartz, Matthew; Bollman, Mike; Sagers, Cynthia; Watrud, Lidia

2014-03-21

Herbicide resistance in weedy plant populations can develop through different mechanisms such as gene flow of herbicide resistance transgenes from crop species into compatible weedy species or by natural evolution of herbicide resistance or tolerance following selection pressure. Results from our previous studies suggest that sub-lethal levels of the herbicide glyphosate can alter the pattern of gene flow between glyphosate resistant Canola®, Brassica napus, and glyphosate sensitive varieties of B. napus and B. rapa. The objectives of this study were to examine the phenological and developmental changes that occur in Brassica crop and weed species following sub-lethal doses of the herbicides glyphosate and glufosinate. We examined several vegetative and reproductive traits of potted plants under greenhouse conditions, treated with sub-lethal herbicide sprays. Our results indicate that exposure of Brassica spp. to a sub-lethal dose of glyphosate results in altering flowering phenology and reproductive function. Flowering of all sensitive species was significantly delayed and reproductive function, specifically male fertility, was suppressed. Higher dosage levels typically contributed to an increase in the magnitude of phenotypic changes. These results demonstrate that Brassica spp. plants that are exposed to sub-lethal doses of glyphosate could be subject to very different pollination patterns and an altered pattern of gene flow that would result from changes in the overlap of flowering phenology between species. Implications include the potential for increased glyphosate resistance evolution and spread in weedy communities exposed to sub-lethal glyphosate.

Rifaximin diminishes neutropenia following potentially lethal whole-body radiation.

PubMed

Jahraus, Christopher D; Schemera, Bettina; Rynders, Patricia; Ramos, Melissa; Powell, Charles; Faircloth, John; Brawner, William R

2010-07-01

Terrorist attacks involving radiological or nuclear weapons are a substantial geopolitical concern, given that large populations could be exposed to potentially lethal doses of radiation. Because of this, evaluating potential countermeasures against radiation-induced mortality is critical. Gut microflora are the most common source of systemic infection following exposure to lethal doses of whole-body radiation, suggesting that prophylactic antibiotic therapy may reduce mortality after radiation exposure. The chemical stability, easy administration and favorable tolerability profile of the non-systemic antibiotic, rifaximin, make it an ideal potential candidate for use as a countermeasure. This study evaluated the use of rifaximin as a countermeasure against low-to-intermediate-dose whole-body radiation in rodents. Female Wistar rats (8 weeks old) were irradiated with 550 cGy to the whole body and were evaluated for 30 d. Animals received methylcellulose, neomycin (179 mg/kg/d) or variably dosed rifaximin (150-2000 mg/kg/d) one hour after irradiation and daily throughout the study period. Clinical assessments (e.g. body weight) were made daily. On postirradiation day 30, blood samples were collected and a complete blood cell count was performed. Animals receiving high doses of rifaximin (i.e. 1000 or 2000 mg/kg/d) had a greater increase in weight from the day of irradiation to postirradiation day 30 compared with animals that received placebo or neomycin. For animals with an increase in average body weight from irradiation day within 80-110% of the group average, methylcellulose rendered an absolute neutrophil count (ANC) of 211, neomycin rendered an ANC of 334, rifaximin 300 mg/kg/d rendered an ANC of 582 and rifaximin 1000 mg/kg/d rendered an ANC of 854 (P = 0.05 for group comparison). Exposure to rifaximin after near-lethal whole-body radiation resulted in diminished levels of neutropenia.

Single dose of an adenovirus vectored mouse interferon-α protects mice from lethal EV71 challenge.

PubMed

Sun, Jialei; Ennis, Jane; Turner, Jeffrey D; Chu, Justin Jang Hann

2016-10-01

Enterovirus 71 (EV71) causes hand-foot-and-mouth diseases as well as neurological complications in young children. Interferon (IFN) can inhibit the replication of many viruses with low cytotoxic effects. Previously, an adenovirus vectored mouse interferon-α (DEF201), subtype 5, was generated by Wu et al, 2007. In this study, the antiviral effects of DEF201 against EV71 were evaluated in a murine model. 6-day-old BALB/c mice were administered a single dose of DEF201 before or after infection with lethal dose of EV71. The survival rate, clinical symptoms, tissue viral loads and histology pathogenesis were evaluated. IFN gene expression following a single dose of DEF201 maintained high concentrations of 100-9000 pg/mL for more than 7 days in mice serum. Pre-infection administration of a single dose of 10 6  PFU of DEF201 offered full protection of the mice against EV71 infection compared with the empty Ad5 vector control. In addition, virus load in DEF201-treated mice muscle tissue was significantly decreased as compared with empty vector control. Histopathology analysis revealed that DEF201 significantly prevented the development of severe tissue damage with reduction of viral antigen in the murine muscle tissue. Post-infection treatment at 6 h offered full protection and partial protection at 12 h, indicating that DEF201 could be used as an anti-EV71 therapeutic agent in early stage of EV71 infection. In addition, our study showed that DEF201 enhanced the neutralization ability of serum in EV71-vaccinated mice, implying that DEF201 could promote the production of specific anti-EV71 antibodies. In conclusion, single dose of DEF201 is highly efficacious as a prophylactic agent against EV71 infection in vivo. Copyright © 2016 Elsevier B.V. All rights reserved.

Issues surrounding lethal injection as a means of capital punishment.

PubMed

Romanelli, Frank; Whisman, Tyler; Fink, Joseph L

2008-12-01

Lethal injection as a method of state-sanctioned capital punishment was initially proposed in the United States in 1977 and used for the first time in 1982. Most lethal injection protocols use a sequential drug combination of sodium thiopental, pancuronium bromide, and potassium chloride. Lethal injection was originally introduced as a more humane form of execution compared with existing mechanical methods such as electrocution, toxic gassing, hanging, or firing squad. Lethal injection has not, however, been without controversy. Several states are considering whether lethal injection meets constitutional scrutiny forbidding cruel and unusual punishment. Recently in the case of Ralph Baze and Thomas C. Bowling, Petitioners, v John D. Rees, Commissioner, Kentucky Department of Corrections et al, the United States Supreme Court upheld the constitutionality of the lethal injection protocol as carried out in the Commonwealth of Kentucky. Most of the debate has surrounded the dosing and procedures used in lethal injection and whether the drug combinations and measures for administering the drugs truly produce a timely, pain-free, and fail-safe death. Many have also raised issues regarding the "medicalization" of execution and the ethics of health care professionals' participation in any part of the lethal injection process. As a result of all these issues, the future of lethal injection as a means of execution in the United States is under significant scrutiny. Outcomes of ongoing legislative and judicial reviews might result in cessation of lethal injection in totality or in alterations involving specific drug combinations or administration procedures.

Lethal and sub-lethal responses of native freshwater mussels exposed to granular Bayluscide®, a sea lamprey larvicide

USGS Publications Warehouse

Newton, Teresa; Boogaard, Michael A.; Gray, Brian R.; Hubert, Terrance D.; Schloesser, Nicholas

2017-01-01

The invasive sea lamprey (Petromyzon marinus) poses a substantial threat to fish communities in the Great Lakes. Efforts to control sea lamprey populations typically involve treating tributary streams with lampricides on a recurring cycle. The presence of a substantial population of larval sea lampreys in the aquatic corridor between Lakes Huron and Erie prompted managers to propose a treatment using the granular formulation of Bayluscide® that targets larval sea lampreys that reside in sediments. However, these treatments could cause adverse effects on native freshwater mussels—imperiled animals that also reside in sediments. We estimated the risk of mortality and sub-lethal effects among eight species of adult and sub-adult mussels exposed to Bayluscide® for durations up to 8 h to mimic field applications. Mortality was appreciable in some species, especially in sub-adults (range, 23–51%). The lethal and sub-lethal effects were positively associated with the duration of exposure in most species and life stage combinations. Estimates of the median time of exposure that resulted in lethal and sub-lethal effects suggest that sub-adults were often affected by Bayluscide® earlier than adults. Siphoning activity and burrowing position of mussels during exposure may have moderated the uptake of Bayluscide® and may have influenced lethal and sub-lethal responses. Given that the various species and life stages were differentially affected, it will be difficult to predict the effects of Bayluscide® treatments on mussels.

Stage-dependent teratogenic and lethal effects exerted by ultraviolet B radiation on Rhinella (Bufo) arenarum embryos.

PubMed

Castañaga, Luis A; Asorey, Cynthia M; Sandoval, María T; Pérez-Coll, Cristina S; Argibay, Teresa I; Herkovits, Jorge

2009-02-01

The adverse effects of ultraviolet B radiation from 547.2 to 30,096 J/m2 on morphogenesis, cell differentiation, and lethality of amphibian embryos at six developmental stages were evaluated from 24 up to 168 h postexposure. The ultraviolet B radiation lethal dose 10, 50, and 90 values were obtained for all developmental stages evaluated. The lethal dose 50 values, considered as the dose causing lethality in the 50% of the organisms exposed, in J/m2 at 168 h postexposure, ranged from 2,307 to 18,930; gill circulation and blastula were the most susceptible and resistant stages, respectively. Ultraviolet B radiation caused malformations in all developmental stages but was significantly more teratogenic at the gill circulation and complete operculum stages. Moreover, at the gill circulation stage, even the lowest dose (547.2 J/m2) resulted in malformations to 100% of embryos. The most common malformations were persistent yolk plug, bifid spine, reduced body size, delayed development, asymmetry, microcephaly and anencephaly, tail and body flexures toward the irradiated side, agenesia or partial gill development, abnormal pigment distribution, and hypermotility. The stage-dependent susceptibility to ultraviolet B radiation during amphibian embryogenesis could be explained in the framework of evoecotoxicology, considering ontogenic features as biomarkers of environmental signatures of living forms ancestors during the evolutionary process. The stage-dependent susceptibility to ultraviolet B radiation on Rhinella (Bufo) arenarum embryos for both lethal and teratogenic effects could contribute to a better understanding of the role of the increased ultraviolet B radiation on worldwide amphibian populations decline.

Comparative toxicity and efficacy of engineered anthrax lethal toxin variants with broad anti-tumor activities

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

Peters, Diane E.; Program of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA; Hoover, Benjamin

2014-09-01

We have previously designed and characterized versions of anthrax lethal toxin that are selectively cytotoxic in the tumor microenvironment and which display broad and potent anti-tumor activities in vivo. Here, we have performed the first direct comparison of the safety and efficacy of three engineered anthrax lethal toxin variants requiring activation by either matrix-metalloproteinases (MMPs), urokinase plasminogen activator (uPA) or co-localized MMP/uPA activities. C57BL/6J mice were challenged with six doses of engineered toxins via intraperitoneal (I.P.) or intravenous (I.V.) dose routes to determine the maximum tolerated dose for six administrations (MTD6) and dose-limiting toxicities. Efficacy was evaluated using the B16-BL6more » syngraft model of melanoma; mice bearing established tumors were treated with six I.P. doses of toxin and tumor measurements and immunohistochemistry, paired with terminal blood work, were used to elaborate upon the anti-tumor mechanism and relative efficacy of each variant. We found that MMP-, uPA- and dual MMP/uPA-activated anthrax lethal toxins exhibited the same dose-limiting toxicity; dose-dependent GI toxicity. In terms of efficacy, all three toxins significantly reduced primary B16-BL6 tumor burden, ranging from 32% to 87% reduction, and they also delayed disease progression as evidenced by dose-dependent normalization of blood work values. While target organ toxicity and effective doses were similar amongst the variants, the dual MMP/uPA-activated anthrax lethal toxin exhibited the highest I.P. MTD6 and was 1.5–3-fold better tolerated than the single MMP- and uPA-activated toxins. Overall, we demonstrate that this dual MMP/uPA-activated anthrax lethal toxin can be administered safely and is highly effective in a preclinical model of melanoma. This modified bacterial cytotoxin is thus a promising candidate for further clinical development and evaluation for use in treating human cancers. - Highlights: • Toxicity and

Soluble factor(s) from bone marrow cells can rescue lethally irradiated mice by protecting endogenous hematopoietic stem cells.

PubMed

Zhao, Yi; Zhan, Yuxia; Burke, Kathleen A; Anderson, W French

2005-04-01

Ionizing radiation-induced myeloablation can be rescued via bone marrow transplantation (BMT) or administration of cytokines if given within 2 hours after radiation exposure. There is no evidence for the existence of soluble factors that can rescue an animal after a lethal dose of radiation when administered several hours postradiation. We established a system that could test the possibility for the existence of soluble factors that could be used more than 2 hours postirradiation to rescue animals. Animals with an implanted TheraCyte immunoisolation device (TID) received lethal-dose radiation and then normal bone marrow Lin- cells were loaded into the device (thereby preventing direct interaction between donor and recipient cells). Animal survival was evaluated and stem cell activity was tested with secondary bone marrow transplantation and flow cytometry analysis. Donor cell gene expression of five antiapoptotic cytokines was examined. Bone marrow Lin- cells rescued lethally irradiated animals via soluble factor(s). Bone marrow cells from the rescued animals can rescue and repopulate secondary lethally irradiated animals. Within the first 6 hours post-lethal-dose radiation, there is no significant change of gene expression of the known radioprotective factors TPO, SCF, IL-3, Flt-3 ligand, and SDF-1. Hematopoietic stem cells can be protected in lethally irradiated animals by soluble factors produced by bone marrow Lin- cells.

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

PubMed

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

2016-01-22

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

Non-Lethal Weapons Program

Science.gov Websites

), 26th Marine Expeditionary Unit (MEU), practice non-lethal control techniques during a non-lethal Skip to main content (Press Enter). Toggle navigation Non-Lethal Weapons Program Search Search JNLWP: Search Search JNLWP: Search Non-Lethal Weapons Program U.S. Department of Defense Non-Lethal

Acute Oral Toxicity of Tetrodotoxin in Mice: Determination of Lethal Dose 50 (LD50) and No Observed Adverse Effect Level (NOAEL).

PubMed

Abal, Paula; Louzao, M Carmen; Antelo, Alvaro; Alvarez, Mercedes; Cagide, Eva; Vilariño, Natalia; Vieytes, Mercedes R; Botana, Luis M

2017-02-24

Tetrodotoxin (TTX) is starting to appear in molluscs from the European waters and is a hazard to seafood consumers. This toxin blocks sodium channels resulting in neuromuscular paralysis and even death. As a part of the risk assessment process leading to a safe seafood level for TTX, oral toxicity data are required. In this study, a 4-level Up and Down Procedure was designed in order to determine for the first time the oral lethal dose 50 (LD 50 ) and the No Observed Adverse Effect Level (NOAEL) in mice by using an accurate well-characterized TTX standard.

Acute Oral Toxicity of Tetrodotoxin in Mice: Determination of Lethal Dose 50 (LD50) and No Observed Adverse Effect Level (NOAEL)

PubMed Central

Abal, Paula; Louzao, M. Carmen; Antelo, Alvaro; Alvarez, Mercedes; Cagide, Eva; Vilariño, Natalia; Vieytes, Mercedes R.; Botana, Luis M.

2017-01-01

Tetrodotoxin (TTX) is starting to appear in molluscs from the European waters and is a hazard to seafood consumers. This toxin blocks sodium channels resulting in neuromuscular paralysis and even death. As a part of the risk assessment process leading to a safe seafood level for TTX, oral toxicity data are required. In this study, a 4-level Up and Down Procedure was designed in order to determine for the first time the oral lethal dose 50 (LD50) and the No Observed Adverse Effect Level (NOAEL) in mice by using an accurate well-characterized TTX standard. PMID:28245573

Non-Lethal Technologies for the Objective Force

DTIC Science & Technology

2001-06-20

Cartridge (Sponge Grenade) 12 Gauge Non-Lethal Munitions XM1012, XM1013 5.56mm XM95 Rifle Launched Non-Lethal Munition Army Soldier Enhancement...Applications, effective 12 Sep 00. • USAMPS will serve as the U.S. Army Training and Doctrine Command’s single voice for all developments and initiatives to...1996 DoD NLW User’s Conference; Joint Concept for NLW’s & Per JMAA Jan 2000 - Joint Mission Area Analysis (JMAA) - 07/11/2001 12 Area Denial-Personnel

Complement component 5 promotes lethal thrombosis

PubMed Central

Mizuno, Tomohiro; Yoshioka, Kengo; Mizuno, Masashi; Shimizu, Mie; Nagano, Fumihiko; Okuda, Tomoyuki; Tsuboi, Naotake; Maruyama, Shoichi; Nagamatsu, Tadashi; Imai, Masaki

2017-01-01

Extracellular histones promote platelet aggregation and thrombosis; this is followed by induction of coagulation disorder, which results in exhaustion of coagulation factors. Complement component 5 (C5) is known to be associated with platelet aggregation and coagulation system activation. To date, the pathological mechanism underlying liver injury has remained unclear. Here, we investigated whether C5 promotes liver injury associated with histone-induced lethal thrombosis. C5-sufficient and C5-deficient mice received single tail vein injections of purified, unfractionated histones obtained from calf thymus (45–75 μg/g). Subsequently, the mice were monitored for survival for up to 72 h. Based on the survival data, the 45 μg/g dose was used for analysis of blood cell count, liver function, blood coagulation ability, and promotion of platelet aggregation and platelet/leukocyte aggregate (PLA) production by extracellular histones. C5-deficient mice were protected from lethal thrombosis and had milder thrombocytopenia, consumptive coagulopathy, and liver injury with embolism and lower PLA production than C5-sufficient mice. These results indicate that C5 is associated with coagulation disorders, PLA production, and embolism-induced liver injury. In conclusion, C5 promotes liver injury associated with histone-induced lethal thrombosis. PMID:28205538

Hypericum perforatum Reduces Paracetamol-Induced Hepatotoxicity and Lethality in Mice by Modulating Inflammation and Oxidative Stress.

PubMed

Hohmann, Miriam S N; Cardoso, Renato D R; Fattori, Victor; Arakawa, Nilton S; Tomaz, José C; Lopes, Norberto P; Casagrande, Rubia; Verri, Waldiceu A

2015-07-01

Hypericum perforatum is a medicinal plant with anti-inflammatory and antioxidant properties, which is commercially available for therapeutic use in Brazil. Herein the effect of H. perforatum extract on paracetamol (acetaminophen)-induced hepatotoxicity, lethality, inflammation, and oxidative stress in male swiss mice were investigated. HPLC analysis demonstrated the presence of rutin, quercetin, hypericin, pseudohypericin, and hyperforin in H. perforatum extract. Paracetamol (0.15-3.0 g/kg, p.o.) induced dose-dependent mortality. The sub-maximal lethal dose of paracetamol (1.5 g/kg, p.o.) was chosen for the experiments in the study. H. perforatum (30-300 mg/kg, i.p.) dose-dependently reduced paracetamol-induced lethality. Paracetamol-induced increase in plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations, and hepatic myeloperoxidase activity, IL-1β, TNF-α, and IFN-γ concentrations as well as decreased reduced glutathione (GSH) concentrations and capacity to reduce 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonate radical cation; ABTS˙(+) ) were inhibited by H. perforatum (300 mg/kg, i.p.) treatment. Therefore, H. perforatum protects mice against paracetamol-induced lethality and liver damage. This effect seems to be related to the reduction of paracetamol-induced cytokine production, neutrophil recruitment, and oxidative stress. Copyright © 2015 John Wiley & Sons, Ltd.

Galantamine is a novel post-exposure therapeutic against lethal VX challenge.

PubMed

Hilmas, Corey J; Poole, Melissa J; Finneran, Kathryn; Clark, Matthew G; Williams, Patrick T

2009-10-15

The ability of galantamine hydrobromide (GAL HBr) treatment to antagonize O-ethyl-S-(2-diisopropylaminoethyl) methylphosphonothiolate (VX)-induced lethality, impairment of muscle tension, and electroencephalographic (EEG) changes was assessed in guinea pigs. Guinea pigs were challenged with 16.8 microg/kg VX (2LD50). One min after challenge, animals were administered 0.5 mg/kg atropine sulfate (ATR) and 25 mg/kg pyridine-2-aldoxime methochloride (2-PAM). In addition, guinea pigs were given 0, 1, 2, 4, 8 or 10 mg/kg GAL as a post-exposure treatment immediately prior to ATR and 2-PAM. Animals were either monitored for 24-h survival, scheduled for electroencephalography (EEG) recording, or euthanized 60 min later for measurement of indirectly-elicited muscle tension in the hemidiaphragm. Post-exposure GAL therapy produced a dose-dependent increase in survival from lethal VX challenge. Optimal clinical benefits were observed in the presence of 10 mg/kg GAL, which led to 100% survival of VX-challenged guinea pigs. Based on muscle physiology studies, GAL post-exposure treatment protected the guinea pig diaphragm, the major effector muscle of respiration, from fatigue, tetanic fade, and muscular paralysis. Protection against the paralyzing effects of VX was dose-dependent. In EEG studies, GAL did not alter seizure onset for all doses tested. At the highest dose tested (10 mg/kg), GAL decreased seizure duration when administered as a post-exposure treatment 1 min after VX. GAL also reduced the high correlation associated between seizure activity and lethality after 2LD50 VX challenge. GAL may have additional benefits both centrally and peripherally that are unrelated to its established mechanism as a reversible acetylcholinesterase inhibitor (AChEI).

Further Characterization of the Mitigation of Radiation Lethality by Protective Wounding

PubMed Central

Dynlacht, Joseph R.; Garrett, Joy; Joel, Rebecca; Lane, Katharina; Mendonca, Marc S.; Orschell, Christie M.

2017-01-01

There continues to be a major effort in the United States to develop mitigators for the treatment of mass casualties that received high-intensity acute ionizing radiation exposures from the detonation of an improvised nuclear device during a radiological terrorist attack. The ideal countermeasure should be effective when administered after exposure, and over a wide range of absorbed doses. We have previously shown that the administration of a subcutaneous incision of a defined length, if administered within minutes after irradiation, protected young adult female C57BL/6 mice against radiation-induced lethality, and increased survival after total-body exposure to an LD50/30 X-ray dose from 50% to over 90%. We refer to this approach as “protective wounding”. In this article, we report on our efforts to further optimize, characterize and demonstrate the validity of the protective wounding response by comparing the response of female and male mice, varying the radiation dose, the size of the wound, and the timing of wounding with respect to administration of the radiation dose. Both male and female mice that received a subcutaneous incision after irradiation were significantly protected from radiation lethality. We observed that the extent of protection against lethality after an LD50/30 X-ray dose was independent of the size of the subcutaneous cut, and that a 3 mm subcutaneous incision is effective at enhancing the survival of mice exposed to a broad range of radiation doses (LD15–LD100). Over the range of 6.2–6.7 Gy, the increase in survival observed in mice that received an incision was associated with an enhanced recovery of hematopoiesis. The enhanced rate of recovery of hematopoiesis was preceded by an increase in the production of a select group of cytokines. Thus, a thorough knowledge of the timing of the cytokine cascade after wounding could aid in the development of novel pharmacological radiation countermeasures that can be administered several days

PARP inhibition as a prototype for synthetic lethal screens.

PubMed

Liu, Xuesong

2013-01-01

Although DNA damaging chemotherapy and radiation therapy remain the main stay of current treatments for cancer patient, these therapies usually have toxic side effect and narrow therapeutic window. One of the challenges in cancer drug discovery is how to identify drugs that selectively kill cancer cells while leaving the normal cell intact. Recently, synthetic lethality has been applied to cancer drug discovery in various settings, and has become a promising approach for identifying novel agents for the treatment of cancer. A prototypical example is the synthetic lethal interaction between PARP inhibition and BRCA deficiency. PARP inhibitors represent the most advanced clinical agents targeting specifically DNA repair mechanisms in cancer therapy. In this chapter, I will review the molecular mechanism for this synthetic lethality and the clinical applications for PARP inhibitors. I will also discuss the formats of synthetic lethal screens, current progress on the utilization of these screens, and some of the advantages and challenges of synthetic lethal screens in cancer drug discovery.

Influence UHF radiation on the process of self-assembly and lethal effect of bacterial lipopolysaccharide

NASA Astrophysics Data System (ADS)

Brill, G. E.; Egorova, A. V.; Bugaeva, I. O.; Postnov, D. E.; Melnikov, A. G.; Ushakova, O. V.

2018-04-01

The influence of low-intensity electromagnetic radiation on the process of self-assembly, spectral-fluorescent characteristics and lethal effect of bacterial lipopolysaccharide (endotoxin) was performed. A solution of bacterial lipopolysaccharide exposed to electromagnetic waves with a frequency of 1 GHz, the power density of 0.1 μW/cm2 for 10 min. In experiments on a large group of control and irradiated mice, a comparative analysis of the estimated lethal dose of endotoxin was performed. It was proved that UHF radiation of certain parameters reduces the lethal effects of bacterial lipopolysaccharide on 26%.

Dose-dependent cytotoxicity evaluation of graphite nanoparticles for diamond-like carbon film application on artificial joints.

PubMed

Liao, T T; Deng, Q Y; Wu, B J; Li, S S; Li, X; Wu, J; Leng, Y X; Guo, Y B; Huang, N

2017-01-24

While a diamond-like carbon (DLC)-coated joint prosthesis represents the implant of choice for total hip replacement in patients, it also leads to concern due to the cytotoxicity of wear debris in the form of graphite nanoparticles (GNs), ultimately limiting its clinical use. In this study, the cytotoxicity of various GN doses was evaluated. Mouse macrophages and osteoblasts were incubated with GNs (<30 nm diameter), followed by evaluation of cytotoxicity by means of assessing inflammatory cytokines, results of alkaline phosphatase assays, and related signaling protein expression. Cytotoxicity evaluation showed that cell viability decreased in a dose-dependent manner (10-100 μg ml -1 ), and steeply declined at GNs concentrations greater than 30 μg ml -1 . Noticeable cytotoxicity was observed as the GN dose exceeded this threshold due to upregulated receptor of activator of nuclear factor kB-ligand expression and downregulated osteoprotegerin expression. Meanwhile, activated macrophage morphology was observed as a result of the intense inflammatory response caused by the high doses of GNs (>30 μg ml -1 ), as observed by the increased release of TNF-α and IL-6. The results suggest that GNs had a significant dose-dependent cytotoxicity in vitro, with a lethal dose of 30 μg ml -1 leading to dramatic increases in cytotoxicity. Our GN cytotoxicity evaluation indicates a safe level for wear debris-related arthropathy and could propel the clinical application of DLC-coated total hip prostheses.

A bacterial cocaine esterase protects against cocaine-induced epileptogenic activity and lethality.

PubMed

Jutkiewicz, Emily M; Baladi, Michelle G; Cooper, Ziva D; Narasimhan, Diwahar; Sunahara, Roger K; Woods, James H

2009-09-01

Cocaine toxicity results in cardiovascular complications, seizures, and death and accounts for approximately 20% of drug-related emergency department visits every year. Presently, there are no treatments to eliminate the toxic effects of cocaine. The present study hypothesizes that a bacterial cocaine esterase with high catalytic efficiency would provide rapid and robust protection from cocaine-induced convulsions, epileptogenic activity, and lethality. Cocaine-induced paroxysmal activity and convulsions were evaluated in rats surgically implanted with radiotelemetry devices (N=6 per treatment group). Cocaine esterase was administered 1 minute after a lethal dose of cocaine or after cocaine-induced convulsions to determine the ability of the enzyme to prevent or reverse, respectively, the effects of cocaine. The cocaine esterase prevented all cocaine-induced electroencephalographic changes and lethality. This effect was specific for cocaine because the esterase did not prevent convulsions and death induced by a cocaine analog, (-)-2beta-carbomethoxy-3beta-phenyltropane. The esterase prevented lethality even after cocaine-induced convulsions occurred. In contrast, the short-acting benzodiazepine, midazolam, prevented cocaine-induced convulsions but not the lethal effects of cocaine. The data showed that cocaine esterase successfully degraded circulating cocaine to prevent lethality and that cocaine-induced convulsions alone are not responsible for the lethal effects of cocaine in this model. Therefore, further investigation into the use of cocaine esterase for treating cocaine overdose and its toxic effects is warranted.

Lethal and Sub-lethal Effects of Four Insecticides on the Aphidophagous Coccinellid Adalia bipunctata (Coleoptera: Coccinellidae).

PubMed

Depalo, Laura; Lanzoni, Alberto; Masetti, Antonio; Pasqualini, Edison; Burgio, Giovanni

2017-12-05

Conventional insecticide assays, which measure the effects of insecticide exposure on short-term mortality, overlook important traits, including persistence of toxicity or sub-lethal effects. Therefore, such approaches are especially inadequate for prediction of the overall impact of insecticides on beneficial arthropods. In this study, the side effects of four modern insecticides (chlorantraniliprole, emamectin benzoate, spinosad, and spirotetramat) on Adalia bipunctata (L.) (Coleoptera: Coccinellidae) were evaluated under laboratory conditions by exposition on treated potted plants. In addition to investigation of acute toxicity and persistence of harmful activity in both larvae and adults of A. bipunctata, demographic parameters were evaluated, to provide a comprehensive picture of the nontarget effects of these products. Field doses of the four insecticides caused detrimental effects to A. bipunctata; but in different ways. Overall, spinosad showed the best toxicological profile among the products tested. Emamectin benzoate could be considered a low-risk insecticide, but had high persistence. Chlorantraniliprole exhibited lethal effects on early instar larvae and adults, along with a long-lasting activity, instead spirotetramat showed a low impact on larval and adult mortality and can be considered a short-lived insecticide. However, demographic analysis demonstrated that chlorantraniliprole and spirotetramat caused sub-lethal effects. Our findings highlight that sole assessment of mortality can lead to underestimation of the full impact of pesticides on nontarget insects. Demographic analysis was demonstrated to be a sensitive method for detection of the sub-lethal effects of insecticides on A. bipunctata, and this approach should be considered for evaluation of insecticide selectivity. © The Author(s) 2017. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Galantamine is a novel post-exposure therapeutic against lethal VX challenge

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

Hilmas, Corey J.; Poole, Melissa J.; Finneran, Kathryn

2009-10-15

The ability of galantamine hydrobromide (GAL HBr) treatment to antagonize O-ethyl-S-(2-diisopropylaminoethyl) methylphosphonothiolate (VX)-induced lethality, impairment of muscle tension, and electroencephalographic (EEG) changes was assessed in guinea pigs. Guinea pigs were challenged with 16.8 {mu}g/kg VX (2LD50). One min after challenge, animals were administered 0.5 mg/kg atropine sulfate (ATR) and 25 mg/kg pyridine-2-aldoxime methochloride (2-PAM). In addition, guinea pigs were given 0, 1, 2, 4, 8 or 10 mg/kg GAL as a post-exposure treatment immediately prior to ATR and 2-PAM. Animals were either monitored for 24-h survival, scheduled for electroencephalography (EEG) recording, or euthanized 60 min later for measurement of indirectly-elicitedmore » muscle tension in the hemidiaphragm. Post-exposure GAL therapy produced a dose-dependent increase in survival from lethal VX challenge. Optimal clinical benefits were observed in the presence of 10 mg/kg GAL, which led to 100% survival of VX-challenged guinea pigs. Based on muscle physiology studies, GAL post-exposure treatment protected the guinea pig diaphragm, the major effector muscle of respiration, from fatigue, tetanic fade, and muscular paralysis. Protection against the paralyzing effects of VX was dose-dependent. In EEG studies, GAL did not alter seizure onset for all doses tested. At the highest dose tested (10 mg/kg), GAL decreased seizure duration when administered as a post-exposure treatment 1 min after VX. GAL also reduced the high correlation associated between seizure activity and lethality after 2LD50 VX challenge. GAL may have additional benefits both centrally and peripherally that are unrelated to its established mechanism as a reversible acetylcholinesterase inhibitor (AChEI)« less

[Are acute toxicity testing and the three Rs rule reconcilable? Example of the lethal dose 50 determination].

PubMed

Dorandeu, Fr; Lallement, G

2003-11-01

Toxicity assessment and demonstration of innocuousness of chemical compounds have been part of the research studies conducted in the fields of pharmacy, agriculture and chemical industry for years. Acute systemic toxicity studies are an important element of the safety evaluation. They remain compulsory for regulatory purposes and important for the public opinion that does not accept the risk anymore. Evolutions of the ethics in animal experiments foster a necessary reduction of the number of animals involved in this type of experiments, following the well-known principle of the three Rs rule of Russell and Burch (1959) (Reduction, refinement and replacement). These two views seem in contradiction. Using the example of acute toxicity testing and focusing on the now very criticized parameter lethal dose 50, we will present approaches, including statistical ones, that a toxicologist can use, when free to choose, to keep on conducting the indispensable in vivo studies while abiding by ethical recommendations.

Materials Applications for Non-Lethal: Aqueous Foams

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

GOOLSBY,TOMMY D.; SCOTT,STEVEN H.

High expansion aqueous foam is an aggregation of bubbles that has the appearance of soap suds and is used to isolate individuals both visually and acoustically. It was developed in the 1920's in England to fight coal mine fires and has been widely used since for fire fighting and dust suppression. It was developed at Sandia National Laboratories (SNL) in the 1970's for nuclear safeguards and security applications. In the mid-1990s, the National Institute of Justice (NIJ), the research arm of the Department of Justice, began a project with SNL to determine the applicability of high expansion aqueous foam formore » correctional applications. NIJ funded the project as part of its search for new and better less-than-lethal weapons for responding to violent and dangerous individuals, where other means of force could lead to serious injuries. The phase one objectives of the project were to select a low-to-no toxicity foam concentrate (foaming agent) with physical characteristics suited for use in a single cell or large prison disturbances, and to determine if the selected foam concentrate could serve as a carrier for Oleoresin Capsicum (OC) irritant. The phase two objectives were to conduct an extensive toxicology review of the selected foam concentrate and OC irritant, and to conduct respiration simulation experiments in the selected high expansion aqueous foam. The phase three objectives were to build a prototype individual cell aqueous foam system and to study the feasibility of aqueous foams for large prison facility disturbances. The phase four and five objectives were to use the prototype system to do large scale foam physical characteristics testing of the selected foam concentrate, and to have the prototype single cell system further evaluated by correctional representatives. Prison rather than street scenarios were evaluated as the first and most likely place for using the aqueous foam since prisons have recurrent incidents where officers and inmates might be

Modeling synthetic lethality

PubMed Central

Le Meur, Nolwenn; Gentleman, Robert

2008-01-01

Background Synthetic lethality defines a genetic interaction where the combination of mutations in two or more genes leads to cell death. The implications of synthetic lethal screens have been discussed in the context of drug development as synthetic lethal pairs could be used to selectively kill cancer cells, but leave normal cells relatively unharmed. A challenge is to assess genome-wide experimental data and integrate the results to better understand the underlying biological processes. We propose statistical and computational tools that can be used to find relationships between synthetic lethality and cellular organizational units. Results In Saccharomyces cerevisiae, we identified multi-protein complexes and pairs of multi-protein complexes that share an unusually high number of synthetic genetic interactions. As previously predicted, we found that synthetic lethality can arise from subunits of an essential multi-protein complex or between pairs of multi-protein complexes. Finally, using multi-protein complexes allowed us to take into account the pleiotropic nature of the gene products. Conclusions Modeling synthetic lethality using current estimates of the yeast interactome is an efficient approach to disentangle some of the complex molecular interactions that drive a cell. Our model in conjunction with applied statistical methods and computational methods provides new tools to better characterize synthetic genetic interactions. PMID:18789146

A Bacterial Cocaine Esterase Protects Against Cocaine-Induced Epileptogenic Activity and Lethality

PubMed Central

Jutkiewicz, Emily M.; Baladi, Michelle G.; Cooper, Ziva D.; Narasimhan, Diwahar; Sunahara, Roger K.; Woods, James H.

2012-01-01

Study objective Cocaine toxicity results in cardiovascular complications, seizures, and death and accounts for approximately 20% of drug-related emergency department visits every year. Presently, there are no treatments to eliminate the toxic effects of cocaine. The present study hypothesizes that a bacterial cocaine esterase with high catalytic efficiency would provide rapid and robust protection from cocaine-induced convulsions, epileptogenic activity, and lethality. Methods Cocaine-induced paroxysmal activity and convulsions were evaluated in rats surgically implanted with radiotelemetry devices (N=6 per treatment group). Cocaine esterase was administered 1 minute after a lethal dose of cocaine or after cocaine-induced convulsions to determine the ability of the enzyme to prevent or reverse, respectively, the effects of cocaine. Results The cocaine esterase prevented all cocaine-induced electroencephalographic changes and lethality. This effect was specific for cocaine because the esterase did not prevent convulsions and death induced by a cocaine analog, (−)-2β-carbomethoxy-3β-phenyltropane. The esterase prevented lethality even after cocaine-induced convulsions occurred. In contrast, the short-acting benzodiazepine, midazolam, prevented cocaine-induced convulsions but not the lethal effects of cocaine. Conclusion The data showed that cocaine esterase successfully degraded circulating cocaine to prevent lethality and that cocaine-induced convulsions alone are not responsible for the lethal effects of cocaine in this model. Therefore, further investigation into the use of cocaine esterase for treating cocaine overdose and its toxic effects is warranted. PMID:19013687

Empirical complexities in the genetic foundations of lethal mutagenesis.

PubMed

Bull, James J; Joyce, Paul; Gladstone, Eric; Molineux, Ian J

2013-10-01

From population genetics theory, elevating the mutation rate of a large population should progressively reduce average fitness. If the fitness decline is large enough, the population will go extinct in a process known as lethal mutagenesis. Lethal mutagenesis has been endorsed in the virology literature as a promising approach to viral treatment, and several in vitro studies have forced viral extinction with high doses of mutagenic drugs. Yet only one empirical study has tested the genetic models underlying lethal mutagenesis, and the theory failed on even a qualitative level. Here we provide a new level of analysis of lethal mutagenesis by developing and evaluating models specifically tailored to empirical systems that may be used to test the theory. We first quantify a bias in the estimation of a critical parameter and consider whether that bias underlies the previously observed lack of concordance between theory and experiment. We then consider a seemingly ideal protocol that avoids this bias-mutagenesis of virions-but find that it is hampered by other problems. Finally, results that reveal difficulties in the mere interpretation of mutations assayed from double-strand genomes are derived. Our analyses expose unanticipated complexities in testing the theory. Nevertheless, the previous failure of the theory to predict experimental outcomes appears to reside in evolutionary mechanisms neglected by the theory (e.g., beneficial mutations) rather than from a mismatch between the empirical setup and model assumptions. This interpretation raises the specter that naive attempts at lethal mutagenesis may augment adaptation rather than retard it.

Single-Dose Intranasal Treatment with DEF201 (Adenovirus Vectored Consensus Interferon) Prevents Lethal Disease Due to Rift Valley Fever Virus Challenge

PubMed Central

Gowen, Brian B.; Ennis, Jane; Bailey, Kevin W.; Vest, Zachary; Scharton, Dionna; Sefing, Eric J.; Turner, Jeffrey D.

2014-01-01

Rift Valley fever virus (RVFV) causes severe disease in humans and ungulates. The virus can be transmitted by mosquitoes, direct contact with infected tissues or fluids, or aerosol, making it a significant biological threat for which there is no approved vaccine or therapeutic. Herein we describe the evaluation of DEF201, an adenovirus-vectored interferon alpha which addresses the limitations of recombinant interferon alpha protein (cost, short half-life), as a pre- and post-exposure treatment in a lethal hamster RVFV challenge model. DEF201 was delivered intranasally to stimulate mucosal immunity and effectively bypass any pre-existing immunity to the vector. Complete protection against RVFV infection was observed from a single dose of DEF201 administered one or seven days prior to challenge while all control animals succumbed within three days of infection. Efficacy of treatment administered two weeks prior to challenge was limited. Post‑exposure, DEF201 was able to confer significant protection when dosed at 30 min or 6 h, but not at 24 h post-RVFV challenge. Protection was associated with reductions in serum and tissue viral loads. Our findings suggest that DEF201 may be a useful countermeasure against RVFV infection and further demonstrates its broad-spectrum capacity to stimulate single dose protective immunity. PMID:24662673

Protection Against Microcystin-LR-Induced Hepatoxicity by Silymarin: Biochemistry, Histopathology and Lethality

DTIC Science & Technology

1990-04-04

wild artichoke (jilybus sdrinum L. Gaertn), completely abolihed the lethal effects, pathological changes, and ,34nificantly decreased the levels of...aminotransferase, and lactate dehydrogenase. Pretreatment of either rats or mice with a single dose of silymarin, a flavonotignane isolated from the wild artichoke

Leukemia inhibitory factor protects against experimental lethal Escherichia coli septic shock in mice.

PubMed Central

Waring, P M; Waring, L J; Billington, T; Metcalf, D

1995-01-01

Leukemia inhibitory factor (LIF) has recently been associated with septic shock in humans. In this study we sought to determine, in mice, the role of LIF in septic shock. During sublethal endotoxemia, serum LIF levels, as determined by radio-receptor competition assay, peaked at 2 h and were low (3 ng/ml), whereas in lethal Escherichia coli septic shock serum LIF levels rose progressively (> 30 ng/ml) in the premorbid phase coincident with the development of tissue injury. Single i.v. injections of high doses (up to 50 micrograms per mouse) of recombinant murine LIF had no obvious acute detrimental effects, whereas continued i.p. administration (30 micrograms per mouse per day) for 3-4 days induced a fatal catabolic state without evidence of preceding hemodynamic collapse or shock. Simultaneous or subsequent administration of high doses of LIF had no effect on mortality from sublethal and lethal E. coli septic shock, whereas prior administration conferred significant protection against lethality (P << 0.001 by log-rank test), an effect that was dose and interval dependent. This protective effect resembled endotoxin tolerance and was characterized by suppression of E. coli-induced serum tumor necrosis factor concentration (P < 0.05), reduction in the number of viable bacteria (P < 0.05), and prevention of sepsis-induced tissue injury. These observations suggest that systemic LIF production is part of the host response to both endotoxin and sepsis-induced tissue injury. Images Fig. 2 Fig. 5 PMID:7877978

Lethal exposure: An integrated approach to pathogen transmission via environmental reservoirs.

PubMed

Turner, Wendy C; Kausrud, Kyrre L; Beyer, Wolfgang; Easterday, W Ryan; Barandongo, Zoë R; Blaschke, Elisabeth; Cloete, Claudine C; Lazak, Judith; Van Ert, Matthew N; Ganz, Holly H; Turnbull, Peter C B; Stenseth, Nils Chr; Getz, Wayne M

2016-06-06

To mitigate the effects of zoonotic diseases on human and animal populations, it is critical to understand what factors alter transmission dynamics. Here we assess the risk of exposure to lethal concentrations of the anthrax bacterium, Bacillus anthracis, for grazing animals in a natural system over time through different transmission mechanisms. We follow pathogen concentrations at anthrax carcass sites and waterholes for five years and estimate infection risk as a function of grass, soil or water intake, age of carcass sites, and the exposure required for a lethal infection. Grazing, not drinking, seems the dominant transmission route, and transmission is more probable from grazing at carcass sites 1-2 years of age. Unlike most studies of virulent pathogens that are conducted under controlled conditions for extrapolation to real situations, we evaluate exposure risk under field conditions to estimate the probability of a lethal dose, showing that not all reservoirs with detectable pathogens are significant transmission pathways.

Lethal exposure: An integrated approach to pathogen transmission via environmental reservoirs

PubMed Central

Turner, Wendy C.; Kausrud, Kyrre L.; Beyer, Wolfgang; Easterday, W. Ryan; Barandongo, Zoë R.; Blaschke, Elisabeth; Cloete, Claudine C.; Lazak, Judith; Van Ert, Matthew N.; Ganz, Holly H.; Turnbull, Peter C. B.; Stenseth, Nils Chr.; Getz, Wayne M.

2016-01-01

To mitigate the effects of zoonotic diseases on human and animal populations, it is critical to understand what factors alter transmission dynamics. Here we assess the risk of exposure to lethal concentrations of the anthrax bacterium, Bacillus anthracis, for grazing animals in a natural system over time through different transmission mechanisms. We follow pathogen concentrations at anthrax carcass sites and waterholes for five years and estimate infection risk as a function of grass, soil or water intake, age of carcass sites, and the exposure required for a lethal infection. Grazing, not drinking, seems the dominant transmission route, and transmission is more probable from grazing at carcass sites 1–2 years of age. Unlike most studies of virulent pathogens that are conducted under controlled conditions for extrapolation to real situations, we evaluate exposure risk under field conditions to estimate the probability of a lethal dose, showing that not all reservoirs with detectable pathogens are significant transmission pathways. PMID:27265371

Lethal and mutagenic effects of ion beams and γ-rays in Aspergillus oryzae.

PubMed

Toyoshima, Yoshiyuki; Takahashi, Akemi; Tanaka, Hisaki; Watanabe, Jun; Mogi, Yoshinobu; Yamazaki, Tatsuo; Hamada, Ryoko; Iwashita, Kazuhiro; Satoh, Katsuya; Narumi, Issay

2012-12-01

Aspergillus oryzae is a fungus that is used widely in traditional Japanese fermentation industries. In this study, the lethal and mutagenic effects of different linear energy transfer (LET) radiation in freeze-dried conidia of A. oryzae were investigated. The lethal effect, which was evaluated by a 90% lethal dose, was dependent on the LET value of the ionizing radiation. The most lethal ionizing radiation among that tested was (12)C(5+) ion beams with an LET of 121keV/μm. The (12)C(5+) ion beams had a 3.6-times higher lethal effect than low-LET (0.2keV/μm) γ-rays. The mutagenic effect was evaluated by the frequency of selenate resistant mutants. (12)C(6+) ion beams with an LET of 86keV/μm were the most effective in inducing selenate resistance. The mutant frequency following exposure to (12)C(6+) ion beams increased with an increase in dose and reached 3.47×10(-3) at 700Gy. In the dose range from 0 to 700Gy, (12)C(5+) ion beams were the second most effective in inducing selenate resistance, the mutant frequency of which reached a maximum peak (1.67×10(-3)) at 400Gy. To elucidate the characteristics of mutation induced by ionizing radiation, mutations in the sulphate permease gene (sB) and ATP sulfurylase gene (sC) loci, the loss of function of which results in a selenate resistant phenotype, were compared between (12)C(5+) ion beams and γ-rays. We detected all types of transversions and transitions. For frameshifts, the frequency of a +1 frameshift was the highest in all cases. Although the incidence of deletions >2bp was generally low, deletions >20bp were characteristic for (12)C(5+) ion beams. γ-rays had a tendency to generate mutants carrying a multitude of mutations in the same locus. Both forms of radiation also induced genome-wide large-scale mutations including chromosome rearrangements and large deletions. These results provide new basic insights into the mutation breeding of A. oryzae using ionizing radiation. Crown Copyright © 2012. Published

HISTOLOGICAL INVESTIGATION OF THE BEHAVIOR OF THE LIVER MITOCHONDRIA OF THE RAT WHOLE-BODY X IRRADIATED WITH A LETHAL DOSE (in Italian)

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

Bronzetti, P.; Malaspina, A.

1958-01-01

It was demonstrated that irradlation of the whole body of rats with a lethal dose of x rays (800 r) produces a reversible modification of the liver cell mitochondria. At first mitochondrla are reduced in number and lose their affinity for iron, then (24 hours after irradiation) they are transformed in granules and react again with Iron. About the seventh day after irradiation, mitochondria of all llver cells of every lobule return to their normal condition. The loss of affinity for iron of mitochondria is discussed as it is considered. The morphological result of the modification of the enzymes relatedmore » to mitochondria determined by the action of x rays. (auth) BIOLOGY« less

Theories of Lethal Mutagenesis: From Error Catastrophe to Lethal Defection.

PubMed

Tejero, Héctor; Montero, Francisco; Nuño, Juan Carlos

2016-01-01

RNA viruses get extinct in a process called lethal mutagenesis when subjected to an increase in their mutation rate, for instance, by the action of mutagenic drugs. Several approaches have been proposed to understand this phenomenon. The extinction of RNA viruses by increased mutational pressure was inspired by the concept of the error threshold. The now classic quasispecies model predicts the existence of a limit to the mutation rate beyond which the genetic information of the wild type could not be efficiently transmitted to the next generation. This limit was called the error threshold, and for mutation rates larger than this threshold, the quasispecies was said to enter into error catastrophe. This transition has been assumed to foster the extinction of the whole population. Alternative explanations of lethal mutagenesis have been proposed recently. In the first place, a distinction is made between the error threshold and the extinction threshold, the mutation rate beyond which a population gets extinct. Extinction is explained from the effect the mutation rate has, throughout the mutational load, on the reproductive ability of the whole population. Secondly, lethal defection takes also into account the effect of interactions within mutant spectra, which have been shown to be determinant for the understanding the extinction of RNA virus due to an augmented mutational pressure. Nonetheless, some relevant issues concerning lethal mutagenesis are not completely understood yet, as so survival of the flattest, i.e. the development of resistance to lethal mutagenesis by evolving towards mutationally more robust regions of sequence space, or sublethal mutagenesis, i.e., the increase of the mutation rate below the extinction threshold which may boost the adaptability of RNA virus, increasing their ability to develop resistance to drugs (including mutagens). A better design of antiviral therapies will still require an improvement of our knowledge about lethal

An orally available, small-molecule polymerase inhibitor shows efficacy against a lethal morbillivirus infection in a large animal model.

PubMed

Krumm, Stefanie A; Yan, Dan; Hovingh, Elise S; Evers, Taylor J; Enkirch, Theresa; Reddy, G Prabhakar; Sun, Aiming; Saindane, Manohar T; Arrendale, Richard F; Painter, George; Liotta, Dennis C; Natchus, Michael G; von Messling, Veronika; Plemper, Richard K

2014-04-16

Measles virus is a highly infectious morbillivirus responsible for major morbidity and mortality in unvaccinated humans. The related, zoonotic canine distemper virus (CDV) induces morbillivirus disease in ferrets with 100% lethality. We report an orally available, shelf-stable pan-morbillivirus inhibitor that targets the viral RNA polymerase. Prophylactic oral treatment of ferrets infected intranasally with a lethal CDV dose reduced viremia and prolonged survival. Ferrets infected with the same dose of virus that received post-infection treatment at the onset of viremia showed low-grade viral loads, remained asymptomatic, and recovered from infection, whereas control animals succumbed to the disease. Animals that recovered also mounted a robust immune response and were protected against rechallenge with a lethal CDV dose. Drug-resistant viral recombinants were generated and found to be attenuated and transmission-impaired compared to the genetic parent virus. These findings may pioneer a path toward an effective morbillivirus therapy that could aid measles eradication by synergizing with vaccination to close gaps in herd immunity due to vaccine refusal.

Lethal effects of Clostridium perfringens epsilon toxin are potentiated by alpha and perfringolysin-O toxins in a mouse model.

PubMed

Fernandez-Miyakawa, Mariano E; Jost, B Helen; Billington, Stephen J; Uzal, Francisco A

2008-03-18

Epsilon toxin (ETX) is the most important virulence factor of Clostridium perfringens type D. Two other important toxins, alpha toxin (CPA) and perfringolysin-O (PFO), are encoded and potentially produced by most C. perfringens type D isolates. The biological effects of these toxins are dissimilar although they are all lethal. Since the possible interaction of these toxins during infection is unknown, the effects of CPA and PFO on the lethal activity of ETX were studied in a mouse model. Mice were injected intravenously or intragastrically with CPA or PFO with or without ETX. Sublethal doses of CPA or PFO did not affect the lethality of ETX when either was injected together with the latter intravenously. However, sublethal or lethal doses of CPA or PFO resulted in reduction of the survival time of mice injected simultaneously with ETX when compared with the intravenous effect of ETX injected alone. When PFO was inoculated intragastrically with ETX, a reduction of the survival time was observed. CPA did not alter the survival time when inoculated intragastrically with ETX. The results of the present study suggest that both CPA and PFO have the potential to enhance the ETX lethal effects during enterotoxemia in natural hosts such as sheep and goats.

Lethal and sub-lethal effects on the Asian common toad Duttaphrynus melanostictus from exposure to hexavalent chromium.

PubMed

Fernando, Vindhya A K; Weerasena, Jagathpriya; Lakraj, G Pemantha; Perera, Inoka C; Dangalle, Chandima D; Handunnetti, Shiroma; Premawansa, Sunil; Wijesinghe, Mayuri R

2016-08-01

Chromium discharged in industrial effluents frequently occurs as an environmental pollutant, but the lethal and sub-lethal effects the heavy metal might cause in animals exposed to it have been insufficiently investigated. Selecting the amphibian Duttaphrynus melanostictus, we carried out laboratory tests to investigate the effects of short and long term exposure to hexavalent chromium (Cr(VI)) in both tadpoles and adult toads. The concentrations used were 0.002, 0.02, 0.2, 1.0 and 2.0mg/L, the first three corresponding to field levels. In vitro exposures were also carried out using toad erythrocytes and Cr(VI) concentrations of 0.0015, 0.003, 0.015, 0.03, 0.15mg/L. Mortality, growth retardation, developmental delays and structural aberrations were noted in the metal-treated tadpoles, with increasing incidence corresponding to increase in Cr(VI) level and duration of exposure. Many of the sub-lethal effects were evident with long term exposure to environmentally relevant levels of the toxicant. Changes in selected blood parameters and erythrocyte morphometry were also detected in Cr(VI) exposed toads, indicating anaemic and leucopenic conditions. In the genotoxicity study, DNA damage indicated by comet assay and increased micronuclei frequency, occurred at the low Cr(VI) concentrations tested. The multiple deleterious effects of exposure to chromium signal the need for monitoring and controlling the discharge of chromium to the environment. The dose-dependency and genotoxic effects observed in this widely distributed Asian toad indicates its suitability for monitoring heavy metal pollution in aquatic systems. Copyright © 2016 Elsevier B.V. All rights reserved.

Protection against both lethal and behavioral effects of soman.

PubMed

Harris, L W; McDonough, J H; Stitcher, D L; Lennox, W J

1984-01-01

This work developed two drug mixtures which alone had no effect on performance of a criterion behavior but when given as a pretreatment would protect against organophosphate-induced lethality and incapacitation. Candidate drugs (alone and together) were given to rats trained to respond on a two-component Fixed Ratio 10 - Extinction (FR10-EXT) schedule. After generating dose response curves for each cholinolytic drug, mixtures of atropine (A) + mecamylamine (M) + pyridostigmine (Py) or physostigmine (Ph) were prepared and a combination of doses that produced no effects on operant performance was determined (Mix I:A = .78, M = .78, Py = .056 mg/kg; Mix II:A = .78, M = .78, Ph = .026 mg/kg). Both pretreatment mixtures provided equivalent protection against the lethal effects of the organophosphate soman; however only Mix II was capable of reversing soman-induced physical incapacitation (PI) as assessed by performance on an accelerating rotarod or FR10 responding. Pretreatment of animals with Mix II resulted in significantly higher levels of brain acetylcholinesterase (AChE) than Mix I pretreated subjects 4 hrs after 1.3 LD50 soman, although peripheral AChE levels were not different. The results indicate organophosphate-induced PI can be attenuated by pretreatment with tertiary carbamates which protect significant amounts of brain AChE from irreversible inhibition.

Microalbuminuria and early renal response to lethal dose Shiga toxin type 2 in rats.

PubMed

Ochoa, Federico; Oltra, Gisela; Gerhardt, Elizabeth; Hermes, Ricardo; Cohen, Lilian; Damiano, Alicia E; Ibarra, Cristina; Lago, Nestor R; Zotta, Elsa

2012-01-01

In Argentina, hemolytic uremic syndrome (HUS) constitutes the most frequent cause of acute renal failure in children. Approximately 2%-4% of patients die during the acute phase, and one-third of the 96% who survive are at risk of chronic renal sequelae. Little information is available about the direct effect of Shiga toxin type 2 (Stx2) on the onset of proteinuria and the evolution of toxin-mediated glomerular or tubular injury. In this work, rats were injected intraperitoneally with recombinant Escherichia coli culture supernatant containing Stx2 (sStx2; 20 μg/kg body weight) to induce HUS. Functional, immunoblotting, and immunohistochemistry studies were carried out to determine alterations in slit diaphragm proteins and the proximal tubule endocytic system at 48 hours post-inoculation. We detected a significant increase in microalbuminuria, without changes in the proteinuria values compared to the control rats. In immunoperoxidase studies, the renal tubules and glomerular mesangium showed an increased expression of transforming growth factor β(1)(TGF-β(1)). The expression of megalin was decreased by immunoperoxidase and the cytoplasm showed a granular pattern of megalin expression by immunofluorescence techniques. Western blot analysis performed in the renal cortex from sStx2-treated and control rats using anti-nephrin and anti-podocalyxin antibodies showed a decreased expression of these proteins. We suggest that the alterations in slit diaphragm proteins and megalin expression could be related to the development of microalbuminuria in response to lethal doses of Stx2.

Lethal acrodysgenital dwarfism: a severe lethal condition resembling Smith-Lemli-Opitz syndrome.

PubMed Central

Merrer, M L; Briard, M L; Girard, S; Mulliez, N; Moraine, C; Imbert, M C

1988-01-01

We report eight cases of a lethal association of failure to thrive, facial dysmorphism, ambiguous genitalia, syndactyly, postaxial polydactyly, and internal developmental anomalies (Hirschsprung's disease, cardiac and renal malformation). This syndrome is likely to be autosomal recessive and resembles Smith-Lemli-Opitz (SLO) syndrome. However, the lethality, the common occurrence of polydactyly, and the sexual ambiguity distinguishes this condition from SLO syndrome. A review of published reports supports the separate classification of this syndrome for which we propose the name lethal acrodysgenital dwarfism. Images PMID:2831368

Suicide Lethality: A Concept Analysis.

PubMed

DeBastiani, Summer; De Santis, Joseph P

2018-02-01

Suicide is a significant health problem internationally. Those who complete suicide may have different behaviors and risk factors than those who attempt a non-fatal suicide. The purpose of this article is to analyze the concept of suicide lethality and propose a clear definition of the concept through the identification of antecedents, attributes, and consequences. A literature search for articles published in the English language between 1970 and 2016 was conducted using MEDLINE, the Cochrane Library, Pubmed, Psychlit, Ovid, PsycINFO, and Proquest. The bibliographies of all included studies were also reviewed to identify additional relevant citations. A concept analysis was conducted on the literature findings using six stages of Walker and Avant's method. The concept analysis differentiated between suicide, lethality, suicidal behavior, and suicide lethality. Presence of a suicide plan or a written suicide note was not found to be associated with the majority of completed suicides included in the definition of suicide lethality. There are a few scales that measure the lethality of a suicide attempt, but none that attempt to measure the concept of suicide lethality as described in this analysis. Clarifying the concept of suicide lethality encourages awareness of the possibility of different suicidal behaviors associated with different suicide outcomes and will inform the development of future nursing interventions. A clearer definition of the concept of suicide lethality will guide clinical practice, research, and policy development aimed at suicide prevention.

Acute and sub-lethal exposure to copper oxide nanoparticles causes oxidative stress and teratogenicity in zebrafish embryos.

PubMed

Ganesan, Santhanamari; Anaimalai Thirumurthi, Naveenkumar; Raghunath, Azhwar; Vijayakumar, Savitha; Perumal, Ekambaram

2016-04-01

Nano-copper oxides are a versatile inorganic material. As a result of their versatility, the immense applications and usage end up in the environment causing a concern for the lifespan of various beings. The ambiguities surround globally on the toxic effects of copper oxide nanoparticles (CuO-NPs). Hence, the present study endeavored to study the sub-lethal acute exposure effects on the developing zebrafish embryos. The 48 hpf LC50 value was about 64 ppm. Therefore, we have chosen the sub-lethal dose of 40 and 60 ppm for the study. Accumulation of CuO-NPs was evidenced from the SEM-EDS and AAS analyzes. The alterations in the AChE and Na(+)/K(+)-ATPase activities disrupted the development process. An increment in the levels of oxidants with a concomitant decrease in the antioxidant enzymes confirmed the induction of oxidative stress. Oxidative stress triggered apoptosis in the exposed embryos. Developmental anomalies were observed with CuO-NPs exposure in addition to oxidative stress in the developing embryos. Decreased heart rate and hatching delay hindered the normal developmental processes. Our work has offered valuable data on the connection between oxidative stress and teratogenicity leading to lethality caused by CuO-NPs. A further molecular mechanism unraveling the uncharted connection between oxidative stress and teratogenicity will aid in the safe use of CuO-NPs. Copyright © 2015 John Wiley & Sons, Ltd.

Interactive lethal and mutagenic effects of ultraviolet light and bleomycin in yeast: synergism or antagonism?

PubMed

Lillo, O L; Severgnini, A A; Nunes, E M

1997-11-01

The mutagenic interactions of ultraviolet light and bleomycin in haploid populations of Saccharomyces cerevisiae were analyzed. Survival and mutation frequency as a function of different bleomycin concentrations after one conditioning dose of UV radiation were determined. Furthermore, corresponding interaction functions and sensitization factors were calculated. A synergistic interaction between UV light and bleomycin was shown for both lethal and mutagenic events when the cells were in nutrient broth during the treatments. Conversely, the interaction between UV light and bleomycin was antagonistic when the cells were in deionized water during the treatment. The magnitude of lethal and mutagenic interactions depends on dose, and thus presumably on the number of lesions. The observed interactions between UV light and bleomycin suggest that the mechanism that is most likely involved is the induction of repair systems with different error probabilities during the delay of cell division.

[Clinical applications of dosing algorithm in the predication of warfarin maintenance dose].

PubMed

Huang, Sheng-wen; Xiang, Dao-kang; An, Bang-quan; Li, Gui-fang; Huang, Ling; Wu, Hai-li

2011-12-27

To evaluate the feasibility of clinical application for genetic based dosing algorithm in the predication of warfarin maintenance dose in Chinese population. The clinical data were collected and blood samples harvested from a total of 126 patients undergoing heart valve replacement. The genotypes of VKORC1 and CYP2C9 were determined by melting curve analysis after PCR. They were divided randomly into the study and control groups. In the study group, the first three doses of warfarin were prescribed according to the predicted warfarin maintenance dose while warfarin was initiated at 2.5 mg/d in the control group. The warfarin doses were adjusted according to the measured international normalized ratio (INR) values. And all subjects were followed for 50 days after an initiation of warfarin therapy. At the end of a 50-day follow-up period, the proportions of the patients on a stable dose were 82.4% (42/51) and 62.5% (30/48) for the study and control groups respectively. The mean durations of reaching a stable dose of warfarin were (27.5 ± 1.8) and (34.7 ± 1.8) days and the median durations were (24.0 ± 1.7) and (33.0 ± 4.5) days in the study and control groups respectively. Significant differences existed in the durations of reaching a stable dose between the two groups (P = 0.012). Compared with the control group, the hazard ratio (HR) for the duration of reaching a stable dose was 1.786 in the study group (95%CI 1.088 - 2.875, P = 0.026). The predicted dosing algorithm incorporating genetic and non-genetic factors may shorten the duration of achieving efficiently a stable dose of warfarin. And the present study validates the feasibility of its clinical application.

Acute lethal toxicity, hyperkalemia associated with renal injury and hepatic damage after intravenous administration of cadmium nitrate in rats.

PubMed

Dote, Emi; Dote, Tomotaro; Shimizu, Hiroyasu; Shimbo, Yukari; Fujihara, Michiko; Kono, Koichi

2007-01-01

Cadmium nitrate Cd(NO(3))(2) (CdN) is commonly used in Ni-Cd battery factories. The possibility of accidental exposure to CdN is great. CdN is very soluble in water compared to other Cd compounds. Therefore, acute toxicity would be expected to be quick due to rapid absorption after exposure. However, the mechanisms of CdN toxicity have not been fully elucidated. We investigated the acute lethal toxicity and harmful systemic effects of acute exposure to large doses of CdN. The lethal dose and dose-response study of the liver and kidney were determined after intravenous administration of CdN in rats. The LD(50) of CdN was determined to be 5.5 mg/kg. Doses of 2.1, 4.2, 6.3 mg/kg were selected for the dose-response study. Liver injury was induced at doses greater than 4.2 mg/kg. Severe hepatic injury occurred in the 6.3 mg/kg group, which would have been caused by acute exposure to the high concentration of Cd that exceeded the critical concentration in hepatic tissue. A remarkable decrease in urine volume in the 6.3 mg/kg group indicated acute renal failure. A decrease in creatinine clearance suggested acute glomerular dysfunction at doses greater than 4.2 mg/kg. Increases in urinary N-acetyl-beta-D-glucosaminidase/creatinine, beta(2)-microglobulin and glucose in the 6.3 mg/kg group indicated proximal tubular injury. Secretion of K ion was also severely affected by proximal tubular injury and severe decreases in urine volume, and an increase in serum K ion was identified at doses greater than 4.2 mg/kg. Thus severe hyperkalemia might be associated with the cardiac-derived lethal toxicity of CdN.

X-ray induced dominant lethal mutations in mature and immature oocytes of guinea-pigs and golden hamsters.

PubMed

Cox, B D; Lyon, M F

1975-06-01

The induction of dominant lethal mutations by doses of 100-400 rad X-rays in oocytes of the guinea-pig and golden hamster was studied using criteria of embryonic mortality. For both species higher yields were obtained from mature than from immature oocytes, in contrast to results for the mouse. Data on fertility indicated that in the golden hamster, as in the mouse, immature oocytes were more sensitive to killing by X-rays than mature oocytes but that the converse was true in the guinea-pig. The dose-response relationship for mutation to dominant lethals in pre-ovulatory oocytes of guinea-pig and golden hamsters was linear, both when based on pre- and post-implantation loss and when on post-implantation loss only. The rate per unit dose was higher for the golden hamster, and the old golden hamsters were possibly slightly more sensitive than young ones. The mutation rate data for mature oocytes of the mouse, using post-implantation loss alone, also fitted a linear dose-response relationship, except that the rate per unit dose was lower than for the other two species.

[Relationship between lethality of hemodialysis patients, erythropoietin dosage for renal anemia treatment and hemodialysis quality].

PubMed

Ziginskiene, Edita; Kuzminskis, Vytautas; Bumblyte, Inga Arūne

2003-01-01

In December of 1999 and 2000 we visited all hemodialysis centers of Lithuania and collected data about all hemodialysis patients, using special questionnaires. The aim of the study was to evaluate the relationship between lethality of hemodialysis patients, erythropoietin dosage for renal anemia treatment and hemodialysis quality. The patients with higher Kt/V, higher levels of iron and albumin, normal levels of phosphorus and parathyroid hormone (PTH) requested lower doses of erythropoietin (analysis of the patients who were on hemodialysis in 2000 more than 6 months). So, we can conclude that adequate hemodialysis procedure and good management of hemodialysis patient are leading to the decrease request of erythropoietin doses for anemia treatment. We compared two groups of patients in order to examine relationship between hemodialysis quality and lethality of hemodialysis patients. We selected incident patients registered in December of 1999 and we divided these patients in December of 2000 in two groups: a) 175 patients, who continued hemodialysis treatment and b) 41 patients, who died in 2000. The results revealed, that dead patients were elder, their duration of weekly hemodialysis was shorter, Hb concentration lower, they had worse nutritional status (blood albumin level was lower). Lethality was associated with underlying diseases such as diabetes, hypertensive nephropathy and renal amyloidosis.

Differential replication of Foot-and-mouth disease viruses in mice determine lethality.

PubMed

Cacciabue, Marco; García-Núñez, María Soledad; Delgado, Fernando; Currá, Anabella; Marrero, Rubén; Molinari, Paula; Rieder, Elizabeth; Carrillo, Elisa; Gismondi, María Inés

2017-09-01

Adult C57BL/6J mice have been used to study Foot-and-mouth disease virus (FMDV) biology. In this work, two variants of an FMDV A/Arg/01 strain exhibiting differential pathogenicity in adult mice were identified and characterized: a non-lethal virus (A01NL) caused mild signs of disease, whereas a lethal virus (A01L) caused death within 24-48h independently of the dose used. Both viruses caused a systemic infection with pathological changes in the exocrine pancreas. Virus A01L reached higher viral loads in plasma and organs of inoculated mice as well as increased replication in an ovine kidney cell line. Complete consensus sequences revealed 6 non-synonymous changes between A01L and A10NL genomes that might be linked to replication differences, as suggested by in silico prediction studies. Our results highlight the biological significance of discrete genomic variations and reinforce the usefulness of this animal model to study viral determinants of lethality. Copyright © 2017 Elsevier Inc. All rights reserved.

CT-based MCNPX dose calculations for gynecology brachytherapy employing a Henschke applicator

NASA Astrophysics Data System (ADS)

Yu, Pei-Chieh; Nien, Hsin-Hua; Tung, Chuan-Jong; Lee, Hsing-Yi; Lee, Chung-Chi; Wu, Ching-Jung; Chao, Tsi-Chian

2017-11-01

The purpose of this study is to investigate the dose perturbation caused by the metal ovoid structures of a Henschke applicator using Monte Carlo simulation in a realistic phantom. The Henschke applicator has been widely used for gynecologic patients treated by brachytherapy in Taiwan. However, the commercial brachytherapy planning system (BPS) did not properly evaluate the dose perturbation caused by its metal ovoid structures. In this study, Monte Carlo N-Particle Transport Code eXtended (MCNPX) was used to evaluate the brachytherapy dose distribution of a Henschke applicator embedded in a Plastic water phantom and a heterogeneous patient computed tomography (CT) phantom. The dose comparison between the MC simulations and film measurements for a Plastic water phantom with Henschke applicator were in good agreement. However, MC dose with the Henschke applicator showed significant deviation (-80.6%±7.5%) from those without Henschke applicator. Furthermore, the dose discrepancy in the heterogeneous patient CT phantom and Plastic water phantom CT geometries with Henschke applicator showed 0 to -26.7% dose discrepancy (-8.9%±13.8%). This study demonstrates that the metal ovoid structures of Henschke applicator cannot be disregard in brachytherapy dose calculation.

Green tea extract-induced lethal toxicity in fasted but not in nonfasted dogs.

PubMed

Wu, Kuei-Meng; Yao, Jiaqin; Boring, Daniel

2011-02-01

Recent chronic toxicity studies performed on green tea extracts in fasted dogs have revealed some unique dose-limiting lethal liver, gastrointestinal, and renal toxicities. Key findings included necrosis of hepatic cells, gastrointestinal epithelia and renal tubules, atrophy of reproductive organs, atrophy and necrosis of hematopoietic tissues, and associated hematological changes. The polyphenol cachetins (a mixture of primarily epigallocatechin gallate [≥55%]; plus up to 10% each of epigallocatechin, epicatechin, and epigallocatechin gallate) appeared to be the causative agents for the observed toxicities because they are the active ingredients of green tea extract studied. Conduct of the study in nonfasted dogs under the same testing conditions and dose levels showed unremarkable results. Assuming both studies were valid, at the identified no observed adverse effect levels (NOAEL) of each study, systemic exposures (based on area under the curve [AUC]) were actually lower in fasted than nonfasted dogs, suggesting that fasting may have rendered the target organ systems potentially more vulnerable to the effects of green tea extract. The toxicity mechanisms that produced lethality are not known, but the results are scientifically intriguing. Because tea drinking has become more popular in the United States and abroad, the mode of action and site of action of green tea extract-induced lethal toxicities during fasting and the role of other phytochemical components of Folia Camellia sinensis (including nonpolyphenol fractions, which are often consumed when whole-leaf products are presented) warrant further investigation.

Whole body protection against lethal ionizing radiation in mice by REC-2001: a semi-purified fraction of Podophyllum hexandrum.

PubMed

Lata, M; Prasad, J; Singh, S; Kumar, R; Singh, L; Chaudhary, P; Arora, R; Chawla, R; Tyagi, S; Soni, N L; Sagar, R K; Devi, M; Sharma, R K; Puri, S C; Tripathi, R P

2009-01-01

The current study has concentrated on assessment of the radioprotective potential of REC-2001, a semi-purified fraction of rhizomes of Podophyllum hexandrum, in Swiss albino Strain 'A' mice exposed to 10 Gy whole-body gamma radiation. Animals were treated with 10 and 15 mg/kg b wt (i.p.) of REC-2001 1h prior to exposure to a lethal dose of gamma-radiation (10 Gy) and observed upto 30 days. For analysis of maximum tolerable dose (MTD), LD(50) and acute toxic dose, different concentrations of the extract were administered to animals and their mortality and morbidity status was observed upto 72 h and one week, respectively. Dose reduction factor (DRF) was determined by exposing REC-2001 pre-treated mice to supra-lethal doses of gamma-radiation. Endogenous spleen colony forming units (CFU), DNA strand breaks in thymocytes (alkaline halo assay) and lipid degradation was studied to understand the mechanism of radioprotection. A single dose of REC-2001 (10 and 15 mg/kg b wt i.p.) exhibited >90% survival in the pre-treated irradiated group versus no survival in radiation control group. Single doses of upto 75 mg/kg b wt (i.p.) did not cause any mortality (MTD) in mice. REC-2001, a dose of 90 mg/kg b wt, resulted in 50% mortality (LD(50)), while the LD(100) was 115 mg/kg b wt REC-2001 exhibited a DRF of 1.62. CFU counts in the REC-2001 treated group were found significantly high (5.33/spleen) as compared to controls. Exposure of thymocytes to 10 Gy radiation resulted in increased halo diameter (45+/-3 microm) in comparison to untreated controls (8+/-1 microm). REC-2001 administration (500 microg/ml) decreased the halo diameter to 15+/-2 microm. Radiation-induced lipid degradation was also inhibited by REC-2001. The present study has revealed that REC-2001 is a promising radioprotective fraction that can be effectively used against lethal doses of gamma-radiation after further investigations in higher animal models.

Sex-Specific Sub-Lethal Effects and Immune Response in Ceratitis capitata Wied. (Diptera: Tephritidae) Challenged with Spinosad.

PubMed

Mura, Maria Elena; Ruiu, Luca

2018-06-21

The main objective of this study was to investigate the effects of the insecticidal compound spinosad on the survival, reproduction, and immune functions of the Mediterranean fruit fly. The lethal and sub-lethal effects were determined on Ceratitis capitata Wied. (Diptera: Tephritidae) challenged with different concentrations of spinosad. A median lethal concentration of 0.28 ppm was observed on flies feeding for 5 days on a treated diet. A significant and concentration-dependent decrease in fecundity, egg hatch rate, and lifespan was also detected in treated compared with control flies. Gene expression analyses conducted on treated insects by RT-qPCR revealed an immunomodulatory action of sub-lethal concentrations of spinosad. Target transcripts included several genes involved in medfly immunity and male or female reproductive functions. While a significant upregulation was detected in treated males a short time after spinosad ingestion, most target genes were downregulated in treated females. Our study confirmed the high toxicity of spinosad to C. capitata , highlighting an indirect effect on insect lifespan and reproductive performance at sub-lethal doses. In addition to defining the acute and sub-lethal toxicity of spinosad against the fly, this study provides new insights on the interaction of this compound with insect physiology.

Lethal mutagenesis: targeting the mutator phenotype in cancer.

PubMed

Fox, Edward J; Loeb, Lawrence A

2010-10-01

The evolution of cancer and RNA viruses share many similarities. Both exploit high levels of genotypic diversity to enable extensive phenotypic plasticity and thereby facilitate rapid adaptation. In order to accumulate large numbers of mutations, we have proposed that cancers express a mutator phenotype. Similar to cancer cells, many viral populations, by replicating their genomes with low fidelity, carry a substantial mutational load. As high levels of mutation are potentially deleterious, the viral mutation frequency is thresholded at a level below which viral populations equilibrate in a traditional mutation-selection balance, and above which the population is no longer viable, i.e., the population undergoes an error catastrophe. Because their mutation frequencies are fine-tuned just below this error threshold, viral populations are susceptible to further increases in mutational load and, recently this phenomenon has been exploited therapeutically by a concept that has been termed lethal mutagenesis. Here we review the application of lethal mutagenesis to the treatment of HIV and discuss how lethal mutagenesis may represent a novel therapeutic approach for the treatment of solid cancers. Copyright © 2010 Elsevier Ltd. All rights reserved.

Japanese quail acute exposure to methamidophos: experimental design, lethal, sub-lethal effects and cholinesterase biochemical and histochemical expression.

PubMed

Foudoulakis, Manousos; Balaskas, Christos; Csato, Attila; Szentes, Csaba; Arapis, Gerassimos

2013-04-15

We exposed the Japanese quail (Coturnix coturnix japonica) to the organophosphate methamidophos using acute oral test. Mortality and sub-lethal effects were recorded in accordance to internationally accepted protocols. In addition cholinesterases were biochemically estimated in tissues of the quail: brain, liver and plasma. Furthermore, brain, liver and duodenum cryostat sections were processed for cholinesterase histochemistry using various substrates and inhibitors. Mortalities occurred mainly in the first 1-2h following application. Sub-lethal effects, such as ataxia, ruffled feathers, tremor, salivation and reduced or no reaction to external stimuli were observed. Biochemical analysis in the brain, liver and plasma indicates a strong cholinesterase dependent inhibition with respect to mortality and sub-lethal effects of the quail. The histochemical staining also indicated a strong cholinesterase inhibition in the organs examined and the analysis of the stained sections allowed for an estimation and interpretation of the intoxication effects of methamidophos, in combination with tissue morphology visible by Haematoxylin and Eosin staining. We conclude that the use of biochemistry and histochemistry for the biomarker cholinesterase, may constitute a significantly novel approach for understanding the results obtained by the acute oral test employed in order to assess the effects of methamidophos and other chemicals known to inhibit this very important nervous system enzyme. Copyright © 2012 Elsevier B.V. All rights reserved.

Dose-Rate Dependence of High-Dose Health Effects in Humans from Photon Radiation with Application to Radiological Terrorism

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

Strom, Daniel J.

2005-01-14

In 1981, as part of a symposium entitled ''The Control of Exposure of the Public to Ionizing Radiation in the Event of Accident or Attack,'' Lushbaugh, H?bner, and Fry published a paper examining ''radiation tolerance'' of various human health endpoints as a function of dose rate. This paper may not have received the notice it warrants. The health endpoints examined by Lushbaugh et al. were the lethal dose that will kill 50% of people within 60 days of exposure without medical care (LD50/60); severe bone marrow damage in healthy men; severe bone marrow damage in leukemia patients; temporary sterility (azoospermia);more » reduced male fertility; and late effects such as cancer. Their analysis was grounded in extensive clinical experience and anchored to a few selected data points, and based on the 1968 dose-rate dependence theory of J.L. Bateman. The Lushbaugh et al. paper did not give predictive equations for the relationships, although they were implied in the text, and the relationships were presented in a non-intuitive way. This work derives the parameters needed in Bateman's equation for each health endpoint, tabulates the results, and plots them in a more conventional manner on logarithmic scales. The results give a quantitative indication of how the human organism can tolerate more radiation dose when it is delivered at lower dose rates. For example, the LD50/60 increases from about 3 grays (300 rads) when given at very high dose rates to over 10 grays (1,000 rads) when given at much lower dose rates over periods of several months. The latter figure is borne out by the case of an individual who survived for at least 19 years after receiving doses in the range of 9 to 17 grays (900-1700 rads) over 106 days. The Lushbaugh et al. work shows the importance of sheltering when confronted with long-term exposure to radiological contamination such as would be expected from a radiological dispersion event, reactor accident, or ground-level nuclear explosion.« less

Regular Aspirin Use and the Risk of Lethal Prostate Cancer in the Physicians' Health Study.

PubMed

Downer, Mary K; Allard, Christopher B; Preston, Mark A; Gaziano, J Michael; Stampfer, Meir J; Mucci, Lorelei A; Batista, Julie L

2017-11-01

Regular aspirin use probably protects against some malignancies including prostate cancer (PC), but its impact on lethal PC is particularly unclear. To investigate the association between regular aspirin and (1) the risk of lethal PC in a large prospective cohort and (2) survival after PC diagnosis. In 1981/82, the Physicians' Health Study randomized 22 071 healthy male physicians to aspirin, β-carotene, both, or placebo. After the trial ended in 1988, annual questionnaires have obtained data on aspirin use, cancer diagnoses, and outcomes up to 2009 for the whole cohort, and to 2015 for PC patients. We evaluated the relationship between regular aspirin (>3 tablets/week) and lethal PC (metastases or PC death). Cox proportional-hazards models estimated hazard ratios (HRs) for the risk of lethal PC in the whole cohort and postdiagnosis survival among men initially diagnosed with nonlethal PC. Risk analysis revealed that 502 men developed lethal PC by 2009. Current and past regular aspirin was associated with a lower risk of lethal PC (current: HR 0.68, 95% confidence interval [CI] 0.52-0.89; past: HR 0.54, 95% CI 0.40-0.74) compared to never users. In the survival analysis, 407/3277 men diagnosed with nonlethal PC developed lethal disease by 2015. Current postdiagnostic aspirin was associated with lower risks of lethal PC (HR 0.68, 95% CI 0.52-0.90) and overall mortality (HR 0.72, 95% CI 0.61-0.9). We could not assess aspirin dose, and inconsistencies were observed in some sensitivity analyses. Current regular aspirin use was associated with a lower risk of lethal PC among all participants. Current postdiagnostic use was associated with improved survival after diagnosis, consistent with a potential inhibitory effect of aspirin on PC progression. A randomized trial is warranted to confirm or refute these findings. We examined the potential effect of regular aspirin use on lethal prostate cancer. We found that taking aspirin was associated with a lower risk of lethal

The Novel Application of Non-Lethal Citizen Science Tissue Sampling in Recreational Fisheries.

PubMed

Williams, Samuel M; Holmes, Bonnie J; Pepperell, Julian G

2015-01-01

Increasing fishing pressure and uncertainty surrounding recreational fishing catch and effort data promoted the development of alternative methods for conducting fisheries research. A pilot investigation was undertaken to engage the Australian game fishing community and promote the non-lethal collection of tissue samples from the black marlin Istiompax indica, a valuable recreational-only species in Australian waters, for the purpose of future genetic research. Recruitment of recreational anglers was achieved by publicizing the project in magazines, local newspapers, social media, blogs, websites and direct communication workshops at game fishing tournaments. The Game Fishing Association of Australia and the Queensland Game Fishing Association were also engaged to advertise the project and recruit participants with a focus on those anglers already involved in the tag-and-release of marlin. Participants of the program took small tissue samples using non-lethal methods which were stored for future genetic analysis. The program resulted in 165 samples from 49 participants across the known distribution of I. indica within Australian waters which was a sufficient number to facilitate a downstream population genetic analysis. The project demonstrated the potential for the development of citizen science sampling programs to collect tissue samples using non-lethal methods in order to achieve targeted research objects in recreationally caught species.

Insulin-Like Growth Factor 1 Mitigates Hematopoietic Toxicity After Lethal Total Body Irradiation

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

Zhou, Dunhua; Deoliveira, Divino; Kang, Yubin

2013-03-15

Purpose: To investigate whether and how insulin-like growth factor 1 (IGF-1) mitigates hematopoietic toxicity after total body irradiation. Methods and Materials: BALB/c mice were irradiated with a lethal dose of radiation (7.5 Gy) and treated with IGF-1 at a dose of 100 μg/dose intravenously once a day for 5 consecutive days starting within 1 hour after exposure. Survival and hematopoietic recovery were monitored. The mechanisms by which IGF-1 promotes hematopoietic recovery were also studied by use of an in vitro culture system. Results: IGF-1 protected 8 of 20 mice (40%) from lethal irradiation, whereas only 2 of 20 mice (10%) inmore » the saline control group survived for more than 100 days after irradiation. A single dose of IGF-1 (500 μg) was as effective as daily dosing for 5 days. Positive effects were noted even when the initiation of treatment was delayed as long as 6 hours after irradiation. In comparison with the saline control group, treatment with IGF-1 significantly accelerated the recovery of both platelets and red blood cells in peripheral blood, total cell numbers, hematopoietic stem cells, and progenitor cells in the bone marrow when measured at day 14 after irradiation. IGF-1 protected both hematopoietic stem cells and progenitor cells from radiation-induced apoptosis and cell death. In addition, IGF-1 was able to facilitate the proliferation and differentiation of nonirradiated and irradiated hematopoietic progenitor cells. Conclusions: IGF-1 mitigates radiation-induced hematopoietic toxicity through protecting hematopoietic stem cells and progenitor cells from apoptosis and enhancing proliferation and differentiation of the surviving hematopoietic progenitor cells.« less

In vivo toxic and lethal cardiovascular effects of a synthetic polymeric 1,3-dodecylpyridinium salt in rodents

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

Grandic, Marjana; Sepcic, Kristina; Turk, Tom

2011-08-15

APS12-2 is one in a series of synthetic analogs of the polymeric alkylpyridinium salts isolated from the marine sponge Reniera sarai. As it is a potential candidate for treating non small cell lung cancer (NSCLC), we have studied its possible toxic and lethal effects in vivo. The median lethal dose (LD{sub 50}) of APS12-2 in mice was determined to be 11.5 mg/kg. Electrocardiograms, arterial blood pressure and respiratory activity were recorded under general anesthesia in untreated, pharmacologically vagotomized and artificially ventilated rats injected with APS12-2. In one group, the in vivo effects of APS12-2 were studied on nerve-evoked muscle contraction.more » Administration of APS12-2 at a dose of 8 mg/kg caused a progressive reduction of arterial blood pressure to a mid-circulatory value, accompanied by bradycardia, myocardial ischemia, ventricular extrasystoles, and second degree atrio-ventricular block. Similar electrocardiogram and arterial blood pressure changes caused by APS12-2 (8 mg/kg) were observed in animals pretreated with atropine and in artificially ventilated animals, indicating that hypoxia and cholinergic effects do not play a crucial role in the toxicity of APS12-2. Application of APS12-2 at sublethal doses (4 and 5.5 mg/kg) caused a decrease of arterial blood pressure, followed by an increase slightly above control values. We found that APS12-2 causes lysis of rat erythrocytes in vitro, therefore it is reasonable to expect the same effect in vivo. Indeed, hyperkalemia was observed in the blood of experimental animals. Hyperkalemia probably plays an important role in APS12-2 cardiotoxicity since no evident changes in histopathology of the heart were found. However, acute lesions were observed in the pulmonary vessels of rats after application of 8 mg/kg APS12-2. Predominant effects were dilation of interalveolar blood vessels and lysis of aggregated erythrocytes within their lumina. - Highlights: > LD{sub 50} estimated in mice (11.5 mg

Lethal photosensitization of biofilm-grown bacteria

NASA Astrophysics Data System (ADS)

Wilson, Michael

1997-12-01

Antibacterial agents are increasingly being used for the prophylaxis and treatment of oral diseases. As these agents can be rendered ineffective by resistance development in the target organisms there is a need to develop alternative antimicrobial approaches. Light-activated antimicrobial agents release singlet oxygen and free radicals which can kill adjacent bacteria and a wide range of cariogenic and periodontopathogenic bacteria has been shown to be susceptible to such agents. In the oral cavity these organisms are present as biofilms (dental plaques) which are less susceptible to traditional antimicrobial agents than bacterial suspensions. The results of these studies have shown that biofilm-grown oral bacteria are also susceptible to lethal photosensitization although the light energy doses required are grater than those needed to kill the organisms when they are grown as aqueous suspensions.

Lethal Forethought: Delayed Reward Discounting Differentiates High- and Low-Lethality Suicide Attempts in Old Age

PubMed Central

Dombrovski, Alexandre Y.; Szanto, Katalin; Siegle, Greg J.; Wallace, Meredith L.; Forman, Steven D.; Sahakian, Barbara; Reynolds, Charles F.; Clark, Luke

2011-01-01

Background The decision to commit suicide may be impulsive, but lethal suicidal acts often involve planning and forethought. People who attempt suicide make disadvantageous decisions in other contexts, but nothing is known about the way they decide about the future. Can the willingness to postpone future gratification differentiate between individuals prone to serious, premeditated and less serious, unplanned suicidal acts? Methods Four groups of depressed participants aged 60+ made choices between smaller immediate and larger delayed monetary rewards: 15 who made high-lethality suicide attempts, 14 who made low-lethality suicide attempts, 12 who seriously contemplated suicide, and 42 people with depression but no history of suicidal thoughts. The reference group was 31 psychiatrically healthy elders. Results Individuals who had made low-lethality attempts displayed an exaggerated preference for immediate rewards compared to non-suicidal depressed and healthy controls. Those who had carried out high-lethality suicide attempts were more willing to delay future rewards, compared to low-lethality attempters. Better planned suicide attempts were also associated with willingness to wait for larger rewards. These effects were unchanged after accounting for education, global cognitive function, substance use disorders, psychotropic medications, and possible brain injury from attempts. Discount rates were correlated with having debt but were not significantly associated with income, hopelessness, depressive severity, premorbid IQ, age at first attempt, or choice of violent means. Conclusions While clinicians often focus on impulsivity in patients at risk for suicide, these data suggest that identifying biological characteristics and treatments for non-impulsive suicidal older people may be even more important. PMID:21329911

Evaluating the lethal and pre-lethal effects of a range of fungi against adult Anopheles stephensi mosquitoes.

PubMed

Blanford, Simon; Jenkins, Nina E; Read, Andrew F; Thomas, Matthew B

2012-11-05

Insecticide resistance is seriously undermining efforts to eliminate malaria. In response, research on alternatives to the use of chemical insecticides against adult mosquito vectors has been increasing. Fungal entomopathogens formulated as biopesticides have received much attention and have shown considerable potential. This research has necessarily focused on relatively few fungal isolates in order to 'prove concept'. Further, most attention has been paid to examining fungal virulence (lethality) and not the other properties of fungal infection that might also contribute to reducing transmission potential. Here, a range of fungal isolates were screened to examine variation in virulence and how this relates to additional pre-lethal reductions in feeding propensity. The Asian malaria vector, Anopheles stephensi was exposed to 17 different isolates of entomopathogenic fungi belonging to species of Beauveria bassiana, Metarhizium anisopliae, Metarhizium acridum and Isaria farinosus. Each isolate was applied to a test substrate at a standard dose rate of 1×109 spores ml-1 and the mosquitoes exposed for six hours. Subsequently the insects were removed to mesh cages where survival was monitored over the next 14 days. During this incubation period the mosquitoes' propensity to feed was assayed for each isolate by offering a feeding stimulant at the side of the cage and recording the number probing. Fungal isolates showed a range of virulence to A. stephensi with some causing >80% mortality within 7 days, while others caused little increase in mortality relative to controls over the study period. Similarly, some isolates had a large impact on feeding propensity, causing >50% pre-lethal reductions in feeding rate, whereas other isolates had very little impact. There was clear correlation between fungal virulence and feeding reduction with virulence explaining nearly 70% of the variation in feeding reduction. However, there were some isolates where either feeding decline

Using a Lethality Index to Assess Susceptibility of Tribolium confusum and Oryzaephilus surinamensis to Insecticides

PubMed Central

Vlontzos, George; Arthur, Frank H.

2015-01-01

We evaluated knockdown caused by four insecticides: alpha-cypermethrin, chlorfenapyr, pirimiphos-methyl and fipronil against adults of Tribolium confusum Jacquelin Duval, the confused flour beetle and Oryzaephilus surinamensis (L.), the sawtoothed grain beetle. Bioassays were conducted on concrete and metal surfaces. Adults of the tested species were exposed on both surfaces treated with the above insecticides at two doses (low and high). Knockdown assessment was done after 15, 30 and 60 min of adult exposure in the treated surfaces. Also, after 1, 3, 5, 7 and 14 d of exposure, a lethality index was calculated with an equation resulting to values from 0 to 100, where 100 indicated complete mortality and 0 complete survival. We also developed a lethality index by ranking each adult on each surface from 0 to 4, 0: adults moved normally, 1: adults were knocked down, but were able to walk for short intervals, 2: adults were knocked down and unable to walk, but with visible movement of antennae etc., 3: adults were knocked down, with very minimal movement of the tarsi and the antennae and 4: adults were dead (no movement). Knockdown of adults immediately after exposure (15–60 min) was higher for pirimiphos-methyl followed by alpha-cypermethrin, for both dose rates tested and species, but only on the metal surface. The lethality index was nearly 100 for all insecticides after 5d of exposure for O. surinamensis, while for T. confusum the adult lethality index was considerably lower for alpha-cypermethrin, suggesting that that recovery from knockdown occurred. Chlorfenapyr was the only insecticide that was more effective on concrete than on metal, while the reverse was noted for the other three insecticides. These results show that knockdown has different levels, which can be used as indicators of insect mortality or recovery. PMID:26560316

CD4 T cell-mediated protection from lethal influenza: perforin and antibody-mediated mechanisms give a one-two punch.

PubMed

Brown, Deborah M; Dilzer, Allison M; Meents, Dana L; Swain, Susan L

2006-09-01

The mechanisms whereby CD4 T cells contribute to the protective response against lethal influenza infection remain poorly characterized. To define the role of CD4 cells in protection against a highly pathogenic strain of influenza, virus-specific TCR transgenic CD4 effectors were generated in vitro and transferred into mice given lethal influenza infection. Primed CD4 effectors conferred protection against lethal infection over a broad range of viral dose. The protection mediated by CD4 effectors did not require IFN-gamma or host T cells, but did result in increased anti-influenza Ab titers compared with untreated controls. Further studies indicated that CD4-mediated protection at high doses of influenza required B cells, and that passive transfer of anti-influenza immune serum was therapeutic in B cell-deficient mice, but only when CD4 effectors were present. Primed CD4 cells also acquired perforin (Pfn)-mediated cytolytic activity during effector generation, suggesting a second mechanism used by CD4 cells to confer protection. Pfn-deficient CD4 effectors were less able to promote survival in intact BALB/c mice and were unable to provide protection in B cell-deficient mice, indicating that Ab-independent protection by CD4 effectors requires Pfn. Therefore, CD4 effectors mediate protection to lethal influenza through at least two mechanisms: Pfn-mediated cytotoxicity early in the response promoted survival independently of Ab production, whereas CD4-driven B cell responses resulted in high titer Abs that neutralized remaining virus.

A single immunization with a dry powder anthrax vaccine protects rabbits against lethal aerosol challenge

PubMed Central

Klas, S.D.; Petrie, C.R.; Warwood, S.J.; Williams, M.S.; Olds, C.L.; Stenz, J.P.; Cheff, A.M.; Hinchcliffe, M.; Richardson, C.; Wimer, S.

2009-01-01

Here we confirm that intranasal (IN) dry powder anthrax vaccine formulations are able to protect rabbits against aerosol challenge 9 weeks after a single immunization. The optimum dose of rPA in our dry powder anthrax vaccine formulation in rabbits was experimentally determined to be 150 μg and therefore was chosen as the target dose for all subsequent experiments. Rabbits received a single dose of either 150 μg rPA, 150 μg rPA + 150 μg of a conjugated 10-mer peptide representing the B. anthracis capsule (conj), or 150 μg of conj alone. All dry powder formulations contained MPL and chitosan (ChiSys®). Significant anti-rPA titers and anthrax lethal toxin neutralizing antibody (TNA) levels were seen with both rPA containing vaccines, although rPA-specific IgG and TNA levels were reduced in rabbits immunized with rPA plus conj. Nine weeks after immunization, rabbits were exposed to a mean aerosol challenge dose of 278 LD50 of Ames spores. Groups immunized with rPA or with rPA + conj had significant increases in survivor proportions compared to the negative control group by Logrank test (p = 0.0001 and 0.003, respectively), and survival was not statistically different for the rPA and rPA + conj immunized groups (p = 0.63). These data demonstrate that a single immunization with our dry powder anthrax vaccine can protect against a lethal aerosol spore challenge 9 weeks later. PMID:18703110

A single immunization with a dry powder anthrax vaccine protects rabbits against lethal aerosol challenge.

PubMed

Klas, S D; Petrie, C R; Warwood, S J; Williams, M S; Olds, C L; Stenz, J P; Cheff, A M; Hinchcliffe, M; Richardson, C; Wimer, S

2008-10-09

Here we confirm that intranasal (IN) dry powder anthrax vaccine formulations are able to protect rabbits against aerosol challenge 9 weeks after a single immunization. The optimum dose of rPA in our dry powder anthrax vaccine formulation in rabbits was experimentally determined to be 150microg and therefore was chosen as the target dose for all subsequent experiments. Rabbits received a single dose of either 150microg rPA, 150microg rPA+150microg of a conjugated 10-mer peptide representing the Bacillus anthracis capsule (conj), or 150microg of conj alone. All dry powder formulations contained MPL and chitosan (ChiSys). Significant anti-rPA titers and anthrax lethal toxin neutralizing antibody (TNA) levels were seen with both rPA containing vaccines, although rPA-specific IgG and TNA levels were reduced in rabbits immunized with rPA plus conj. Nine weeks after immunization, rabbits were exposed to a mean aerosol challenge dose of 278 LD50 of Ames spores. Groups immunized with rPA or with rPA+conj had significant increases in survivor proportions compared to the negative control group by Logrank test (p=0.0001 and 0.003, respectively), and survival was not statistically different for the rPA and rPA+conj immunized groups (p=0.63). These data demonstrate that a single immunization with our dry powder anthrax vaccine can protect against a lethal aerosol spore challenge 9 weeks later.

[Oral toxicity at 60-days of sacha inchi oil (Plukenetia volubilis L.) and linseed (Linum usitatissimum L.), and determination of lethal dose 50 in rodents].

PubMed

Gorriti, Arilmi; Arroyo, Jorge; Quispe, Fredy; Cisneros, Braulio; Condorhuamán, Martín; Almora, Yuan; Chumpitaz, Víctor

2010-09-01

To evaluate the oral toxicity at 60 days and to determine the lethal dose 50 (LD 50) of raw sacha inchi (Plukenetia volubilis L.) and linseed (Linum ussitatisimum) oils in Holtzman rats and mice of the strain Balb C57 respectively. For the evaluation of the oral toxicity of repeated doses for 60 days, 24 male Holtzman rats were used, divided in three groups of 8 each, the groups were: physiologic saline solution 4 mL/kg (FSS), sacha inchi oil 0.5 mL/kg (SI05) and linseed oil 0.5 mL/kg (L05), during the experiment the body weight was controlled weekly, and signs of toxicity in the research groups, as well as total cholesterol, HDL, glucose, triglycerides and alkaline phosphatase at days 30 and 60 after initiating the experiment. For the evaluation of the LD50 male mice of the Balb C57 strain were used in groups of 10 animals, and they were administered increasing oral doses of raw oils until reaching 1 mL/kg (37 g/kg). The serum parameters in the rats indicated there is no toxicity at 60 days and that the administration of the oils lowered the levels of cholesterol, triglycerides and increased the HDL in comparison with the control group. The LD50 shows that the raw sacha inchi and linseed oils have doses above 37 g/kg of body weight. Sacha inchi and linseed oils are harmless at 60 days and present a LD50 above the 37 g/kg of animal.

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

PubMed

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

2016-01-01

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

Median lethal dose determination for percutaneous exposure to soman and VX in guinea pigs and the effectiveness of decontamination with M291 SDK or SANDIA foam.

PubMed

Clarkson, Edward D; Schulz, Susan M; Railer, Roy F; Smith, Kelly H

2012-08-03

Soman (GD) and VX are chemical warfare agents that can be absorbed through the skin. We determined the median lethal dose (MLD) for the cutaneous application of GD and VX in anesthetized haired guinea pigs and then tested the ability of a currently fielded decontamination kit, the M291 Skin Decontamination Kit (SDK), and decontaminating foam made by SANDIA Labs to decontaminate areas that have been exposed to cutaneous applications of GD and VX. The fur of guinea pigs was clipped on the left flank 24h prior to exposure. Animals were anesthetized and 5 min later neat GD or neat VX was applied. The MLD for percutaneous exposure to GD was 11.6 mg/kg, and to VX it was 0.10mg/kg. To test the ability of the M291 SDK, either GD or VX was applied and removed 1 min later with the pads of the M291 SDK clasped in a pair of forceps and wiped across the flank of the animal. The MLDs for GD and VX removed with the M291 SDK pads were 76.9 mg/kg and 0.87 mg/kg, respectively. When neat GD or neat VX was applied and removed 1 min later in the same manner with gauze soaked in SANDIA foam (MDF-100), the MLDs were 412 mg/kg and 10.4 mg/kg respectively. These data demonstrate that GD and VX are significantly less potent when applied cutaneously than previously reported for subcutaneous injections and indicate that improvement is needed on the limited protective ratio provided by the M291 SDK. Published by Elsevier Ireland Ltd.

Are High-Lethality Suicide Attempters With Bipolar Disorder a Distinct Phenotype?

PubMed Central

Oquendo, Maria A.; Carballo, Juan Jose; Rajouria, Namita; Currier, Dianne; Tin, Adrienne; Merville, Jessica; Galfalvy, Hanga C.; Sher, Leo; Grunebaum, Michael F.; Burke, Ainsley K.; Mann, J. John

2013-01-01

Because Bipolar Disorder (BD) individuals making highly lethal suicide attempts have greater injury burden and risk for suicide, early identification is critical. BD patients were classified as high- or low-lethality attempters. High-lethality attempts required inpatient medical treatment. Mixed effects logistic regression models and permutation analyses examined correlations between lethality, number, and order of attempts. High-lethality attempters reported greater suicidal intent and more previous attempts. Multiple attempters showed no pattern of incremental lethality increase with subsequent attempts, but individuals with early high-lethality attempts more often made high-lethality attempts later. A subset of high-lethality attempters make only high-lethality attempts. However, presence of previous low-lethality attempts does not indicate that risk for more lethal, possibly successful, attempts is reduced. PMID:19590998

Monte Carlo skin dose simulation in intraoperative radiotherapy of breast cancer using spherical applicators.

PubMed

Moradi, F; Ung, N M; Khandaker, M U; Mahdiraji, G A; Saad, M; Abdul Malik, R; Bustam, A Z; Zaili, Z; Bradley, D A

2017-07-28

The relatively new treatment modality electronic intraoperative radiotherapy (IORT) is gaining popularity, irradiation being obtained within a surgically produced cavity being delivered via a low-energy x-ray source and spherical applicators, primarily for early stage breast cancer. Due to the spatially dramatic dose-rate fall off with radial distance from the source and effects related to changes in the beam quality of the low keV photon spectra, dosimetric account of the Intrabeam system is rather complex. Skin dose monitoring in IORT is important due to the high dose prescription per treatment fraction. In this study, modeling of the x-ray source and related applicators were performed using the Monte Carlo N-Particle transport code. The dosimetric characteristics of the model were validated against measured data obtained using an ionization chamber and EBT3 film as dosimeters. By using a simulated breast phantom, absorbed doses to the skin for different combinations of applicator size (1.5-5 cm) and treatment depth (0.5-3 cm) were calculated. Simulation results showed overdosing of the skin (>30% of prescribed dose) at a treatment depth of 0.5 cm using applicator sizes larger than 1.5 cm. Skin doses were significantly increased with applicator size, insofar as delivering 12 Gy (60% of the prescribed dose) to skin for the largest sized applicator (5 cm diameter) and treatment depth of 0.5 cm. It is concluded that the recommended 0.5-1 cm distance between the skin and applicator surface does not guarantee skin safety and skin dose is generally more significant in cases with the larger applicators. • Intrabeam x-ray source and spherical applicators were simulated and skin dose was calculated. • Skin dose for constant skin to applicator distance strongly depends on applicator size. • Use of larger applicators generally results in higher skin dose. • The recommended 0.5-1 cm skin to applicator distance does not guarantee skin safety.

Monte Carlo skin dose simulation in intraoperative radiotherapy of breast cancer using spherical applicators

NASA Astrophysics Data System (ADS)

Moradi, F.; Ung, N. M.; Khandaker, M. U.; Mahdiraji, G. A.; Saad, M.; Malik, R. Abdul; Bustam, A. Z.; Zaili, Z.; Bradley, D. A.

2017-08-01

The relatively new treatment modality electronic intraoperative radiotherapy (IORT) is gaining popularity, irradiation being obtained within a surgically produced cavity being delivered via a low-energy x-ray source and spherical applicators, primarily for early stage breast cancer. Due to the spatially dramatic dose-rate fall off with radial distance from the source and effects related to changes in the beam quality of the low keV photon spectra, dosimetric account of the Intrabeam system is rather complex. Skin dose monitoring in IORT is important due to the high dose prescription per treatment fraction. In this study, modeling of the x-ray source and related applicators were performed using the Monte Carlo N-Particle transport code. The dosimetric characteristics of the model were validated against measured data obtained using an ionization chamber and EBT3 film as dosimeters. By using a simulated breast phantom, absorbed doses to the skin for different combinations of applicator size (1.5-5 cm) and treatment depth (0.5-3 cm) were calculated. Simulation results showed overdosing of the skin (>30% of prescribed dose) at a treatment depth of 0.5 cm using applicator sizes larger than 1.5 cm. Skin doses were significantly increased with applicator size, insofar as delivering 12 Gy (60% of the prescribed dose) to skin for the largest sized applicator (5 cm diameter) and treatment depth of 0.5 cm. It is concluded that the recommended 0.5-1 cm distance between the skin and applicator surface does not guarantee skin safety and skin dose is generally more significant in cases with the larger applicators. Highlights: • Intrabeam x-ray source and spherical applicators were simulated and skin dose was calculated. • Skin dose for constant skin to applicator distance strongly depends on applicator size. • Use of larger applicators generally results in higher skin dose. • The recommended 0.5-1 cm skin to applicator distance does not guarantee skin

Synergistic Lethality of Mifepristone and LY294002 in Ovarian Cancer Cells

PubMed Central

Wempe, Stacy L.; Gamarra-Luques, Carlos D.; Telleria, Carlos M.

2013-01-01

We have previously shown that the antiprogestin and antiglucocorticoid mifepristone inhibits the growth of ovarian cancer cells. In this work, we hypothesized that cellular stress caused by mifepristone is limited to cytostasis and that cell killing is avoided as a consequence of the persistent activity of the PI3K/Akt survival pathway. To investigate the role of this pathway in mifepristone-induced growth inhibition, human ovarian cancer cells of various histological subtypes and genetic backgrounds were exposed to cytostatic doses of mifepristone in the presence or absence of the PI3K inhibitor, LY294002. The activation of Akt in ovarian cancer cells, as marked by its phosphorylation on Ser473, was not modified by cytostatic concentrations of mifepristone, but it was blocked upon treatment with LY294002. The combination mifepristone/LY294002, but not the individual drugs, killed ovarian cancer cells via apoptosis, as attested by genomic DNA fragmentation and cleavage of caspase-3, and the concomitant downregulation of antiapoptotic proteins Bcl-2 and XIAP. From a pharmacological standpoint, when assessing cell growth inhibition using a median-dose analysis algorithm, the interaction between mifepristone and LY294002 was synergistic. The lethality caused by the combination mifepristone/LY294004 in 2-dimensional cell cultures was recapitulated in organized, 3-dimensional spheroids. This study demonstrates that mifepristone and LY294002 when used individually cause cell growth arrest; yet, when combined, they cause lethality. PMID:23420486

Extracts of Renealmia alpinia (Rottb.) MAAS Protect against Lethality and Systemic Hemorrhage Induced by Bothrops asper Venom: Insights from a Model with Extract Administration before Venom Injection.

PubMed

Patiño, Arley Camilo; Quintana, Juan Carlos; Gutiérrez, José María; Rucavado, Alexandra; Benjumea, Dora María; Pereañez, Jaime Andrés

2015-04-30

Renealmia alpinia (Rottb.) MAAS, obtained by micropropagation (in vitro) and wild forms have previously been shown to inhibit some toxic activities of Bothrops asper snake venom if preincubated before injection. In this study, assays were performed in a murine model in which extracts were administered for three days before venom injection. R. alpinia extracts inhibited lethal activity of B. asper venom injected by intraperitoneal route. Median Effective Dose (ED50) values were 36.6 ± 3.2 mg/kg and 31.7 ± 5.4 mg/kg (p > 0.05) for R. alpinia wild and in vitro extracts, respectively. At a dose of 75 mg/kg, both extracts totally inhibited the lethal activity of the venom. Moreover, this dose prolonged survival time of mice receiving a lethal dose of venom by the intravenous route. At 75 mg/kg, both extracts of R. alpinia reduced the extent of venom-induced pulmonary hemorrhage by 48.0% (in vitro extract) and 34.7% (wild extract), in agreement with histological observations of lung tissue. R. alpinia extracts also inhibited hemorrhage in heart and kidneys, as evidenced by a decrease in mg of hemoglobin/g of organ. These results suggest the possibility of using R. alpinia as a prophylactic agent in snakebite, a hypothesis that needs to be further explored.

A novel highly reproducible and lethal nonhuman primate model for orthopox virus infection.

PubMed

Kramski, Marit; Mätz-Rensing, Kerstin; Stahl-Hennig, Christiane; Kaup, Franz-Josef; Nitsche, Andreas; Pauli, Georg; Ellerbrok, Heinz

2010-04-29

The intentional re-introduction of Variola virus (VARV), the agent of smallpox, into the human population is of great concern due its bio-terroristic potential. Moreover, zoonotic infections with Cowpox (CPXV) and Monkeypox virus (MPXV) cause severe diseases in humans. Smallpox vaccines presently available can have severe adverse effects that are no longer acceptable. The efficacy and safety of new vaccines and antiviral drugs for use in humans can only be demonstrated in animal models. The existing nonhuman primate models, using VARV and MPXV, need very high viral doses that have to be applied intravenously or intratracheally to induce a lethal infection in macaques. To overcome these drawbacks, the infectivity and pathogenicity of a particular CPXV was evaluated in the common marmoset (Callithrix jacchus).A CPXV named calpox virus was isolated from a lethal orthopox virus (OPV) outbreak in New World monkeys. We demonstrated that marmosets infected with calpox virus, not only via the intravenous but also the intranasal route, reproducibly develop symptoms resembling smallpox in humans. Infected animals died within 1-3 days after onset of symptoms, even when very low infectious viral doses of 5x10(2) pfu were applied intranasally. Infectious virus was demonstrated in blood, saliva and all organs analyzed.We present the first characterization of a new OPV infection model inducing a disease in common marmosets comparable to smallpox in humans. Intranasal virus inoculation mimicking the natural route of smallpox infection led to reproducible infection. In vivo titration resulted in an MID(50) (minimal monkey infectious dose 50%) of 8.3x10(2) pfu of calpox virus which is approximately 10,000-fold lower than MPXV and VARV doses applied in the macaque models. Therefore, the calpox virus/marmoset model is a suitable nonhuman primate model for the validation of vaccines and antiviral drugs. Furthermore, this model can help study mechanisms of OPV pathogenesis.

Effects of DDE and PCB (Aroclor 1260) on experimentally poisoned little brown bats (Myotis lucifugus): Lethal brain concentrations

USGS Publications Warehouse

Clark, D.R.; Stafford, C.J.

1981-01-01

Adult female little brown bats (Myotis lucifugus) were collected in a church attic in North East, Cecil County, Md. Mealworms (Tenebrio molitor) containing organochlorine pollutants were fed to the bats as follows: 5 bats were dosed at 480 ppm DDE, 12 at 150 ppm DDE, 5 at 1000 ppm polychlorinated biphenyl (PCB; Aroclor 1260), and 12 at 15 ppm PCB. Seven other bats were fed untreated mealworms. The objective was to elevate brain levels of DDE and PCB to lethality and measure these concentrations. During 40 d of dosage, one DDE-dosed bat and two PCB-dosed bats died after exhibiting the prolonged tremor that characterizes organochlorine poisoning. After dosage, surviving bats were starved to elevate brain levels of toxicants, and three additional DDE-dosed bats had tremors before dying. The mean brain concentration of DDE diagnostic of death was estimated as 603 ppm, range 540-670 ppm. This mean is 16-18% higher than means for Mexican free-tailed bats (Tadarida brasiliensis) and common grackles (Quiscalus quiscula), and may indicate less sensitivity. Lethal brain concentrations of Aroclor 1260 were 1300 and 1500 ppm. Such values appear to be higher than values (Aroclor 1254) for brown-headed cowbirds (Molothrus ater). During starvation, DDE-dosed bats lost weight about 24% faster than controls. If smaller amounts of stored DDE cause increases in metabolic rates of nonfeeding bats, as during hibernation or migration, the result could be premature energy depletion and increased mortality.

Evaluation of the performance of three elastomers for non-lethal projectile applications

NASA Astrophysics Data System (ADS)

Thota, N.; Epaarachchi, J.; Lau, K. T.

2015-09-01

Less lethal kinetic ammunitions with soft noses such as eXact iMpact 1006, National Sports Spartan and B&T have been commonly used by military and law enforcement officers in the situations where lethal force is not warranted. In order to explore new materials to be used as nose in such ammunitions, a scholastic study using finite element simulations has been carried out to evaluate the effectiveness of two rubber like elastomers and a polyolefinic foam (low density, highly compressible, stiff and closed cell type of thermos plastic elastomer). State-of-the art thorax surrogate MTHOTA has been employed for the evaluation of blunt thoracic trauma. Force-rigid wall method was employed for the evaluation of head damage curves for each material. XM 1006 has been used as the benchmark projectile for the purpose of comparison. Both blunt thoracic trauma and head damage criterion point of view, both rubbers (R1 and R2) have yielded high values of VCmax and peak impact force. Polyolefinic foam (F1) considered in the study has yielded very promising VCmax values and very less peak impact force when compared with those of bench mark projectile XM 1006.

Synthetic Lethal Networks for Precision Oncology: Promises and Pitfalls.

PubMed

Shen, John Paul; Ideker, Trey

2018-06-19

Synthetic lethal interactions, in which the simultaneous loss-of-function of two genes produces a lethal phenotype, are being explored as a means to therapeutically exploit cancer-specific vulnerabilities and expand the scope of precision oncology. Currently, three FDA approved drugs work by targeting the synthetic lethal interaction between BRCA1/2 and PARP. This review examines additional efforts to discover networks of synthetic lethal interactions and discusses both challenges and opportunities regarding the translation of new synthetic lethal interactions into the clinic. Copyright © 2018. Published by Elsevier Ltd.

Command and Control for Distributed Lethality

DTIC Science & Technology

2017-06-01

based systems engineering (MBSE) approach to C2 within the distributed lethality environment requires development of methodologies to provide...lethality environment requires development of methodologies to provide definition and structure for existing operational concepts while providing...2  D.  SCOPE AND METHODOLOGY ............................................................2  E.  STAKEHOLDER ANALYSIS

Androstenediol and dehydroepiandrosterone protect mice against lethal bacterial infections and lipopolysaccharide toxicity.

PubMed

Ben-Nathan, D; Padgett, D A; Loria, R M

1999-05-01

The protective effects of the hormones androstenediol (androstene-3beta, 17beta,-diol; AED) and dehydroepiandrosterone (5-androsten-3beta-ol-17-one; DHEA) on the pathophysiology of two lethal bacterial infections and endotoxin shock were examined. The infections included a gram-positive organism (Enterococcus faecalis) and a gram-negative organism (Pseudomonas aeruginosa). Both hormones protected mice from the lethal bacterial infections and from lipopolysaccharide (LPS) challenge. Treatment of animals lethally infected with P. aeruginosa with DHEA resulted in a 43% protection whereas treatment with AED gave a 67% protection. Both hormones also protected completely animals infected with an LD50 dose of E. faecalis. Similarly, the 88% mortality rate seen in LPS challenge was reduced to 17% and 8.5%, by treatment with DHEA and AED, respectively. The protective influences of both steroids were shown not to be directly antibacterial, but primarily an indirect antitoxin reaction. DHEA appears to mediate its protective effect by a mechanism that blocks the toxin-induced production of pathophysiological levels of tumour necrosis factor-alpha (TNF-alpha) and interleukin-1. AED usually had greater protective effects than DHEA; however, the AED effect was independent of TNF-alpha suppression, both in vivo and in vitro. The data suggest that both DHEA and AED may have a role in the neuro-endocrine regulation of antibacterial immune resistance.

Gene Expression in Parp1 Deficient Mice Exposed to a Median Lethal Dose of Gamma Rays.

PubMed

Kumar, M A Suresh; Laiakis, Evagelia C; Ghandhi, Shanaz A; Morton, Shad R; Fornace, Albert J; Amundson, Sally A

2018-05-10

There is a current interest in the development of biodosimetric methods for rapidly assessing radiation exposure in the wake of a large-scale radiological event. This work was initially focused on determining the exposure dose to an individual using biological indicators. Gene expression signatures show promise for biodosimetric application, but little is known about how these signatures might translate for the assessment of radiological injury in radiosensitive individuals, who comprise a significant proportion of the general population, and who would likely require treatment after exposure to lower doses. Using Parp1 -/- mice as a model radiation-sensitive genotype, we have investigated the effect of this DNA repair deficiency on the gene expression response to radiation. Although Parp1 is known to play general roles in regulating transcription, the pattern of gene expression changes observed in Parp1 -/- mice 24 h postirradiation to a LD 50/30 was remarkably similar to that in wild-type mice after exposure to LD 50/30 . Similar levels of activation of both the p53 and NFκB radiation response pathways were indicated in both strains. In contrast, exposure of wild-type mice to a sublethal dose that was equal to the Parp1 -/- LD 50/30 , which resulted in a lower magnitude gene expression response. Thus, Parp1 -/- mice displayed a heightened gene expression response to radiation, which was more similar to the wild-type response to an equitoxic dose than to an equal absorbed dose. Gene expression classifiers trained on the wild-type data correctly identified all wild-type samples as unexposed, exposed to a sublethal dose or exposed to an LD 50/30 . All unexposed samples from Parp1 -/- mice were also correctly classified with the same gene set, and 80% of irradiated Parp1 -/- samples were identified as exposed to an LD 50/30 . The results of this study suggest that, at least for some pathways that may influence radiosensitivity in humans, specific gene expression

Lethal Injection for Execution: Chemical Asphyxiation?

PubMed Central

Zimmers, Teresa A; Sheldon, Jonathan; Lubarsky, David A; López-Muñoz, Francisco; Waterman, Linda; Weisman, Richard; Koniaris, Leonidas G

2007-01-01

Background Lethal injection for execution was conceived as a comparatively humane alternative to electrocution or cyanide gas. The current protocols are based on one improvised by a medical examiner and an anesthesiologist in Oklahoma and are practiced on an ad hoc basis at the discretion of prison personnel. Each drug used, the ultrashort-acting barbiturate thiopental, the neuromuscular blocker pancuronium bromide, and the electrolyte potassium chloride, was expected to be lethal alone, while the combination was intended to produce anesthesia then death due to respiratory and cardiac arrest. We sought to determine whether the current drug regimen results in death in the manner intended. Methods and Findings We analyzed data from two US states that release information on executions, North Carolina and California, as well as the published clinical, laboratory, and veterinary animal experience. Execution outcomes from North Carolina and California together with interspecies dosage scaling of thiopental effects suggest that in the current practice of lethal injection, thiopental might not be fatal and might be insufficient to induce surgical anesthesia for the duration of the execution. Furthermore, evidence from North Carolina, California, and Virginia indicates that potassium chloride in lethal injection does not reliably induce cardiac arrest. Conclusions We were able to analyze only a limited number of executions. However, our findings suggest that current lethal injection protocols may not reliably effect death through the mechanisms intended, indicating a failure of design and implementation. If thiopental and potassium chloride fail to cause anesthesia and cardiac arrest, potentially aware inmates could die through pancuronium-induced asphyxiation. Thus the conventional view of lethal injection leading to an invariably peaceful and painless death is questionable. PMID:17455994

The Slimeball: The Development of Broad-Scale Maritime Non-Lethal Weaponry

DTIC Science & Technology

2009-04-01

commercial applications from waste management to horticulture to baby diapers. By some estimates, it can absorb one thousand times its volume in water...www.nytimes.com/2008/10/31/world/africa/31pirates.html?pagewanted=1&_r=1. Goolsby, Tommy D. “Aqueous Foam as a Less-Than-Lethal Technology for Prison

Aqueous foam as a less-than-lethal technology for prison applications

NASA Astrophysics Data System (ADS)

Goolsby, Tommy D.

1997-01-01

High expansion aqueous foam is an aggregation of bubbles that has the appearance of soap suds and is used to isolate individuals both visually and acoustically. It was developed in the 1920's in England to fight coal mine fires and has been widely used since for fire fighting and dust suppression. It was developed at Sandia National Laboratories (SNL) in the 1970's for nuclear safeguards and security applications. In late 1994, the National Institute of Justice (NIJ), the research arm of the Department of Justice, began a project with SNL to determine the applicability of high expansion aqueous foam for correctional applications. NIJ funded the project as part of its search for new and better less-than-lethal weapons for responding to violent and dangerous individuals, where other means of force could lead to serious injuries. The phase one objectives of the project were to select a low-to-no toxicity foam concentrate with physical characteristics suited for use in a single cell or large prison disturbances, and to determine if the selected foam concentrate could serve as a carrier for Oleoresin Capsicum (OC) irritant. The phase two objective were to conduct an extensive toxicology review of the selected foam concentrate and OC irritant, and to conduct respiration simulation experiments in the selected high expansion aqueous foam. The phase three objectives were to build a prototype individual cell aqueous foam system and to study the feasibility of aqueous foams for large prison facility disturbances. The phase four and five objectives were to use the prototype system to do large scale foam physical characteristics testing of the selected foam concentrate, and to have the prototype single cell system further evaluated by correctional representatives. Prison rather than street scenarios were evaluated as the first and most likely place for using the aqueous foam since prisons have recurrent incidents where officers and inmates might be seriously injured during

Evaluation of Inhaled Versus Deposited Dose Using the Exponential Dose-Response Model for Inhalational Anthrax in Nonhuman Primate, Rabbit, and Guinea Pig.

PubMed

Gutting, Bradford W; Rukhin, Andrey; Mackie, Ryan S; Marchette, David; Thran, Brandolyn

2015-05-01

The application of the exponential model is extended by the inclusion of new nonhuman primate (NHP), rabbit, and guinea pig dose-lethality data for inhalation anthrax. Because deposition is a critical step in the initiation of inhalation anthrax, inhaled doses may not provide the most accurate cross-species comparison. For this reason, species-specific deposition factors were derived to translate inhaled dose to deposited dose. Four NHP, three rabbit, and two guinea pig data sets were utilized. Results from species-specific pooling analysis suggested all four NHP data sets could be pooled into a single NHP data set, which was also true for the rabbit and guinea pig data sets. The three species-specific pooled data sets could not be combined into a single generic mammalian data set. For inhaled dose, NHPs were the most sensitive (relative lowest LD50) species and rabbits the least. Improved inhaled LD50 s proposed for use in risk assessment are 50,600, 102,600, and 70,800 inhaled spores for NHP, rabbit, and guinea pig, respectively. Lung deposition factors were estimated for each species using published deposition data from Bacillus spore exposures, particle deposition studies, and computer modeling. Deposition was estimated at 22%, 9%, and 30% of the inhaled dose for NHP, rabbit, and guinea pig, respectively. When the inhaled dose was adjusted to reflect deposited dose, the rabbit animal model appears the most sensitive with the guinea pig the least sensitive species. © 2014 Society for Risk Analysis.

The Toll-Like Receptor 5 Agonist Entolimod Mitigates Lethal Acute Radiation Syndrome in Non-Human Primates.

PubMed

Krivokrysenko, Vadim I; Toshkov, Ilia A; Gleiberman, Anatoli S; Krasnov, Peter; Shyshynova, Inna; Bespalov, Ivan; Maitra, Ratan K; Narizhneva, Natalya V; Singh, Vijay K; Whitnall, Mark H; Purmal, Andrei A; Shakhov, Alexander N; Gudkov, Andrei V; Feinstein, Elena

2015-01-01

There are currently no approved medical radiation countermeasures (MRC) to reduce the lethality of high-dose total body ionizing irradiation expected in nuclear emergencies. An ideal MRC would be effective even when administered well after radiation exposure and would counteract the effects of irradiation on the hematopoietic system and gastrointestinal tract that contribute to its lethality. Entolimod is a Toll-like receptor 5 agonist with demonstrated radioprotective/mitigative activity in rodents and radioprotective activity in non-human primates. Here, we report data from several exploratory studies conducted in lethally irradiated non-human primates (rhesus macaques) treated with a single intramuscular injection of entolimod (in the absence of intensive individualized supportive care) administered in a mitigative regimen, 1-48 hours after irradiation. Following exposure to LD50-70/40 of radiation, injection of efficacious doses of entolimod administered as late as 25 hours thereafter reduced the risk of mortality 2-3-fold, providing a statistically significant (P<0.01) absolute survival advantage of 40-60% compared to vehicle treatment. Similar magnitude of survival improvement was also achieved with drug delivered 48 hours after irradiation. Improved survival was accompanied by predominantly significant (P<0.05) effects of entolimod administration on accelerated morphological recovery of hematopoietic and immune system organs, decreased severity and duration of thrombocytopenia, anemia and neutropenia, and increased clonogenic potential of the bone marrow compared to control irradiated animals. Entolimod treatment also led to reduced apoptosis and accelerated crypt regeneration in the gastrointestinal tract. Together, these data indicate that entolimod is a highly promising potential life-saving treatment for victims of radiation disasters.

Extracts of Renealmia alpinia (Rottb.) MAAS Protect against Lethality and Systemic Hemorrhage Induced by Bothrops asper Venom: Insights from a Model with Extract Administration before Venom Injection

PubMed Central

Patiño, Arley Camilo; Quintana, Juan Carlos; Gutiérrez, José María; Rucavado, Alexandra; Benjumea, Dora María; Pereañez, Jaime Andrés

2015-01-01

Renealmia alpinia (Rottb.) MAAS, obtained by micropropagation (in vitro) and wild forms have previously been shown to inhibit some toxic activities of Bothrops asper snake venom if preincubated before injection. In this study, assays were performed in a murine model in which extracts were administered for three days before venom injection. R. alpinia extracts inhibited lethal activity of B. asper venom injected by intraperitoneal route. Median Effective Dose (ED50) values were 36.6 ± 3.2 mg/kg and 31.7 ± 5.4 mg/kg (p > 0.05) for R. alpinia wild and in vitro extracts, respectively. At a dose of 75 mg/kg, both extracts totally inhibited the lethal activity of the venom. Moreover, this dose prolonged survival time of mice receiving a lethal dose of venom by the intravenous route. At 75 mg/kg, both extracts of R. alpinia reduced the extent of venom-induced pulmonary hemorrhage by 48.0% (in vitro extract) and 34.7% (wild extract), in agreement with histological observations of lung tissue. R. alpinia extracts also inhibited hemorrhage in heart and kidneys, as evidenced by a decrease in mg of hemoglobin/g of organ. These results suggest the possibility of using R. alpinia as a prophylactic agent in snakebite, a hypothesis that needs to be further explored. PMID:25941768

Nonreplicating Influenza A Virus Vaccines Confer Broad Protection against Lethal Challenge

PubMed Central

Baz, Mariana; Boonnak, Kobporn; Paskel, Myeisha; Santos, Celia; Powell, Timothy; Townsend, Alain

2015-01-01

ABSTRACT New vaccine technologies are being investigated for their ability to elicit broadly cross-protective immunity against a range of influenza viruses. We compared the efficacies of two intranasally delivered nonreplicating influenza virus vaccines (H1 and H5 S-FLU) that are based on the suppression of the hemagglutinin signal sequence, with the corresponding H1N1 and H5N1 cold-adapted (ca) live attenuated influenza virus vaccines in mice and ferrets. Administration of two doses of H1 or H5 S-FLU vaccines protected mice and ferrets from lethal challenge with homologous, heterologous, and heterosubtypic influenza viruses, and two doses of S-FLU and ca vaccines yielded comparable effects. Importantly, when ferrets immunized with one dose of H1 S-FLU or ca vaccine were challenged with the homologous H1N1 virus, the challenge virus failed to transmit to naive ferrets by the airborne route. S-FLU technology can be rapidly applied to any emerging influenza virus, and the promising preclinical data support further evaluation in humans. PMID:26489862

Detection of warfare agents in liquid foods using the brine shrimp lethality assay.

PubMed

Lumor, Stephen E; Diez-Gonzalez, Francisco; Labuza, Theodore P

2011-01-01

The brine shrimp lethality assay (BSLA) was used for rapid and non-specific detection of biological and chemical warfare agents at concentrations considerably below that which will cause harm to humans. Warfare agents detected include T-2 toxin, trimethylsilyl cyanide, and commercially available pesticides such as dichlorvos, diazinon, dursban, malathion, and parathion. The assay was performed by introducing 50 μL of milk or orange juice contaminated with each analyte into vials containing 10 freshly hatched brine shrimp nauplii in seawater. This was incubated at 28 °C for 24 h, after which mortality was determined. Mortality was converted to probits and the LC(50) was determined for each analyte by plotting probits of mortality against analyte concentration (log(10)). Our findings were the following: (1) the lethal effects of toxins dissolved in milk were observed, with T-2 toxin being the most lethal and malathion being the least, (2) except for parathion, the dosage (based on LC(50)) of analyte in a cup of milk (200 mL) consumed by a 6-y-old (20 kg) was less than the respective published rat LD(50) values, and (3) the BSLA was only suitable for detecting toxins dissolved in orange juice if incubation time was reduced to 6 h. Our results support the application of the BSLA for routine, rapid, and non-specific prescreening of liquid foods for possible sabotage by an employee or an intentional bioterrorist act. Practical Application: The findings of this study strongly indicate that the brine shrimp lethality assay can be adapted for nonspecific detection of warfare agents or toxins in food at any point during food production and distribution.

Non-lethal genotyping of Tribolium castaneum adults using genomic DNA extracted from wing tissue.

PubMed

Strobl, Frederic; Ross, J Alexander; Stelzer, Ernst H K

2017-01-01

The red flour beetle Tribolium castaneum has become the second most important insect model organism and is frequently used in developmental biology, genetics and pest-associated research. Consequently, the methodological arsenal increases continuously, but many routinely applied techniques for Drosophila melanogaster and other insect species are still unavailable. For example, a protocol for non-lethal genotyping has not yet been adapted but is particularly useful when individuals with known genotypes are required for downstream experiments. In this study, we present a workflow for non-lethal genotyping of T. castaneum adults based on extracting genomic DNA from wing tissue. In detail, we describe a convenient procedure for wing dissection and a custom method for wing digestion that allows PCR-based genotyping of up to fifty adults in less than an afternoon with a success rate of about 86%. The amount of template is sufficient for up to ten reactions while viability and fertility of the beetles are preserved. We prove the applicability of our protocol by genotyping the white / scarlet gene pair alleles from the black-eyed San Bernadino wild-type and white-eyed Pearl recessive mutant strains spanning four generations. Non-lethal genotyping has the potential to improve and accelerate many workflows: Firstly, during the establishment process of homozygous cultures or during stock keeping of cultures that carry recessively lethal alleles, laborious test crossing is replaced by non-lethal genotyping. Secondly, in genome engineering assays, non-lethal genotyping allows the identification of appropriate founders before they are crossed against wild-types, narrowing the efforts down to only the relevant individuals. Thirdly, non-lethal genotyping simplifies experimental strategies, in which genotype and behavior should be correlated, since the genetic configuration of potential individuals can be determined before the actual behavior assays is performed.

Neutralization Capacity of Monovalant Antivenom Against Existing Lethal Scorpions in the Turkish Scorpiofauna

PubMed Central

Ozkan, Ozcan; Yağmur, Ersen Aydın

2017-01-01

In this study, Mesobuthus gibbosus and Mesobuthus eupeus eupeus venom samples were compared for lethality, in-vivo effects and proteins. Neutralization capacity of monovalent Androctonus crassicauda antivenom (RSHA anti-Ac) was tested against the lethal effects of the venoms. Venom was obtained from mature scorpions by electrical stimulation of the telson. The lethality of the venom and potency of Horse RSHA anti-Ac were determined in Swiss mice. The protein profiles of the scorpion venoms were analysed by NuPAGE® 4–12% gradient Bis-Tris gel followed by Coomassie blue staining. Western blotting was performed to determine immunogenic compounds in the venom samples. The median lethal doses of M. e. eupeus, M.gibbosus scorpion and A.crassicauda venoms were determined to be 1.92 mg/kg by i.v. injection route, 0.67 mg/kg and 0.24 mg/kg by s.c. injection route, respectively. A.crassicauda (Olivier, 1807) venom was used as control. One millilitre of the RSHA anti-Ac neutralises 23 LD50 of M. e. eupeus, 32 LD50 of M.gibbosus and 42 LD50 of A. crassicauda venom in mice. Analysis of electrophoresis indicates that three scorpion venoms posses low molecular weight proteins. Immunoblotting indicated that RSHA anti-Ac strongly reacted with both the specific venom and Mesobuthus species venoms which have antigenic similarity. The result of our study showed that M.e. eupeus and M.gibbosus could be medically important scorpions for humans, particullary children. The RSHA anti-Ac can be used in the treatment of envenomation by M. e.eupeus and M.gibbosus scorpion stings. PMID:28979319

Clinical correlates of planned, more lethal suicide attempts in major depressive disorder.

PubMed

Nakagawa, Atsuo; Grunebaum, Michael F; Oquendo, Maria A; Burke, Ainsley K; Kashima, Haruo; Mann, J John

2009-01-01

Assessment of suicide plans is standard in acute psychiatric care, but there is a limited evidence base to guide this routine clinical practice. The purpose of this study was to investigate clinical correlates of suicide planning in depressed patients. 151 patients with major depressive disorder and a lifetime history of suicide attempt were studied. Subjects received a comprehensive evaluation including structured diagnostic interview for Axis I and II disorders, current symptoms, impulsivity, and systematic assessment of suicide planning prior to the most recent suicide attempt. Seriousness of suicide attempt planning correlated with lethality of suicidal acts. Comorbid anxiety disorder and anxiety correlated with less suicide planning. Specifically, this negative correlation was with comorbid panic disorder. Planning did not correlate with severity of depression or aggressive/impulsive traits. Cross-sectional design, retrospective recall of suicide planning data, limited applicability to completed suicide or other psychiatric disorders. In major depression, comorbid panic disorder appears protective against more carefully planned, higher lethality suicide attempts. Surprisingly, severity of depression and aggressive impulsive traits do not predict planning or lethality of suicide attempts. We have previously reported that anxiety severity protects against the probability of a suicide attempt and now extend that observation to show there is protection against lethality of a suicide attempt. Treatment of anxiety without directly treating major depression may place patients at greater risk of suicidal behavior.

Acute toxicity, twenty-eight days repeated dose toxicity and genotoxicity of vanadyl trehalose in kunming mice.

PubMed

Jiang, Pingzhe; Ni, Zaizhong; Wang, Bin; Ma, Baicheng; Duan, Huikun; Li, Xiaodan; Ma, Xiaofeng; Wei, Qian; Ji, Xiangzhen; Liu, Qiqi; Xing, Shuguang; Li, Minggang

2017-04-01

A new trend has been developed using vanadium and organic ligands to form novel compounds in order to improve the beneficial actions and reduce the toxicity of vanadium compounds. In present study, vanadyl trehalose was explored the oral acute toxicity, 28 days repeated dose toxicity and genotoxicity in Kunming mice. The Median Lethal Dose (LD 50 ) of vanadyl trehalose was revealed to be 1000 mg/kg body weight in fasted Kunming mice. Stomach and intestine were demonstrated to be the main target organs of vanadyl trehalose through 28 days repeated dose toxicity study. And vanadyl trehalose also showed particular genotoxicity through mouse bone marrow micronucleus and mouse sperm malformation assay. In brief, vanadyl trehalose presented certain, but finite toxicity, which may provide experimental basis for the clinical application. Copyright © 2017 Elsevier Inc. All rights reserved.

Effects of DDE on experimentally poisoned free-tailed bats (Tadarida brasiliensis): Lethal brain concentrations

USGS Publications Warehouse

Clark, D.R.; Kroll, J.C.

1977-01-01

Adult female free-tailed bats (Tadarida brasiliensis) were collected at Bracken Cave, Texas, and shipped to the Patuxent Wildlife Research Center. Treated mealworms (Tenebrio molitor) containing 107 ppm DDE were fed to 17 bats; five other bats were fed untreated mealworms. After 40 days on dosage, during which one dosed bat was killed accidentally, four dosed bats were frozen and the remaining 17 were starved to death. The objective was to elevate brain levels of DDE to lethality and measure these concentrations. After the feeding period, dosed bats weighed less than controls. After starvation, the body condition of dosed bats was poorer than that of controls even though there was no difference in the amounts of carcass fat. During starvation, dosed bats lost weight faster than controls. Also, four dosed bats exhibited the prolonged tremoring that characterizes DDE poisoning. DDE increased in brains of starving bats as fat was metabolized. The estimated mean brain concentration of DDE diagnostic of death was 519 ppm with a range of 458-564 ppm. These values resemble diagnostic levels known for two species of passerine birds, but they exceed published levels for two free-tailed bats from Carlsbad Caverns, New Mexico.

Lethal and sub-lethal effects of spinosad on bumble bees (Bombus impatiens Cresson).

PubMed

Morandin, Lora A; Winston, Mark L; Franklin, Michelle T; Abbott, Virginia A

2005-07-01

Recent developments of new families of pesticides and growing awareness of the importance of wild pollinators for crop pollination have stimulated interest in potential effects of novel pesticides on wild bees. Yet pesticide toxicity studies on wild bees remain rare, and few studies have included long-term monitoring of bumble bee colonies or testing of foraging ability after pesticide exposure. Larval bees feeding on exogenous pollen and exposed to pesticides during development may result in lethal or sub-lethal effects during the adult stage. We tested the effects of a naturally derived biopesticide, spinosad, on bumble bee (Bombus impatiens Cresson) colony health, including adult mortality, brood development, weights of emerging bees and foraging efficiency of adults that underwent larval development during exposure to spinosad. We monitored colonies from an early stage, over a 10-week period, and fed spinosad to colonies in pollen at four levels: control, 0.2, 0.8 and 8.0 mg kg(-1), during weeks 2 through 5 of the experiment. At concentrations that bees would likely encounter in pollen in the wild (0.2-0.8 mg kg(-1)) we detected minimal negative effects to bumble bee colonies. Brood and adult mortality was high at 8.0 mg kg(-1) spinosad, about twice the level that bees would be exposed to in a 'worst case' field scenario, resulting in colony death two to four weeks after initial pesticide exposure. At more realistic concentrations there were potentially important sub-lethal effects. Adult worker bees exposed to spinosad during larval development at 0.8 mg kg(-1) were slower foragers on artificial complex flower arrays than bees from low or no spinosad treated colonies. Inclusion of similar sub-lethal assays to detect effects of pesticides on pollinators would aid in development of environmentally responsible pest management strategies. Copyright 2005 Society of Chemical Industry

The radiobiology of laser-driven particle beams: focus on sub-lethal responses of normal human cells

NASA Astrophysics Data System (ADS)

Manti, L.; Perozziello, F. M.; Borghesi, M.; Candiano, G.; Chaudhary, P.; Cirrone, G. A. P.; Doria, D.; Gwynne, D.; Leanza, R.; Prise, K. M.; Romagnani, L.; Romano, F.; Scuderi, V.; Tramontana, A.

2017-03-01

Accelerated proton beams have become increasingly common for treating cancer. The need for cost and size reduction of particle accelerating machines has led to the pioneering investigation of optical ion acceleration techniques based on laser-plasma interactions as a possible alternative. Laser-matter interaction can produce extremely pulsed particle bursts of ultra-high dose rates (>= 109 Gy/s), largely exceeding those currently used in conventional proton therapy. Since biological effects of ionizing radiation are strongly affected by the spatio-temporal distribution of DNA-damaging events, the unprecedented physical features of such beams may modify cellular and tissue radiosensitivity to unexplored extents. Hence, clinical applications of laser-generated particles need thorough assessment of their radiobiological effectiveness. To date, the majority of studies have either used rodent cell lines or have focussed on cancer cell killing being local tumour control the main objective of radiotherapy. Conversely, very little data exist on sub-lethal cellular effects, of relevance to normal tissue integrity and secondary cancers, such as premature cellular senescence. Here, we discuss ultra-high dose rate radiobiology and present preliminary data obtained in normal human cells following irradiation by laser-accelerated protons at the LULI PICO2000 facility at Laser Lab Europe, France.

A Novel Highly Reproducible and Lethal Nonhuman Primate Model for Orthopox Virus Infection

PubMed Central

Kramski, Marit; Mätz-Rensing, Kerstin; Stahl-Hennig, Christiane; Kaup, Franz-Josef; Nitsche, Andreas; Pauli, Georg; Ellerbrok, Heinz

2010-01-01

The intentional re-introduction of Variola virus (VARV), the agent of smallpox, into the human population is of great concern due its bio-terroristic potential. Moreover, zoonotic infections with Cowpox (CPXV) and Monkeypox virus (MPXV) cause severe diseases in humans. Smallpox vaccines presently available can have severe adverse effects that are no longer acceptable. The efficacy and safety of new vaccines and antiviral drugs for use in humans can only be demonstrated in animal models. The existing nonhuman primate models, using VARV and MPXV, need very high viral doses that have to be applied intravenously or intratracheally to induce a lethal infection in macaques. To overcome these drawbacks, the infectivity and pathogenicity of a particular CPXV was evaluated in the common marmoset (Callithrix jacchus). A CPXV named calpox virus was isolated from a lethal orthopox virus (OPV) outbreak in New World monkeys. We demonstrated that marmosets infected with calpox virus, not only via the intravenous but also the intranasal route, reproducibly develop symptoms resembling smallpox in humans. Infected animals died within 1–3 days after onset of symptoms, even when very low infectious viral doses of 5×102 pfu were applied intranasally. Infectious virus was demonstrated in blood, saliva and all organs analyzed. We present the first characterization of a new OPV infection model inducing a disease in common marmosets comparable to smallpox in humans. Intranasal virus inoculation mimicking the natural route of smallpox infection led to reproducible infection. In vivo titration resulted in an MID50 (minimal monkey infectious dose 50%) of 8.3×102 pfu of calpox virus which is approximately 10,000-fold lower than MPXV and VARV doses applied in the macaque models. Therefore, the calpox virus/marmoset model is a suitable nonhuman primate model for the validation of vaccines and antiviral drugs. Furthermore, this model can help study mechanisms of OPV pathogenesis. PMID

Protection of Melanized Cryptococcus neoformans from Lethal Dose Gamma Irradiation Involves Changes in Melanin's Chemical Structure and Paramagnetism

PubMed Central

Khajo, Abdelahad; Bryan, Ruth A.; Friedman, Matthew; Burger, Richard M.; Levitsky, Yan; Casadevall, Arturo; Magliozzo, Richard S.; Dadachova, Ekaterina

2011-01-01

Certain fungi thrive in highly radioactive environments including the defunct Chernobyl nuclear reactor. Cryptococcus neoformans (C. neoformans), which uses L-3,4-dihydroxyphenylalanine (L-DOPA) to produce melanin, was used here to investigate how gamma radiation under aqueous aerobic conditions affects the properties of melanin, with the aim of gaining insight into its radioprotective role. Exposure of melanized fungal cell in aqueous suspensions to doses of γ-radiation capable of killing 50 to 80% of the cells did not lead to a detectable loss of melanin integrity according to EPR spectra of melanin radicals. Moreover, upon UV-visible (Xe-lamp) illumination of melanized cells, the increase in radical population was unchanged after γ-irradiation. Gamma-irradiation of frozen cell suspensions and storage of samples for several days at 77 K however, produced melanin modification noted by a reduced radical population and reduced photoresponse. More direct evidence for structural modification of melanin came from the detection of soluble products with absorbance maxima near 260 nm in supernatants collected after γ-irradiation of cells and cell-free melanin. These products, which include thiobarbituric acid (TBA)-reactive aldehydes, were also generated by Fenton reagent treatment of cells and cell-free melanin. In an assay of melanin integrity based on the metal (Bi+3) binding capacity of cells, no detectable loss in binding was detected after γ-irradiation. Our results show that melanin in C. neoformans cells is susceptible to some damage by hydroxyl radical formed in lethal radioactive aqueous environments and serves a protective role in melanized fungi that involves sacrificial breakdown. PMID:21966422

Prophylaxis with human serum butyrylcholinesterase protects guinea pigs exposed to multiple lethal doses of soman or VX.

PubMed

Saxena, Ashima; Sun, Wei; Fedorko, James M; Koplovitz, Irwin; Doctor, Bhupendra P

2011-01-01

Human serum butyrylcholinesterase (Hu BChE) is currently under advanced development as a bioscavenger for the prophylaxis of organophosphorus (OP) nerve agent toxicity in humans. It is estimated that a dose of 200mg will be required to protect a human against 2×LD(50) of soman. To provide data for initiating an investigational new drug application for the use of this enzyme as a bioscavenger in humans, we purified enzyme from Cohn fraction IV-4 paste and initiated safety and efficacy evaluations in mice, guinea pigs, and non-human primates. In mice, we demonstrated that a single dose of enzyme that is 30 times the therapeutic dose circulated in blood for at least four days and did not cause any clinical pathology in these animals. In this study, we report the results of safety and efficacy evaluations conducted in guinea pigs. Various doses of Hu BChE delivered by i.m. injections peaked at ∼24h and had a mean residence time of 78-103h. Hu BChE did not exhibit any toxicity in guinea pigs as measured by general observation, serum chemistry, hematology, and gross and histological tissue changes. Efficacy evaluations showed that Hu BChE protected guinea pigs from an exposure of 5.5×LD(50) of soman or 8×LD(50) of VX. These results provide convincing data for the development of Hu BChE as a bioscavenger that can protect humans against all OP nerve agents. Published by Elsevier Inc.

Stimulation of Lung Innate Immunity Protects against Lethal Pneumococcal Pneumonia in Mice

PubMed Central

Clement, Cecilia G.; Evans, Scott E.; Evans, Christopher M.; Hawke, David; Kobayashi, Ryuji; Reynolds, Paul R.; Moghaddam, Seyed J.; Scott, Brenton L.; Melicoff, Ernestina; Adachi, Roberto; Dickey, Burton F.; Tuvim, Michael J.

2008-01-01

Rationale: The lungs are a common site of serious infection in both healthy and immunocompromised subjects, and the most likely route of delivery of a bioterror agent. Since the airway epithelium shows great structural plasticity in response to inflammatory stimuli, we hypothesized it might also show functional plasticity. Objectives: To test the inducibility of lung defenses against bacterial challenge. Methods: Mice were treated with an aerosolized lysate of ultraviolet-killed nontypeable (unencapsulated) Haemophilus influenzae (NTHi), then challenged with a lethal dose of live Streptococcus pneumoniae (Spn) delivered by aerosol. Measurements and Main Results: Treatment with the NTHi lysate induced complete protection against challenge with a lethal dose of Spn if treatment preceded challenge by 4 to 24 hours. Lesser levels of protection occurred at shorter (83% at 2 h) and longer (83% at 48–72 h) intervals between treatment and challenge. There was also some protection when treatment was given 2 hours after challenge (survival increased from 14 to 57%), but not 24 hours after challenge. Protection did not depend on recruited neutrophils or resident mast cells and alveolar macrophages. Protection was specific to the airway route of infection, correlated in magnitude and time with rapid bacterial killing within the lungs, and was associated with increases of multiple antimicrobial polypeptides in lung lining fluid. Conclusions: We infer that protection derives from stimulation of local innate immune mechanisms, and that activated lung epithelium is the most likely cellular effector of this response. Augmentation of innate antimicrobial defenses of the lungs might have therapeutic value. PMID:18388354

Ebola GP-specific monoclonal antibodies protect mice and guinea pigs from lethal Ebola virus infection.

PubMed

Qiu, Xiangguo; Fernando, Lisa; Melito, P Leno; Audet, Jonathan; Feldmann, Heinz; Kobinger, Gary; Alimonti, Judie B; Jones, Steven M

2012-01-01

Ebola virus (EBOV) causes acute hemorrhagic fever in humans and non-human primates with mortality rates up to 90%. So far there are no effective treatments available. This study evaluates the protective efficacy of 8 monoclonal antibodies (MAbs) against Ebola glycoprotein in mice and guinea pigs. Immunocompetent mice or guinea pigs were given MAbs i.p. in various doses individually or as pools of 3-4 MAbs to test their protection against a lethal challenge with mouse- or guinea pig-adapted EBOV. Each of the 8 MAbs (100 µg) protected mice from a lethal EBOV challenge when administered 1 day before or after challenge. Seven MAbs were effective 2 days post-infection (dpi), with 1 MAb demonstrating partial protection 3 dpi. In the guinea pigs each MAb showed partial protection at 1 dpi, however the mean time to death was significantly prolonged compared to the control group. Moreover, treatment with pools of 3-4 MAbs completely protected the majority of animals, while administration at 2-3 dpi achieved 50-100% protection. This data suggests that the MAbs generated are capable of protecting both animal species against lethal Ebola virus challenge. These results indicate that MAbs particularly when used as an oligoclonal set are a potential therapeutic for post-exposure treatment of EBOV infection.

A cardiovascular drug rescues mice from lethal sepsis by selectively attenuating a late-acting proinflammatory mediator, high mobility group box 1.

PubMed

Li, Wei; Li, Jianhua; Ashok, Mala; Wu, Rongqian; Chen, Dazhi; Yang, Lihong; Yang, Huan; Tracey, Kevin J; Wang, Ping; Sama, Andrew E; Wang, Haichao

2007-03-15

The pathogenesis of sepsis is mediated in part by bacterial endotoxin, which stimulates macrophages/monocytes to sequentially release early (e.g., TNF, IL-1, and IFN-gamma) and late (e.g., high mobility group box 1 (HMGB1) protein) proinflammatory cytokines. The recent discovery of HMGB1 as a late mediator of lethal sepsis has prompted investigation for development of new experimental therapeutics. We found that many steroidal drugs (such as dexamethasone and cortisone) and nonsteroidal anti-inflammatory drugs (such as aspirin, ibuprofen, and indomethacin) failed to influence endotoxin-induced HMGB1 release even at superpharmacological concentrations (up to 10-25 microM). However, several steroid-like pigments (tanshinone I, tanshinone IIA, and cryptotanshinone) of a popular Chinese herb, Danshen (Salvia miltiorrhiza), dose dependently attenuated endotoxin-induced HMGB1 release in macrophage/monocyte cultures. A water-soluble tanshinone IIA sodium sulfonate derivative (TSNIIA-SS), which has been widely used as a Chinese medicine for patients with cardiovascular disorders, selectively abrogated endotoxin-induced HMGB1 cytoplasmic translocation and release in a glucocorticoid receptor-independent manner. Administration of TSNIIA-SS significantly protected mice against lethal endotoxemia and rescued mice from lethal sepsis even when the first dose was given 24 h after the onset of sepsis. The therapeutic effects were partly attributable to attenuation of systemic accumulation of HMGB1 (but not TNF and NO) and improvement of cardiovascular physiologic parameters (e.g., decrease in total peripheral vascular resistance and increase in cardiac stroke volume) in septic animals. Taken together, these data re-enforce the pathogenic role of HMGB1 in lethal sepsis, and support a therapeutic potential for TSNIIA-SS in the treatment of human sepsis.

A Cardiovascular Drug Rescues Mice from Lethal Sepsis by Selectively Attenuating a Late-Acting Proinflammatory Mediator, High Mobility Group Box 11

PubMed Central

Li, Wei; Li, Jianhua; Ashok, Mala; Wu, Rongqian; Chen, Dazhi; Yang, Lihong; Yang, Huan; Tracey, Kevin J.; Wang, Ping; Sama, Andrew E.; Wang, Haichao

2007-01-01

The pathogenesis of sepsis is mediated in part by bacterial endotoxin, which stimulates macrophages/monocytes to sequentially release early (e.g., TNF, IL-1, and IFN-γ) and late (e.g., high mobility group box 1 (HMGB1) protein) proinflammatory cytokines. The recent discovery of HMGB1 as a late mediator of lethal sepsis has prompted investigation for development of new experimental therapeutics. We found that many steroidal drugs (such as dexamethasone and cortisone) and nonsteroidal anti-inflammatory drugs (such as aspirin, ibuprofen, and indomethacin) failed to influence endotoxin-induced HMGB1 release even at superpharmacological concentrations (up to 10–25 μM). However, several steroid-like pigments (tanshinone I, tanshinone IIA, and cryptotanshinone) of a popular Chinese herb, Danshen (Salvia miltiorrhiza), dose dependently attenuated endotoxin-induced HMGB1 release in macrophage/monocyte cultures. A water-soluble tanshinone IIA sodium sulfonate derivative (TSNIIA-SS), which has been widely used as a Chinese medicine for patients with cardiovascular disorders, selectively abrogated endotoxin-induced HMGB1 cytoplasmic translocation and release in a glucocorticoid receptor-independent manner. Administration of TSNIIA-SS significantly protected mice against lethal endotoxemia and rescued mice from lethal sepsis even when the first dose was given 24 h after the onset of sepsis. The therapeutic effects were partly attributable to attenuation of systemic accumulation of HMGB1 (but not TNF and NO) and improvement of cardiovascular physiologic parameters (e.g., decrease in total peripheral vascular resistance and increase in cardiac stroke volume) in septic animals. Taken together, these data re-enforce the pathogenic role of HMGB1 in lethal sepsis, and support a therapeutic potential for TSNIIA-SS in the treatment of human sepsis. PMID:17339485

Lethal ricin intoxication in two adult dogs: toxicologic and histopathologic findings.

PubMed

Roels, Stefan; Coopman, Vera; Vanhaelen, Pascal; Cordonnier, Jan

2010-05-01

Two adult dogs with the same owner were intoxicated by ingestion of fertilizer composed of residual plant material of the castor bean plant (Ricinus communis L.). Both dogs died within 2 and 3 days, respectively, after the first signs of vomiting and abundant hemorrhagic diarrhea. Toxicologic and histopathologic examinations were performed on different organs. Histopathologic examination of the kidneys revealed tubular degeneration and necrosis and membranous glomerulonephritis. Additionally, myocardial degeneration with localized inflammation, lymphoid necrosis, and depletion in the spleen and mesenteric lymph nodes and hemorrhagic ulcerative gastroenteritis were found. The 2 cases could be used to elucidate the lethal dose of ricin and the histopathologic lesions in dogs.

Metabolic Response of Escherichia coli upon Treatment with Hypochlorite at Sub-Lethal Concentrations

PubMed Central

Winter, Jeannette; Eisenreich, Wolfgang

2015-01-01

Hypochlorite is a reactive oxygen species that is worldwide as an antibacterial disinfectant. Hypochlorite exposure is known to cause oxidative damage to DNA and proteins. As a response to these effects, the metabolite profiles of organisms treated with sub-lethal doses of hypochlorite are assumed to be severely modified; however, the nature of these changes is hardly understood. Therefore, using nuclear magnetic resonance spectroscopy and gas chromatography-coupled mass spectrometry, we analyzed the time-dependent impact of hypochlorite exposure with a sub-lethal concentration (50 µM) on the metabolite profile of the Escherichia coli strain MG1655. Principle component analysis clearly distinguished between the metabolite profiles of bacteria treated for 0, 5,10, 20, 40, or 60 min. Major changes in the relative amounts of fatty acids, acetic acid, and formic acid occurred within the first 5 min. Comparative gas chromatography-coupled mass spectrometry analyses revealed that the amounts of free methionine and alanine were significantly decreased in the treated cells, demonstrating their susceptibility to hypochlorite exposure. The concentrations of succinate, urea, orotic acid, 2-aminobutyric acid, and 2-hydroxybutyric acid were also severely affected, indicating general changes in the metabolic network by hypochlorite. However, most metabolite levels relaxed to the reference values of untreated cells after 40–60 min, reflecting the capability of E. coli to rapidly adapt to environmental stress factors such as the presence of sub-lethal oxidant levels. PMID:25932918

Increased productivity in poultry birds by sub-lethal dose of antibiotics is arbitrated by selective enrichment of gut microbiota, particularly short-chain fatty acid producers.

PubMed

Banerjee, Sohini; Sar, Abhijit; Misra, Arijit; Pal, Srikanta; Chakraborty, Arindom; Dam, Bomba

2018-02-01

Antibiotics are widely used at sub-lethal concentrations as a feed supplement to enhance poultry productivity. To understand antibiotic-induced temporal changes in the structure and function of gut microbiota of chicken, two flocks were maintained for six weeks on a carbohydrate- and protein-rich diet. The feed in the conventional diet (CD) group was supplemented with sub-lethal doses of chlorotetracycline, virginiamycin and amoxicillin, while the organic diet (OD) had no such addition. Antibiotic-fed birds were more productive, with a lower feed conversion ratio (FCR). Their faecal samples also had higher total heterotrophic bacterial load and antibiotic resistance capability. Deep sequencing of 16S rDNA V1-V2 amplicons revealed Firmicutes as the most dominant phylum at all time points, with the predominant presence of Lactobacillales members in the OD group. The productivity indicator, i.e. higher Firmicutes:Bacteroidetes ratio, particularly in the late growth phase, was more marked in CD amplicon sequences, which was supported by culture-based enumerations on selective media. CD datasets also showed the prevalence of known butyrate-producing genera such as Faecalibacterium, Ruminococcus, Blautia, Coprococcus and Bacteroides, which correlates closely with their higher PICRUSt-based in silico predicted 'glycan biosynthesis and metabolism'-related Kyoto Encyclopedia of Genes and Genomes (KEGG) orthologues. Semi-quantitative end-point PCR targeting of the butyryl-CoA: acetate CoA-transferase gene also confirmed butyrate producers as being late colonizers, particularly in antibiotic-fed birds in both the CD flocks and commercial rearing farms. Thus, antibiotics preferentially enrich bacterial populations, particularly short-chain fatty acid producers that can efficiently metabolize hitherto undigestable feed material such as glycans, thereby increasing the energy budget of the host and its productivity.

Understanding reduced inorganic mercury accumulation in rice following selenium application: Selenium application routes, speciation and doses.

PubMed

Tang, Wenli; Dang, Fei; Evans, Douglas; Zhong, Huan; Xiao, Lin

2017-02-01

Selenium (Se) has recently been demonstrated to reduce inorganic mercury (IHg) accumulation in rice plants, while its mechanism is far from clear. Here, we aimed at exploring the potential effects of Se application routes (soil or foliar application with Se), speciation (selenite and selenate), and doses on IHg-Se antagonistic interactions in soil-rice systems. Results of our pot experiments indicated that soil application but not foliar application could evidently reduce tissue IHg concentrations (root: 0-48%, straw: 15-58%, and brown rice: 26-74%), although both application routes resulted in comparable Se accumulation in aboveground tissues. Meanwhile, IHg distribution in root generally increased with amended Se doses in soil, suggesting antagonistic interactions between IHg and Se in root. These results provided initial evidence that IHg-Se interactions in the rhizosphere (i.e., soil or rice root), instead of those in the aboveground tissues, could probably be more responsible for the reduced IHg bioaccumulation following Se application. Furthermore, Se dose rather than Se speciation was found to be more important in controlling IHg accumulation in rice. Our findings regarding the importance of IHg-Se interactions in the rhizosphere, together with the systematic investigation of key factors affecting IHg-Se antagonism and IHg bioaccumulation, advance our understanding of Hg dynamics in soil-rice systems. Copyright © 2016 Elsevier Ltd. All rights reserved.

Infection with non-lethal West Nile virus Eg101 strain induces immunity that protects mice against the lethal West Nile virus NY99 strain.

PubMed

Kumar, Mukesh; O'Connell, Maile; Namekar, Madhuri; Nerurkar, Vivek R

2014-06-06

Herein we demonstrate that infection of mice with West Nile virus (WNV) Eg101 provides protective immunity against lethal challenge with WNV NY99. Our data demonstrated that WNV Eg101 is largely non-virulent in adult mice when compared to WNV NY99. By day 6 after infection, WNV-specific IgM and IgG antibodies, and neutralizing antibodies were detected in the serum of all WNV Eg101 infected mice. Plaque reduction neutralization test data demonstrated that serum from WNV Eg101 infected mice neutralized WNV Eg101 and WNV NY99 strains with similar efficiency. Three weeks after infection, WNV Eg101 immunized mice were challenged subcutaneously or intracranially with lethal dose of WNV NY99 and observed for additional three weeks. All the challenged mice were protected against disease and no morbidity and mortality was observed in any mice. In conclusion, our data for the first time demonstrate that infection of mice with WNV Eg101 induced high titers of WNV specific IgM and IgG antibodies, and cross-reactive neutralizing antibodies, and the resulting immunity protected all immunized animals from both subcutaneous and intracranial challenge with WNV NY99. These observations suggest that WNV Eg101 may be a suitable strain for the development of a vaccine in humans against virulent strains of WNV.

Studies on fate and toxicity of nanoalumina in male albino rats: Lethality, bioaccumulation and genotoxicity.

PubMed

Morsy, Gamal M; El-Ala, Kawther S Abou; Ali, Atef A

2016-02-01

The purpose of this study is to follow-up the distribution, lethality percentile doses (LDs) and bioaccumulation of aluminium oxide nanoparticles (Al2O3-NPs, average diameter 9.83 ± 1.61 nm) in some tissues of male albino rats, and to evaluate its genotoxicity to the brain tissues, during acute and sublethal experiments. The LDs of Al2O3-NPs, including median lethal dose (LD50), were estimated after intraperitoneal injection. The computed LD50 at 24 and 48 h were 15.10 and 12.88 g/kg body weight (b.w.), respectively. For acute experiments, the bioaccumulation of aluminium (Al) in the brain, liver, kidneys, intestine and spleen was estimated after 48 h of injection with a single acute dose (3.9, 6.4 and 8.5 g/kg b.w.), while for sublethal experiments it was after 1, 3, 7, 14 and 28 days of injection with 1.3 g/kg b.w. once in 2 days. Multi-way analysis of variance affirmed that Al uptake, in acute experiments, was significantly affected by the injected doses, organs (brain, liver, kidneys, intestine and spleen) and their interactions, while for sublethal experiments an altogether effect based on time (1, 3, 7, 14, 28 days), doses (0 and 1.3 g), organs and their interactions was reported. In addition, Al accumulated in the brain, liver, kidney, intestine and spleen of rats administered with Al2O3-NPs were significantly higher than the corresponding controls, during acute and sublethal experiments. The uptake of Al by the spleen of rats injected with acute doses was greater than that accumulated by kidney>brain>intestine>liver, whereas the brain of rats injected with sublethal dose accumulated lesser amount of Al followed by the kidneydoses (in acute term) and the experimental periods (in sublethal term). In the acute and sublethal experiments, comet assay parameters such as the tail intensity (i.e. DNA percentage), tail extent moment and olive tail

Protective effects of S+ ketamine and atropine against lethality and brain damage during soman-induced status epilepticus in guinea-pigs.

PubMed

Dorandeu, Frederic; Baille, Valerie; Mikler, John; Testylier, Guy; Lallement, Guy; Sawyer, Thomas; Carpentier, Pierre

2007-05-20

Soman poisoning is known to induce full-blown tonic-clonic seizures, status epilepticus (SE), seizure-related brain damage (SRBD) and lethality. Previous studies in guinea-pigs have shown that racemic ketamine (KET), with atropine sulfate (AS), is very effective in preventing death, stopping seizures and protecting sensitive brain areas when given up to 1h after a supra-lethal challenge of soman. The active ketamine isomer, S(+) ketamine (S-KET), is more potent than the racemic mixture and it also induces less side-effects. To confirm the efficacy of KET and to evaluate the potential of S-KET for delayed medical treatment of soman-induced SE, we studied different S-KET dose regimens using the same paradigm used with KET. Guinea-pigs received pyridostigmine (26 microg/kg, IM) 30min before soman (62 microg/kg, 2 LD(50), IM), followed by therapy consisting of atropine methyl nitrate (AMN) (4 mg/kg, IM) 1min following soman exposure. S-KET, with AS (10mg/kg), was then administered IM at different times after the onset of seizures, starting at 1h post-soman exposure. The protective efficacy of S-KET proved to be comparable to KET against lethality and SRBD, but at doses two to three times lower. As with KET, delaying treatment by 2h post-poisoning greatly reduced efficacy. Conditions that may have led to an increased S-KET brain concentration (increased doses or number of injections, adjunct treatment with the oxime HI-6) did not prove to be beneficial. In summary, these observations confirm that ketamine, either racemic or S-KET, in association with AS and possibly other drugs, could be highly effective in the delayed treatment of severe soman intoxication.

Lethality of Rendang packaged in multilayer retortable pouch with sterilization process

NASA Astrophysics Data System (ADS)

Praharasti, A. S.; Kusumaningrum, A.; Frediansyah, A.; Nurhikmat, A.; Khasanah, Y.; Suprapedi

2017-01-01

Retort Pouch had become a choice to preserve foods nowadays, besides the used of the can. Both had their own advantages, and Retort Pouch became more popular for the reason of cheaper and easier to recycle. General Method usually used to estimate the lethality of commercial heat sterilization process. Lethality value wa s used for evaluating the efficacy of the thermal process. This study aimed to find whether different layers of pouch materials affect the lethality value and to find differences lethality in two types of multilayer retort pouch, PET/Aluminum Foil/Nylon/RCPP and PET/Nylon/Modified Aluminum/CPP. The result showed that the different layer arrangement was resulted different Sterilization Value (SV). PET/Nylon/Modified Aluminum/CPP had better heat penetration, implied by the higher value of lethality. PET/Nylon/Modified Aluminum/CPP had the lethality value of 6,24 minutes, whereas the lethality value of PET/Aluminum Foil/Nylon/RCPP was 3,54 minutes.

Comparison of cellular lethality in DNA repair-proficient or -deficient cell lines resulting from exposure to 70 MeV/n protons or 290 MeV/n carbon ions.

PubMed

Genet, Stefan C; Maeda, Junko; Fujisawa, Hiroshi; Yurkon, Charles R; Fujii, Yoshihiro; Romero, Ashley M; Genik, Paula C; Fujimori, Akira; Kitamura, Hisashi; Kato, Takamitsu A

2012-11-01

Charged particle therapy utilizing protons or carbon ions has been rapidly intensifying over recent years. The present study was designed to jointly investigate these two charged particle treatment modalities with respect to modeled anatomical depth-dependent dose and linear energy transfer (LET) deliveries to cells with either normal or compromised DNA repair phenotypes. We compared cellular lethality in response to dose, LET and Bragg peak location for accelerated protons and carbon ions at 70 and 290 MeV/n, respectively. A novel experimental live cell irradiation OptiCell™ in vitro culture system using three different Chinese hamster ovary (CHO) cells as a mammalian model was conducted. A wild-type DNA repair-competent CHO cell line (CHO 10B2) was compared to two other CHO cell lines (51D1 and xrs5), each genetically deficient with respect to one of the two major DNA repair pathways (homologous recombination and non-homologous end joining pathways, respectively) following genotoxic insults. We found that wild-type and homologous recombination-deficient (Rad51D) cellular lethality was dependent on both the dose and LET of the carbon ions, whereas it was only dependent on dose for protons. The non-homologous end joining deficient cell line (Ku80 mutant) showed nearly identical dose-response profiles for both carbon ions and protons. Our results show that the increasingly used modality of carbon ions as charged particle therapy is advantageous to protons in a radiotherapeutic context, primarily for tumor cells proficient in non-homologous end joining DNA repair where cellular lethality is dependent not only on the dose as in the case of more common photon therapeutic modalities, but more importantly on the carbon ion LETs. Genetic characterization of patient tumors would be key to individualize and optimize the selection of radiation modality, clinical outcome and treatment cost.

Dendritic Cell Targeting of Bacillus anthracis Protective Antigen Expressed by Lactobacillus acidophilus Protects Mice from Lethal Challenge

DTIC Science & Technology

2008-10-28

highly immunogenic, which may prevent their use in vaccine regimens requiring multiple doses (4). Probiotics are defined as ‘‘live microorganisms that...Sterne lethal challenge (Fig. 3 B and C). Thus, results from these studies further highlight the efficacy of employing probiotic lactic acid bacteria in...delivery via probiotic lactic acid bacteria is in their ability to induce antigen-specific IgA responses in feces, saliva, bronchoalveolar, mesenteric

Fasting protects mice from lethal DNA damage by promoting small intestinal epithelial stem cell survival.

PubMed

Tinkum, Kelsey L; Stemler, Kristina M; White, Lynn S; Loza, Andrew J; Jeter-Jones, Sabrina; Michalski, Basia M; Kuzmicki, Catherine; Pless, Robert; Stappenbeck, Thaddeus S; Piwnica-Worms, David; Piwnica-Worms, Helen

2015-12-22

Short-term fasting protects mice from lethal doses of chemotherapy through undetermined mechanisms. Herein, we demonstrate that fasting preserves small intestinal (SI) architecture by maintaining SI stem cell viability and SI barrier function following exposure to high-dose etoposide. Nearly all SI stem cells were lost in fed mice, whereas fasting promoted sufficient SI stem cell survival to preserve SI integrity after etoposide treatment. Lineage tracing demonstrated that multiple SI stem cell populations, marked by Lgr5, Bmi1, or HopX expression, contributed to fasting-induced survival. DNA repair and DNA damage response genes were elevated in SI stem/progenitor cells of fasted etoposide-treated mice, which importantly correlated with faster resolution of DNA double-strand breaks and less apoptosis. Thus, fasting preserved SI stem cell viability as well as SI architecture and barrier function suggesting that fasting may reduce host toxicity in patients undergoing dose intensive chemotherapy.

[Bladder tumor lethality. Results in the autonomous community of Rioja between 1975-1991].

PubMed

Fernández Fernández, A; Gil Fabra, J; Fernández Ruíz, M; Angulo Castellanos, M G; Blanco Martín, E; Otero Mauricio, G

1998-01-01

Between 1975-1991, a total of 557 cases of bladder carcinoma were identified in the Autonomous Community of La Rioja (CAR) which were followed up to December 1994. The overall lethality was 21.9%. 492 cases with 22.35% lethality were identified in males. In females, however, there was 65 cases with 18.46% lethality. The comparison of males and females lethality resulted in p = 0.525. Lethality between cases diagnosed within each 5-year period analyzed is: 1975-1981: 177 cases, lethality 23.72%. 1982-1986: 168 cases, lethality 30.95%. 1987-1991: 212 cases, lethality 13.20%. Between the first and the second 5-year periods, p = 0.132; between the first and third 5-year periods p = 0.007 and between the second and third 5-year periods p < 0.000. Bladder tumours accounts in CAR for a 22.35% lethality. Lethality is higher in males that in females but the difference is not statistically significant. In the last 5-year period assessed, 1987-1991, a reduction of lethality from bladder neoplasms has been documented.

Sub-lethal effects of the neurotoxic pyrethroid insecticide Fastac 50EC on the general motor and locomotor activities of the non-targeted beneficial carabid beetle Platynus assimilis (Coleoptera: Carabidae).

PubMed

Tooming, Ene; Merivee, Enno; Must, Anne; Sibul, Ivar; Williams, Ingrid

2014-06-01

Sub-lethal effects of pesticides on behavioural endpoints are poorly studied in carabids (Coleoptera: Carabidae) though changes in behaviour caused by chemical stress may affect populations of these non-targeted beneficial insects. General motor activity and locomotion are inherent in many behavioural patterns, and changes in these activities that result from xenobiotic influence mirror an integrated response of the insect to pesticides. Influence of pyrethroid insecticides over a wide range of sub-lethal doses on the motor activities of carabids still remains unclear. Video tracking of Platynus assimilis showed that brief exposure to alpha-cypermethrin at sub-lethal concentrations ranged from 0.01 to 100 mg L(-1) caused initial short-term (< 2 h) locomotor hyperactivity followed by a long-term (>24 h) locomotor hypo-activity. In addition, significant short- and long-term concentration and time-dependent changes occurred in general motor activity patterns and rates. Conspicuous changes in motor activity of Platynus assimilis beetles treated at alpha-cypermethrin concentrations up to 75,000-fold lower than maximum field recommended concentration (MFRC) suggest that many, basic fitness-related behaviours might be severely injured as well. These changes may negatively affect carabid populations in agro-ecosystems. Long-term hypo-activity could directly contribute to decreased trap captures of carabids frequently observed after insecticide application in the field. © 2013 Society of Chemical Industry.

Lethal domestic violence in eastern North Carolina.

PubMed

Gilliland, M G; Spence, P R; Spence, R L

2000-01-01

Strategies for preventing domestic violence can be tailored to a particular geographic or socioeconomic area if the patterns of domestic violence in the area are known. National statistics, although widely available, may not be applicable to a specific region. We reviewed homicide deaths in Eastern North Carolina between 1978 and 1999 to identify patterns in this rural area. Approximately 20% of the homicide deaths in eastern North Carolina are caused by intimate partners. Women accounted for 53% of the victims in 1976, similar to national figures but not rising to 72% as seen nationally in 1998. Latinos are an increasing presence in the area, but had only one recorded episode of lethal violence against an intimate partner. Gunshots accounted for most of the deaths (59% in men, 72% in women). Knowledge of such patterns can assist in selecting prevention strategies for this particular area. Over the last 25 years increasing attention has been devoted to domestic violence (DV), initially defined as abuse committed against a spouse, former spouse, fiancée, boy- or girlfriend, or cohabitant. As time has passed, the definition has been broadened to include other family members--elders, children, and siblings. The Centers for Disease Control and Prevention (CDC) now uses the term "intimate partner violence" for intentional emotional or physical abuse inflicted by a spouse, ex-spouse, a present or former boy- or girlfriend, or date. For the purposes of this paper, we consider DV interchangeable with intimate partner violence. There has been a national concern that abusive events are under-reported. The National Crime Victimization Survey, an anonymous household survey, indicated nearly 1 million incidents of non-lethal intimate partner violence per year between 1992 and 1996. The number decreased from 1.1 million in 1993 to 840,000 in 1996. Attempts to validate such data for a given geographic area often require subjects to violate anonymity--this may account for lower

Increased expression of connective tissue growth factor (CTGF) in multiple organs after exposure of non-human primates (NHP) to lethal doses of radiation

PubMed Central

Zhang, Pei; Cui, Wanchang; Hankey, Kim G.; Gibbs, Allison M.; Smith, Cassandra P.; Taylor-Howell, Cheryl; Kearney, Sean R.; MacVittie, Thomas J.

2015-01-01

Exposure to sufficiently high doses of ionizing radiation is known to cause fibrosis in many different organs and tissues. Connective tissue growth factor (CTGF/CCN2), a member of the CCN family of matricellular proteins, plays an important role in the development of fibrosis in multiple organs. The aim of the present study was to quantify the gene and protein expression of CTGF in a variety of organs from non-human primates (NHP) that were previously exposed to potentially lethal doses of radiation. Tissues from non-irradiated NHP, and NHP exposed to whole thoracic lung irradiation (WTLI) or partial-body irradiation with 5% bone marrow sparing (PBI/BM5) were examined by real-time quantitative reverse transcription PCR, western blot, and immunohistochemistry. Expression of CTGF was elevated in the lung tissues of NHP exposed to WTLI relative to the lung tissues of the non-irradiated NHP. Increased expression of CTGF was also observed in multiple organs from NHP exposed to PBI/BM5 compared to non-irradiated NHP; these included the lung, kidney, spleen, thymus and liver. These irradiated organs also exhibited histological evidence of increased collagen deposition compared to the control tissues. There was significant correlation of CTGF expression with collagen deposition in the lung and spleen of NHP exposed to PBI/BM5. Significant correlations were observed between spleen and multiple organs on CTGF expression and collagen deposition respectively, suggesting possible crosstalk between spleen and other organs. Our data suggest that CTGF levels are increased in multiple organs after radiation exposure and that inflammatory cell infiltration may contribute to the elevated levels of CTGF in multiple organs. PMID:26425899

A Recombinant Adenovirus Expressing Ovine Interferon Tau Prevents Influenza Virus-Induced Lethality in Mice.

PubMed

Martín, V; Pascual, E; Avia, M; Rangel, G; de Molina, A; Alejo, A; Sevilla, N

2016-01-06

Ovine interferon tau (IFN-τ) is a unique type I interferon with low toxicity and a broad host range in vivo. We report the generation of a nonreplicative recombinant adenovirus expressing biologically active IFN-τ. Using the B6.A2G-Mx1 mouse model, we showed that single-dose intranasal administration of recombinant Ad5-IFN-τ can effectively prevent lethality and disease induced by highly virulent hv-PR8 influenza virus by activating the interferon response and preventing viral replication. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Sub-lethal and lethal toxicities of elevated CO2 on embryonic, juvenile, and adult stages of marine medaka Oryzias melastigma.

PubMed

Lee, Changkeun; Kwon, Bong-Oh; Hong, Seongjin; Noh, Junsung; Lee, Junghyun; Ryu, Jongseong; Kang, Seong-Gil; Khim, Jong Seong

2018-06-06

The potential leakage from marine CO 2 storage sites is of increasing concern, but few studies have evaluated the probable adverse effects on marine organisms. Fish, one of the top predators in marine environments, should be an essential representative species used for water column toxicity testing in response to waterborne CO 2 exposure. In the present study, we conducted fish life cycle toxicity tests to fully elucidate CO 2 toxicity mechanism effects. We tested sub-lethal and lethal toxicities of elevated CO 2 concentrations on marine medaka (Oryzias melastigma) at different developmental stages. At each developmental stage, the test species was exposed to varying concentrations of gaseous CO 2 (control air, 5%, 10%, 20%, and 30%), with 96 h of exposure at 0-4 d (early stage), 4-8 d (middle stage), and 8-12 d (late stage). Sub-lethal and lethal effects, including early developmental delays, cardiac edema, tail abnormalities, abnormal pigmentation, and mortality were monitored daily during the 14 d exposure period. At the embryonic stage, significant sub-lethal and lethal effects were observed at pH < 6.30. Hypercapnia can cause long-term and/or delayed developmental embryonic problems, even after transfer back to clean seawater. At fish juvenile and adult stages, significant mortality was observed at pH < 5.70, indicating elevated CO 2 exposure might cause various adverse effects, even during short-term exposure periods. It should be noted the early embryonic stage was found more sensitive to CO 2 exposure than other developmental stages of the fish life cycle. Overall, the present study provided baseline information for potential adverse effects of high CO 2 concentration exposure on fish developmental processes at different life cycle stages in marine ecosystems. Copyright © 2018 Elsevier Ltd. All rights reserved.

Ribavirin protects Syrian hamsters against lethal hantavirus pulmonary syndrome--after intranasal exposure to Andes virus.

PubMed

Ogg, Monica; Jonsson, Colleen B; Camp, Jeremy V; Hooper, Jay W

2013-11-08

Andes virus, ANDV, harbored by wild rodents, causes the highly lethal hantavirus pulmonary syndrome (HPS) upon transmission to humans resulting in death in 30% to 50% of the cases. As there is no treatment for this disease, we systematically tested the efficacy of ribavirin in vitro and in an animal model. In vitro assays confirmed antiviral activity and determined that the most effective doses were 40 µg/mL and above. We tested three different concentrations of ribavirin for their capability to prevent HPS in the ANDV hamster model following an intranasal challenge. While the highest level of ribavirin (200 mg/kg) was toxic to the hamster, both the middle (100 mg/kg) and the lowest concentration (50 mg/kg) prevented HPS in hamsters without toxicity. Specifically, 8 of 8 hamsters survived intranasal challenge for both of those groups whereas 7 of 8 PBS control-treated animals developed lethal HPS. Further, we report that administration of ribavirin at 50 mg/kg/day starting on days 6, 8, 10, or 12 post-infection resulted in significant protection against HPS in all groups. Administration of ribavirin at 14 days post-infection also provided a significant level of protection against lethal HPS. These data provide in vivo evidence supporting the potential use of ribavirin as a post-exposure treatment to prevent HPS after exposure by the respiratory route.

Efficacy comparison of scopolamine (SCP) and diazepam (DZ) against soman-induced lethality in guinea pigs

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

Harris, L.W.; Gennings, C.; Carter, W.H.

1994-12-31

Diazepam (DZ) and scopolamine (SCP) are known to be beneficial when each is used in combination with atropine (AT) + oxime therapy against intoxication by soman, but the efficacy of each might be expected to vary with the dosage of AT. Thus, the therapeutic efficacy of SCP (5 doses; 0 - 0.86 mg/kg) versus DZ (5 doses; 0 - 5 mg/kg), when used in conjunction with AT (3 doses; 0.5 - S mg/kg) + 2-PAM (25 mg/kg) therapy, was tested in groups of pyridostigmine pretreated guinea pigs exposed to 1.6, 2.0, 2.5 or 3.2 LD5Os of soman. Response surface methodologymore » was employed to describe the relationship between lethality and the AT/DZ or AT/SCP dosages. Results show that within the indicated dose ranges used, the efficacy of SCP is not dependent on the presence of AT, whereas AT is needed for DZ to maintain the lowest probability of death. These findings suggest that in guinea pigs SCP could supplement AT or replace DZ as therapy against nerve agent intoxication.« less

Impact of non-constant concentration exposure on lethality of inhaled hydrogen cyanide.

PubMed

Sweeney, Lisa M; Sommerville, Douglas R; Channel, Stephen R

2014-03-01

The ten Berge model, also known as the toxic load model, is an empirical approach in hazard assessment modeling for estimating the relationship between the inhalation toxicity of a chemical and the exposure duration. The toxic load (TL) is normally expressed as a function of vapor concentration (C) and duration (t), with TL equaling C(n) × t being a typical form. Hypothetically, any combination of concentration and time that yields the same "toxic load" will give a constant biological response. These formulas have been developed and tested using controlled, constant concentration animal studies, but the validity of applying these assumptions to time-varying concentration profiles has not been tested. Experiments were designed to test the validity of the model under conditions of non-constant acute exposure. Male Sprague-Dawley rats inhaled constant or pulsed concentrations of hydrogen cyanide (HCN) generated in a nose-only exposure system for 5, 15, or 30 min. The observed lethality of HCN for the 11 different C versus t profiles was used to evaluate the ability of the model to adequately describe the lethality of HCN under the conditions of non-constant inhalation exposure. The model was found to be applicable under the tested conditions, with the exception of the median lethality of very brief, high concentration, discontinuous exposures.

Reduced-dose C-arm computed tomography applications at a pediatric institution.

PubMed

Acord, Michael; Shellikeri, Sphoorti; Vatsky, Seth; Srinivasan, Abhay; Krishnamurthy, Ganesh; Keller, Marc S; Cahill, Anne Marie

2017-12-01

Reduced-dose C-arm computed tomography (CT) uses flat-panel detectors to acquire real-time 3-D images in the interventional radiology suite to assist with anatomical localization and procedure planning. To describe dose-reduction techniques for C-arm CT at a pediatric institution and to provide guidance for implementation. We conducted a 5-year retrospective study on procedures using an institution-specific reduced-dose protocol: 5 or 8 s Dyna Rotation, 248/396 projection images/acquisition and 0.1-0.17 μGy/projection dose at the detector with 0.3/0.6/0.9-mm copper (Cu) filtration. We categorized cases by procedure type and average patient age and calculated C-arm CT and total dose area product (DAP). Two hundred twenty-two C-arm CT-guided procedures were performed with a dose-reduction protocol. The most common procedures were temporomandibular and sacroiliac joint injections (48.6%) and sclerotherapy (34.2%). C-arm CT was utilized in cases of difficult percutaneous access in less common applications such as cecostomy and gastrostomy placement, foreign body retrieval and thoracentesis. C-arm CT accounted for between 9.9% and 80.7% of the total procedural DAP. Dose-reducing techniques can preserve image quality for intervention while reducing radiation exposure to the child. This technology has multiple applications within pediatric interventional radiology and can be considered as an adjunctive imaging tool in a variety of procedures, particularly when percutaneous access is challenging despite routine fluoroscopic or ultrasound guidance.

A computer program for calculation of approximate embryo/fetus radiation dose in nuclear medicine applications.

PubMed

Bayram, Tuncay; Sönmez, Bircan

2012-04-01

In this study, we aimed to make a computer program that calculates approximate radiation dose received by embryo/fetus in nuclear medicine applications. Radiation dose values per MBq-1 received by embryo/fetus in nuclear medicine applications were gathered from literature for various stages of pregnancy. These values were embedded in the computer code, which was written in Fortran 90 program language. The computer program called nmfdose covers almost all radiopharmaceuticals used in nuclear medicine applications. Approximate radiation dose received by embryo/fetus can be calculated easily at a few steps using this computer program. Although there are some constraints on using the program for some special cases, nmfdose is useful and it provides practical solution for calculation of approximate dose to embryo/fetus in nuclear medicine applications. None declared.

The Klebsiella pneumoniae O Antigen Contributes to Bacteremia and Lethality during Murine Pneumonia

PubMed Central

Shankar-Sinha, Sunita; Valencia, Gabriel A.; Janes, Brian K.; Rosenberg, Jessica K.; Whitfield, Chris; Bender, Robert A.; Standiford, Ted J.; Younger, John G.

2004-01-01

Bacterial surface carbohydrates are important pathogenic factors in gram-negative pneumonia infections. Among these factors, O antigen has been reported to protect pathogens against complement-mediated killing. To examine further the role of O antigen, we insertionally inactivated the gene encoding a galactosyltransferase necessary for serotype O1 O-antigen synthesis (wbbO) from Klebsiella pneumoniae 43816. Analysis of the mutant lipopolysaccharide by sodium dodecyl sulfate-polyacrylamide gel electrophoresis confirmed the absence of O antigen. In vitro, there were no detectable differences between wild-type K. pneumoniae and the O-antigen-deficient mutant in regard to avid binding by murine complement C3 or resistance to serum- or whole-blood-mediated killing. Nevertheless, the 72-h 50% lethal dose of the wild-type strain was 30-fold greater than that of the mutant (2 × 103 versus 6 × 104 CFU) after intratracheal injection in ICR strain mice. Despite being less lethal, the mutant organism exhibited comparable intrapulmonary proliferation at 24 h compared to the level of the wild type. Whole-lung chemokine expression (CCL3 and CXCL2) and bronchoalveolar inflammatory cell content were also similar between the two infections. However, whereas the wild-type organism produced bacteremia within 24 h of infection in every instance, bacteremia was not seen in mutant-infected mice. These results suggest that during murine pneumonia caused by K. pneumoniae, O antigen contributes to lethality by increasing the propensity for bacteremia and not by significantly changing the early course of intrapulmonary infection. PMID:14977947

[Underlying Mechanisms of Methamphetamine-Induced Self-Injurious Behavior and Lethal Effects in Mice].

PubMed

Mori, Tomohisa; Sawaguchi, Toshiko

2018-01-01

Relatively high doses of psychostimulants induce neurotoxicity on the dopaminergic system and self-injurious behavior (SIB) in rodents. However the underlying neuronal mechanisms of SIB remains unclear. Dopamine receptor antagonists, N-methyl-D-aspartic acid (NMDA) receptor antagonists, Nitric Oxide Synthase (NOS) inhibitors and free radical scavengers significantly attenuate methamphetamine-induced SIB. These findings indicate that activation of dopamine as well as NMDA receptors followed by radical formation and oxidative stress, especially when mediated by NOS activation, is associated with methamphetamine-induced SIB. On the other hand, an increase in the incidence of polydrug abuse is a major problem worldwide. Coadministered methamphetamine and morphine induced lethality in more than 80% in mice, accompanied by an increase in the number of poly (ADP-ribose) polymerase (PARP)-immunoreactive cells in the heart, kidney and liver. The lethal effect and the increase in the incidence of rupture or PARP-immunoreactive cells induced by the coadministration of methamphetamine and morphine were significantly attenuated by pretreatment with a phospholipase A2 inhibitor or a radical scavenger, or by cooling of body from 30 to 90 min after drug administration. These results suggest that free radicals play an important role in the increased lethality induced by the coadministration of methamphetamine and morphine. Therefore, free radical scavengers and cooling are beneficial for preventing death that is induced by the coadministration of methamphetamine and morphine. These findings may help us better understand for masochistic behavior, which is a clinical phenomenon on SIB, as well as polydrug-abuse-induced acute toxicity.

The individual tolerance concept is not the sole explanation for the probit dose-effect model

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

Newman, M.C.; McCloskey, J.T.

2000-02-01

Predominant methods for analyzing dose- or concentration-effect data (i.e., probit analysis) are based on the concept of individual tolerance or individual effective dose (IED, the smallest characteristic dose needed to kill an individual). An alternative explanation (stochasticity hypothesis) is that individuals do not have unique tolerances: death results from stochastic processes occurring similarly in all individuals. These opposing hypotheses were tested with two types of experiments. First, time to stupefaction (TTS) was measured for zebra fish (Brachydanio rerio) exposed to benzocaine. The same 40 fish were exposed during five trials to test if the same order for TTS was maintainedmore » among trials. The IED hypothesis was supported with a minor stochastic component being present. Second, eastern mosquitofish (Gambusia holbrooki) were exposed to sublethal or lethal NaCl concentrations until a large portion of the lethally exposed fish died. After sufficient time for recovery, fish sublethally exposed and fish surviving lethal exposure were exposed simultaneously to lethal NaCl concentrations. No statistically significant effect was found of previous exposure on survival time but a large stochastic component to the survival dynamics was obvious. Repetition of this second type of test with pentachlorophenol also provided no support for the IED hypothesis. The authors conclude that neither hypothesis alone was the sole or dominant explanation for the lognormal (probit) model. Determination of the correct explanation (IED or stochastic) or the relative contributions of each is crucial to predicting consequences to populations after repeated or chronic exposures to any particular toxicant.« less

The phylogenetic roots of human lethal violence.

PubMed

Gómez, José María; Verdú, Miguel; González-Megías, Adela; Méndez, Marcos

2016-10-13

The psychological, sociological and evolutionary roots of conspecific violence in humans are still debated, despite attracting the attention of intellectuals for over two millennia. Here we propose a conceptual approach towards understanding these roots based on the assumption that aggression in mammals, including humans, has a significant phylogenetic component. By compiling sources of mortality from a comprehensive sample of mammals, we assessed the percentage of deaths due to conspecifics and, using phylogenetic comparative tools, predicted this value for humans. The proportion of human deaths phylogenetically predicted to be caused by interpersonal violence stood at 2%. This value was similar to the one phylogenetically inferred for the evolutionary ancestor of primates and apes, indicating that a certain level of lethal violence arises owing to our position within the phylogeny of mammals. It was also similar to the percentage seen in prehistoric bands and tribes, indicating that we were as lethally violent then as common mammalian evolutionary history would predict. However, the level of lethal violence has changed through human history and can be associated with changes in the socio-political organization of human populations. Our study provides a detailed phylogenetic and historical context against which to compare levels of lethal violence observed throughout our history.

SU-E-T-118: Dose Verification for Accuboost Applicators Using TLD, Ion Chamber and Gafchromic Film Measurements

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

Chisela, W; Yao, R; Dorbu, G

Purpose: To verify dose delivered with HDR Accuboost applicators using TLD, ion chamber and Gafchromic film measurements and to examine applicator leakage. Methods: A microSelectron HDR unit was used to deliver a dose of 50cGy to the mid-plane of a 62mm thick solid water phantom using dwell times from Monte Carlo pre-calculated nomograms for a 60mm, 70mm Round and 60mm Skin-Dose Optimized (SDO) applicators respectively. GafChromic EBT3+ film was embedded in the phantom midplane horizontally to measure dose distribution. Absolute dose was also measured with TLDs and an ADCL calibrated parallel-plate ion chamber placed in the film plane at fieldmore » center for each applicator. The film was calibrated using 6MV x-ray beam. TLDs were calibrated in a Cs-137 source at UW-Madison calibration laboratory. Radiation leakage through the tungsten alloy shell was measured with a film wrapped around outside surface of a 60mm Round applicator. Results: Measured maximum doses at field center are consistently lower than predicated by 5.8% for TLD, 8.8% for ion chamber, and 2.6% for EBT3+ film on average, with measurement uncertainties of 2.2%, 0.3%, and 2.9% for TLD, chamber, film respectively. The total standard uncertainties for ion chamber and Gafchromic film measurement are 4.9% and 4.6% respectively[1]. The area defined by the applicator aperture was covered by 80% of maximum dose for 62mm compression thickness. When 100cGy is delivered to mid-plane with a 60mm Round applicator, surface dose ranges from 60cGy to a maximum of 145cGy, which occurs at source entrance to the applicator. Conclusion: Measured doses by all three techniques are consistently lower than predicted in our measurements. For a compression thickness of 62 mm, the field size defined by the applicator is only covered by 80% of prescribed dose. Radiation leakage of up to 145cGy was found at the source entrance of applicators.« less

Airpower’s Emasculation? -- Non-lethal Weapons in Joint Urban Operations

DTIC Science & Technology

2005-02-14

Lethal, Subdue the Enemy Without Killing,” 14, US Military Non-Lethal Weapons, 10 November 1997, <http://www.geocities.com/ Area51 /Shadowlands/6583...37 “Non-Lethal, Subdue the Enemy Without Killing,” 10-11, US Military Non-Lethal Weapons, 10 November 1997, <http://www.geocities.com/ Area51 ... Area51 /Shadowlands/6583/project035.html> [15 December 2004]. 42 “US Plans for Use of Gas in Iraq,” The Sunshine Project, 7 February 2003, <http

SU-E-T-795: Validations of Dose Calculation Accuracy of Acuros BV in High-Dose-Rate (HDR) Brachytherapy with a Shielded Cylinder Applicator Using Monte Carlo Simulation

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

Li, Y; Department of Engineering Physics, Tsinghua University, Beijing; Tian, Z

Purpose: Acuros BV has become available to perform accurate dose calculations in high-dose-rate (HDR) brachytherapy with phantom heterogeneity considered by solving the Boltzmann transport equation. In this work, we performed validation studies regarding the dose calculation accuracy of Acuros BV in cases with a shielded cylinder applicator using Monte Carlo (MC) simulations. Methods: Fifteen cases were considered in our studies, covering five different diameters of the applicator and three different shielding degrees. For each case, a digital phantom was created in Varian BrachyVision with the cylinder applicator inserted in the middle of a large water phantom. A treatment plan withmore » eight dwell positions was generated for these fifteen cases. Dose calculations were performed with Acuros BV. We then generated a voxelized phantom of the same geometry, and the materials were modeled according to the vendor’s specifications. MC dose calculations were then performed using our in-house developed fast MC dose engine for HDR brachytherapy (gBMC) on a GPU platform, which is able to simulate both photon transport and electron transport in a voxelized geometry. A phase-space file for the Ir-192 HDR source was used as a source model for MC simulations. Results: Satisfactory agreements between the dose distributions calculated by Acuros BV and those calculated by gBMC were observed in all cases. Quantitatively, we computed point-wise dose difference within the region that receives a dose higher than 10% of the reference dose, defined to be the dose at 5mm outward away from the applicator surface. The mean dose difference was ∼0.45%–0.51% and the 95-percentile maximum difference was ∼1.24%–1.47%. Conclusion: Acuros BV is able to accurately perform dose calculations in HDR brachytherapy with a shielded cylinder applicator.« less

[Prognostic value of the lethal triad among patients with multiple trauma].

PubMed

González Balverde, María; Ramírez Lizardo, Ernesto J; Cardona Muñoz, Ernesto G; Totsuka Sutto, Sylvia E; García Benavides, Leonel

2013-11-01

Patients who have suffered multiple traumatic injuries, have a serious risk for death. Hypothermia, acidosis and coagulopathy are three complications in these patients, whose presence is known as lethal triad and indicates bad prognosis. To determine if the lethal triad in multiple trauma patients is associated with higher mortality and Injury Score Severity (ISS). One hundred multiple trauma patients aged 26 to 56 years (90 males), admitted to an emergency room, were studied. Body temperature, prothrombin time, partial thromboplastin time, platelet count and blood gases were determined on admission. Twenty six patients had the lethal triad and 15% died in the emergency room within the first 6 hours. No death was recorded among the 74 patients without the lethal triad. The mean ISS among patients with and without the lethal triad was 31.7 and 25.6, respectively (p < 0.05). The presence of the lethal triad among patients with multiple trauma is associated with a higher mortality and ISS.

Development of a high precision dosimetry system for the measurement of surface dose rate distribution for eye applicators.

PubMed

Eichmann, Marion; Flühs, Dirk; Spaan, Bernhard

2009-10-01

The therapeutic outcome of the therapy with ophthalmic applicators is highly dependent on the application of a sufficient dose to the tumor, whereas the dose applied to the surrounding tissue needs to be minimized. The goal for the newly developed apparatus described in this work is the determination of the individual applicator surface dose rate distribution with a high spatial resolution and a high precision in dose rate with respect to time and budget constraints especially important for clinical procedures. Inhomogeneities of the dose rate distribution can be detected and taken into consideration for the treatment planning. In order to achieve this, a dose rate profile as well as a surface profile of the applicator are measured and correlated with each other. An instrumental setup has been developed consisting of a plastic scintillator detector system and a newly designed apparatus for guiding the detector across the applicator surface at a constant small distance. It performs an angular movement of detector and applicator with high precision. The measurements of surface dose rate distributions discussed in this work demonstrate the successful operation of the measuring setup. Measuring the surface dose rate distribution with a small distance between applicator and detector and with a high density of measuring points results in a complete and gapless coverage of the applicator surface, being capable of distinguishing small sized spots with high activities. The dosimetrical accuracy of the measurements and its analysis is sufficient (uncertainty in the dose rate in terms of absorbed dose to water is <7%), especially when taking the surgical techniques in positioning of the applicator on the eyeball into account. The method developed so far allows a fully automated quality assurance of eye applicators even under clinical conditions. These measurements provide the basis for future calculation of a full 3D dose rate distribution, which then can be used as input for

Development of a high precision dosimetry system for the measurement of surface dose rate distribution for eye applicators

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

Eichmann, Marion; Fluehs, Dirk; Spaan, Bernhard

2009-10-15

Purpose: The therapeutic outcome of the therapy with ophthalmic applicators is highly dependent on the application of a sufficient dose to the tumor, whereas the dose applied to the surrounding tissue needs to be minimized. The goal for the newly developed apparatus described in this work is the determination of the individual applicator surface dose rate distribution with a high spatial resolution and a high precision in dose rate with respect to time and budget constraints especially important for clinical procedures. Inhomogeneities of the dose rate distribution can be detected and taken into consideration for the treatment planning. Methods: Inmore » order to achieve this, a dose rate profile as well as a surface profile of the applicator are measured and correlated with each other. An instrumental setup has been developed consisting of a plastic scintillator detector system and a newly designed apparatus for guiding the detector across the applicator surface at a constant small distance. It performs an angular movement of detector and applicator with high precision. Results: The measurements of surface dose rate distributions discussed in this work demonstrate the successful operation of the measuring setup. Measuring the surface dose rate distribution with a small distance between applicator and detector and with a high density of measuring points results in a complete and gapless coverage of the applicator surface, being capable of distinguishing small sized spots with high activities. The dosimetrical accuracy of the measurements and its analysis is sufficient (uncertainty in the dose rate in terms of absorbed dose to water is <7%), especially when taking the surgical techniques in positioning of the applicator on the eyeball into account. Conclusions: The method developed so far allows a fully automated quality assurance of eye applicators even under clinical conditions. These measurements provide the basis for future calculation of a full 3D dose rate

Design and characterization of a new high-dose-rate brachytherapy Valencia applicator for larger skin lesions

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

Candela-Juan, C., E-mail: ccanjuan@gmail.com; Niatsetski, Y.; Laarse, R. van der

Purpose: The aims of this study were (i) to design a new high-dose-rate (HDR) brachytherapy applicator for treating surface lesions with planning target volumes larger than 3 cm in diameter and up to 5 cm in size, using the microSelectron-HDR or Flexitron afterloader (Elekta Brachytherapy) with a {sup 192}Ir source; (ii) to calculate by means of the Monte Carlo (MC) method the dose distribution for the new applicator when it is placed against a water phantom; and (iii) to validate experimentally the dose distributions in water. Methods: The PENELOPE2008 MC code was used to optimize dwell positions and dwell times.more » Next, the dose distribution in a water phantom and the leakage dose distribution around the applicator were calculated. Finally, MC data were validated experimentally for a {sup 192}Ir mHDR-v2 source by measuring (i) dose distributions with radiochromic EBT3 films (ISP); (ii) percentage depth–dose (PDD) curve with the parallel-plate ionization chamber Advanced Markus (PTW); and (iii) absolute dose rate with EBT3 films and the PinPoint T31016 (PTW) ionization chamber. Results: The new applicator is made of tungsten alloy (Densimet) and consists of a set of interchangeable collimators. Three catheters are used to allocate the source at prefixed dwell positions with preset weights to produce a homogenous dose distribution at the typical prescription depth of 3 mm in water. The same plan is used for all available collimators. PDD, absolute dose rate per unit of air kerma strength, and off-axis profiles in a cylindrical water phantom are reported. These data can be used for treatment planning. Leakage around the applicator was also scored. The dose distributions, PDD, and absolute dose rate calculated agree within experimental uncertainties with the doses measured: differences of MC data with chamber measurements are up to 0.8% and with radiochromic films are up to 3.5%. Conclusions: The new applicator and the dosimetric data provided here will be a

Cross-protection among lethal H5N2 influenza viruses induced by DNA vaccine to the hemagglutinin.

PubMed Central

Kodihalli, S; Haynes, J R; Robinson, H L; Webster, R G

1997-01-01

Inoculation of mice with hemagglutinin (HA)-expressing DNA affords reliable protection against lethal influenza virus infection, while in chickens the same strategy has yielded variable results. Here we show that gene gun delivery of DNA encoding an H5 HA protein confers complete immune protection to chickens challenged with lethal H5 viruses. In tests of the influence of promoter selection on vaccine efficacy, close correlations were obtained between immune responses and the dose of DNA administered, whether a cytomegalovirus (CMV) immediate-early promoter or a chicken beta-actin promoter was used. Perhaps most important, the HA-DNA vaccine conferred 95% cross-protection against challenge with lethal antigenic variants that differed from the primary antigen by 11 to 13% (HA1 amino acid sequence homology). Overall, the high levels of protection seen with gene gun delivery of HA-DNA were as good as, if not better than, those achieved with a conventional whole-virus vaccine, with fewer instances of morbidity and death. The absence of detectable antibody titers after primary immunization, together with the rapid appearance of high titers immediately after challenge, implicates efficient B-cell priming as the principal mechanism of DNA-mediated immune protection. Our results suggest that the efficacy of HA-DNA influenza virus vaccine in mice extends to chickens and probably to other avian species as well. Indeed, the H5 preparation we describe offers an attractive means to protect the domestic poultry industry in the United States from lethal H5N2 viruses, which continue to circulate in Mexico. PMID:9094608

Application of non-lethal stable isotope analysis to assess feeding patterns of juvenile pallid sturgeon Scaphirhynchus albus: a comparison of tissue types and sample preservation methods

USGS Publications Warehouse

Andvik, R.T.; VanDeHey, J.A.; Fincel, M.J.; French, William E.; Bertrand, K.N.; Chipps, Steven R.; Klumb, Robert A.; Graeb, B.D.S.

2010-01-01

Traditional techniques for stable isotope analysis (SIA) generally require sacrificing animals to collect tissue samples; this can be problematic when studying diets of endangered species such as the pallid sturgeon Scaphirhynchus albus. Our objectives were to (i) determine if pectoral fin tissue (non-lethal) could be a substitute for muscle tissue (lethal) in SIA of juvenile pallid sturgeon, and (ii) evaluate the influence of preservation techniques on stable isotope values. In the laboratory, individual juvenile pallid sturgeon were held for up to 186 day and fed chironomids, fish, or a commercially available pellet diet. Significant, positive relationships (r² ≥ 0.8) were observed between fin and muscle tissues for both δ15N and δ13C; in all samples isotopes were enriched in fins compared to muscle tissue. Chironomid and fish based diets of juvenile pallid sturgeon were distinguishable for fast growing fish (0.3 mm day−1) using stable δ15N and δ13C isotopes. Frozen and preserved fin tissue δ15N isotopes were strongly related (r2 = 0.89) but δ13C isotopes were weakly related (r2 = 0.16). Therefore, freezing is recommended for preservation of fin clips to avoid the confounding effect of enrichment by ethanol. This study demonstrates the utility of a non-lethal technique to assess time integrated food habits of juvenile pallid sturgeon and should be applicable to other threatened or endangered species.

EVALUATING THE PREDICTIVE VALIDITY OF SUICIDAL INTENT AND MEDICAL LETHALITY IN YOUTH

PubMed Central

Sapyta, Jeffrey; Goldston, David B.; Erkanli, Alaattin; Daniel, Stephanie S.; Heilbron, Nicole; Mayfield, Andrew; Treadway, S. Lyn

2012-01-01

Objectives To examine whether suicidal intent and medical lethality of past suicide attempts are predictive of future attempts, the association between intent and lethality, and the consistency of these characteristics across repeated attempts among youth. Method Suicide attempts in a 15-year prospective study of 180 formerly psychiatrically hospitalized adolescents (Mage at hospitalization = 14.83; 51% female; 80% Caucasian) were characterized using the Subjective Intent Rating Scale and Lethality of Attempt Rating Scale. Anderson-Gill recurrent events survival models and generalized estimating equations were used to assess predictive validity. Generalized linear models were used to examine stability of characteristics across attempts. Results Neither intent nor lethality from the most recent attempt predicted future attempts. The highest level of intent and most severe lethality of attempts during the follow-up predicted subsequent attempts, but the degree to which highest intent and most severe lethality contributed to prediction after considering methods of suicide attempts, past number of attempts, or psychiatric diagnoses was mixed. Across successive attempts, there was little consistency in reported characteristics. Intent and lethality were related to each other only for attempts occurring in early adulthood. Conclusions Highest intent and lethality were better predictors of future attempts than intent and lethality of the most recent attempt. However, these characteristics should only be considered as predictors within the context of other factors. For youth, clinicians should not infer true intent from the lethality of attempts, nor assume that characteristics of future suicide attempts will be similar to previous attempts. PMID:22250854

Comparison of dose volume parameters evaluated using three forward planning – optimization techniques in cervical cancer brachytherapy involving two applicators

PubMed Central

Basu-Roy, Somapriya; Kar, Sanjay Kumar; Das, Sounik; Lahiri, Annesha

2017-01-01

Purpose This study is intended to compare dose-volume parameters evaluated using different forward planning- optimization techniques, involving two applicator systems in intracavitary brachytherapy for cervical cancer. It looks for the best applicator-optimization combination to fulfill recommended dose-volume objectives in different high-dose-rate (HDR) fractionation schedules. Material and methods We used tandem-ring and Fletcher-style tandem-ovoid applicator in same patients in two fractions of brachytherapy. Six plans were generated for each patient utilizing 3 forward optimization techniques for each applicator used: equal dwell weight/times (‘no optimization’), ‘manual dwell weight/times’, and ‘graphical’. Plans were normalized to left point A and dose of 8 Gy was prescribed. Dose volume and dose point parameters were compared. Results Without graphical optimization, maximum width and thickness of volume enclosed by 100% isodose line, dose to 90%, and 100% of clinical target volume (CTV); minimum, maximum, median, and average dose to both rectum and bladder are significantly higher with Fletcher applicator. Even if it is done, dose to both points B, minimum dose to CTV, and treatment time; dose to 2 cc (D2cc) rectum and rectal point etc.; D2cc, minimum, maximum, median, and average dose to sigmoid colon; D2cc of bladder remain significantly higher with this applicator. Dose to bladder point is similar (p > 0.05) between two applicators, after all optimization techniques. Conclusions Fletcher applicator generates higher dose to both CTV and organs at risk (2 cc volumes) after all optimization techniques. Dose restriction to rectum is possible using graphical optimization only during selected HDR fractionation schedules. Bladder always receives dose higher than recommended, and 2 cc sigmoid colon always gets permissible dose. Contrarily, graphical optimization with ring applicators fulfills all dose volume objectives in all HDR fractionations

Bacterial Dose-Dependent Role of G Protein-Coupled Receptor Kinase 5 in Escherichia coli-Induced Pneumonia.

PubMed

Packiriswamy, Nandakumar; Steury, Michael; McCabe, Ian C; Fitzgerald, Scott D; Parameswaran, Narayanan

2016-05-01

G protein-coupled receptor kinase 5 (GRK5) is a serine/threonine kinase previously shown to mediate polymicrobial sepsis-induced inflammation. The goal of the present study was to examine the role of GRK5 in monomicrobial pulmonary infection by using an intratracheal Escherichia coli infection model of pneumonia. We used sublethal and lethal doses of E. coli to examine the mechanistic differences between low-grade and high-grade inflammation induced by E. coli infection. With a sublethal dose of E. coli, GRK5 knockout (KO) mice exhibited higher plasma CXCL1/KC levels and enhanced lung neutrophil recruitment early after infection, and lower bacterial loads, than wild-type (WT) mice. The inflammatory response was also diminished, and resolution of inflammation advanced, in the lungs of GRK5 KO mice. In contrast to the reduced bacterial loads in GRK5 KO mice following a sublethal dose, at a lethal dose of E. coli, the bacterial burdens remained high in GRK5 KO mice relative to those in WT mice. This occurred in spite of enhanced plasma CXCL1 levels as well as neutrophil recruitment in the KO mice. But the recruited neutrophils (following high-dose infection) exhibited decreased CD11b expression and reduced reactive oxygen species production, suggesting decreased neutrophil activation or increased neutrophil exhaustion in the GRK5 KO mice. In agreement with the increased bacterial burden, KO mice showed poorer survival than WT mice following E. coli infection at a lethal dose. Overall, our data suggest that GRK5 negatively regulates CXCL1/KC levels during bacterial pneumonia but that the role of GRK5 in the clinical outcome in this model is dependent on the bacterial dose. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

AS-2, a novel inhibitor of p53-dependent apoptosis, prevents apoptotic mitochondrial dysfunction in a transcription-independent manner and protects mice from a lethal dose of ionizing radiation

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

Morita, Akinori, E-mail: morita@tokushima-u.ac.jp; Ariyasu, Shinya; Wang, Bing

2014-08-08

Highlights: • A bidentate HQ derivative, AS-2, suppresses p53-dependent apoptosis by DNA damage. • AS-2 does not significantly affect nuclear p53 response. • UV-excited blue emission of AS-2 clearly showed its extranuclear localization. • AS-2 prevents mitochondrial dysfunction despite the increase of mitochondrial p53. • AS-2 protects mice from a radiation dose that causes lethal hematopoietic syndrome. - Abstract: In a previous study, we reported that some tetradentate zinc(II) chelators inhibit p53 through the denaturation of its zinc-requiring structure but a chelator, Bispicen, a potent inhibitor of in vitro apoptosis, failed to show any efficient radioprotective effect against irradiated micemore » because the toxicity of the chelator to mice. The unsuitability of using tetradentate chelators as radioprotectors prompted us to undertake a more extensive search for p53-inhibiting agents that are weaker zinc(II) chelators and therefore less toxic. Here, we show that an 8-hydroxyquinoline (8HQ) derivative, AS-2, suppresses p53-dependent apoptosis through a transcription-independent mechanism. A mechanistic study using cells with different p53 characteristics revealed that the suppressive effect of AS-2 on apoptosis is specifically mediated through p53. In addition, AS-2 was less effective in preventing p53-mediated transcription-dependent events than pifithrin-μ (PFTμ), an inhibitor of transcription-independent apoptosis by p53. Fluorescence visualization of the extranuclear distribution of AS-2 also supports that it is ineffective on the transcription-dependent pathway. Further investigations revealed that AS-2 suppressed mitochondrial apoptotic events, such as the mitochondrial release of intermembrane proteins and the loss of mitochondrial membrane potential, although AS-2 resulted in an increase in the mitochondrial translocation of p53 as opposed to the decrease of cytosolic p53, and did not affect the apoptotic interaction of p53 with Bcl-2

Application of Benchmark Dose Methodology to a Variety of Endpoints and Exposures

EPA Science Inventory

This latest beta version (1.1b) of the U.S. Environmental Protection Agency (EPA) Benchmark Dose Software (BMDS) is being distributed for public comment. The BMDS system is being developed as a tool to facilitate the application of benchmark dose (BMD) methods to EPA hazardous p...

Characterization of Thymol blue Radiochromic dosimeters for high dose applications

NASA Astrophysics Data System (ADS)

Aldweri, Feras M.; Abuzayed, Manar H.; Al-Ajaleen, Musab S.; Rabaeh, Khalid A.

2018-03-01

Thymol blue (TB) solutions and Thymol blue Polyvinyl Alcohol (TB-PVA) films have been introduced as Radiochromic dosimeter for high dose applications. The dosimeters were irradiated with gamma ray (60Co source) from 5 to 30 kGy for film, and from 0.150 kGy to 4 kGy for solution. The optical density of unirradiated and irradiated TB solution as well as TB-PVA film dosimeters were studied in terms of absorbance at 434 nm using UV/VIS spectrophotometer. The effects of scan temperature, light pre-gamma irradiation, dose rate, relative humidity and stability of the absorbance of solutions and films after irradiation were investigated. We found the dose sensitivity of TB solution and TB-PVA film dosimeters increases significantly with increases of the absorbed dose as well as with the increases of TB dye concentrations. The useful dose range of developed TB solutions and TB-PVA films dosimeters is in the range 0.125-1 kGy and of 5-20 kGy, respectively.

Therapeutic use of recombinant human G-CSF (RHG-CSF) in a canine model of sublethal and lethal whole-body irradiation

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

Macvittie, T.J.; Monroy, R.L.; Patchen, M.L.

The short biologic half-life of the peripheral neutrophil (PMN) requires an active granulopoietic response to replenish functional PMSs and to remain a competent host defence in irradiated animals. Recombinant human G-CSF (rhG-CSF) was studied for its ability to modulate hemopoiesis in normal dogs as well as to decrease therapeutically the severity and duration of neutropenia in sublethally and lethally irradiated dogs. For the normal dog, subcutaneous administration of rhG-CSF induced neutrophilia within hours after the first injection; total PMSs continued to increase (with plateau phases) to mean peak values of 1000 per cent of baseline at the end of themore » treatment period (12-14 days). Bone-marrow-derived granulocyte-macrophage colony-forming cells (GM-CFC) increased significantly during treatment. For a sublethal 200 cGy dose, treatment with rhG-CSF for 14 consecutive days decreased the severity and shortened the duration of neutropenia and thrombocytopenia. The radiation-induced lethality of 60 per cent after a dose of 350 cGy was associated with marrow-derived GM-CFC survival of 1 per cent.« less

Comparison of doses to the rectum derived from treatment planning system with in-vivo dose values in vaginal vault brachytherapy using cylinder applicators

PubMed Central

Obed, Rachel Ibhade; Akinlade, Bidemi Idayat; Ntekim, Atara

2015-01-01

Purpose In-vivo measurements to determine doses to organs-at-risk can be an essential part of brachytherapy quality assurance (QA). This study compares calculated doses to the rectum with measured dose values as a means of QA in vaginal vault brachytherapy using cylinder applicators. Material and methods At the Department of Radiotherapy, University College Hospital (UCH), Ibadan, Nigeria, intracavitary brachytherapy (ICBT) was delivered by a GyneSource high-dose-rate (HDR) unit with 60Co. Standard 2D treatment plans were created with HDR basic 2.6 software for prescription doses 5-7 Gy at points 5 mm away from the posterior surface of vaginal cylinder applicators (20, 25, and 30 mm diameters). The LiF:Mg, Ti thermoluminescent dosimeter rods (1 x 6 mm) were irradiated to a dose of 7 Gy on Theratron 60Co machine for calibration purpose prior to clinical use. Measurements in each of 34 insertions involving fourteen patients were performed with 5 TLD-100 rods placed along a re-usable rectal marker positioned in the rectum. The dosimeters were read in Harshaw 3500 TLD reader and compared with doses derived from the treatment planning system (TPS) at 1 cm away from the dose prescription points. Results The mean calculated and measured doses ranged from 2.1-3.8 Gy and 1.2-5.6 Gy with averages of 3.0 ± 0.5 Gy and 3.1 ± 1.1 Gy, respectively, for treatment lengths 2-8 cm along the cylinder-applicators. The mean values correspond to 48.9% and 50.8% of the prescribed doses, respectively. The deviations of the mean in-vivo doses from the TPS values ranged from –1.9 to 2.1 Gy with a p-value of 0.427. Conclusions This study was part of efforts to verify rectal dose obtained from the TPS during vaginal vault brachytherapy. There was no significant difference in the dose to the rectum from the two methods of measurements. PMID:26816506

Anthrax lethal factor inhibitors as potential countermeasure of the infection.

PubMed

Kumar, B V S Suneel; Malik, Siddharth; Grandhi, Pradeep; Dayam, Raveendra; Sarma, J A R P

2014-01-01

Anthrax Lethal Factor (LF) is a zinc-dependent metalloprotease, one of the virulence factor of anthrax infection. Three forms of the anthrax infection have been identified: cutaneous (through skin), gastrointestinal (through alimentary tract), and pulmonary (by inhalation of spores). Anthrax toxin is composed of protective antigen (PA), lethal factor (LF), and edema factor (EF). Protective antigen mediates the entry of Lethal Factor/Edema Factor into the cytosol of host cells. Lethal factor (LF) inactivates mitogen-activated protein kinase kinase inducing cell death, and EF is an adenylyl cyclase impairing host defenses. In the past few years, extensive studies are undertaken to design inhibitors targeting LF. The current review focuses on the small molecule inhibitors targeting LF activity and its structure activity relationships (SAR).

Lethal violence and psychosis: a clinical profile.

PubMed

Nestor, P G; Haycock, J; Doiron, S; Kelly, J; Kelly, D

1995-01-01

To investigate the relationship between lethal violence and psychosis, the authors examined symptomatology, neuropsychological functioning, and the nature of perpetrator-victim relationships of patients with psychotic disorders who were committed to a forensic psychiatric hospital following violent, primarily criminal behavior. A severely violent group, composed primarily of psychotic patients charged with murder, was compared with a less severely violent group that was composed primarily of psychotic patients involved with property crimes. As compared with the less violent group, the severely violent group was more likely to have delusional beliefs about specific personal targets and to have delusions about significant others being replaced by impostors. These beliefs were accompanied by higher scores on neuropsychological tests of intellectual and academic abilities. A high number of their blood relatives were victims of psychotic murder. These results indicated that a higher incidence of lethal or near lethal acts of violence may characterize intellectually intact but psychotic individuals with organize delusions involving personal, accessible targets.

Back to the future: revisiting HIV-1 lethal mutagenesis

PubMed Central

Dapp, Michael J.; Patterson, Steven E.; Mansky, Louis M.

2012-01-01

The concept of eliminating HIV-1 infectivity by elevating the viral mutation rate was first proposed over a decade ago, even though the general concept had been conceived earlier for RNA viruses. Lethal mutagenesis was originally viewed as a novel chemotherapeutic approach for treating HIV-1 infection in which use of a viral mutagen would over multiple rounds of replication lead to the lethal accumulation of mutations, rendering the virus population non infectious – known as the slow mutation accumulation model. There have been limitations in obtaining good efficacy data with drug leads, leaving some doubt into clinical translation. More recent studies of the APOBEC3 proteins as well as new progress in the use of nucleoside analogs for inducing lethal mutagenesis have helped to refocus attention on rapid induction of HIV-1 lethal mutagenesis in a single or limited number of replication cycles leading to a rapid mutation accumulation model. PMID:23195922

High-dose irradiated food: Current progress, applications, and prospects

NASA Astrophysics Data System (ADS)

Feliciano, Chitho P.

2018-03-01

Food irradiation as an established and mature technology has gained more attention in the food industry for ensuring food safety and quality. Primarily used for phytosanitary applications, its use has been expanded for developing various food products for varied purposes (e.g. ready-to-eat & ready-to-cook foods, hospital diets, etc.). This paper summarized and analyzed the recent progress and application of high-dose irradiation and discussed its prospects in the field of food product development, its safety and quality.

[Secondary metabolites, lethality and antimicrobial activity of extracts from three corals and three marine mollusks from Sucre, Venezuela].

PubMed

Ordaz, Gabriel; D'Armas, Haydelba; Yáñez, Dayanis; Hernández, Juan; Camacho, Angel

2010-06-01

The study of biochemical activity of extracts obtained from marine organisms is gaining interest as some have proved to have efficient health or industrial applications. To evaluate lethality and antimicrobial activities, some chemical tests were performed on crude extracts of the octocorals Eunicea sp., Muricea sp. and Pseudopterogorgia acerosa and the mollusks Pteria colymbus, Phyllonotus pomum and Chicoreus brevifrons, collected in Venezuelan waters. The presence of secondary metabolites like alkaloids, unsaturated sterols and pentacyclic triterpenes in all invertebrates, was evidenced. Additionally, sesquiterpenlactones, saponins, tannins, cyanogenic and cardiotonic glycosides were also detected in some octocoral extracts, suggesting that biosynthesis of these metabolites is typical in this group. From the lethality bioassays, all extracts resulted lethal to Artemia salina (LC50<1000 microg/ml) with an increased of lethal activity with exposition time. P. pomum extract showed the highest lethality rate (LC50=46.8 microg/ml). Compared to the octocorals, mollusks extracts displayed more activity and a greater action spectrum against different bacterial strains, whereas octocorals also inhibited some fungi strains growth. Staphylococcus aureus was the most susceptible to the antimicrobial power of the extracts (66.7%), whereas Pseudomonas aeruginosa, Candida albicans and Aspergillus niger were not affected. The antibiosis shown by marine organisms extracts indicates that some of their biosynthesized metabolites are physiologically active, and may have possible cytotoxic potential or as a source of antibiotic components.

Identification of lethal cluster of genes in the yeast transcription network

NASA Astrophysics Data System (ADS)

Rho, K.; Jeong, H.; Kahng, B.

2006-05-01

Identification of essential or lethal genes would be one of the ultimate goals in drug designs. Here we introduce an in silico method to select the cluster with a high population of lethal genes, called lethal cluster, through microarray assay. We construct a gene transcription network based on the microarray expression level. Links are added one by one in the descending order of the Pearson correlation coefficients between two genes. As the link density p increases, two meaningful link densities pm and ps are observed. At pm, which is smaller than the percolation threshold, the number of disconnected clusters is maximum, and the lethal genes are highly concentrated in a certain cluster that needs to be identified. Thus the deletion of all genes in that cluster could efficiently lead to a lethal inviable mutant. This lethal cluster can be identified by an in silico method. As p increases further beyond the percolation threshold, the power law behavior in the degree distribution of a giant cluster appears at ps. We measure the degree of each gene at ps. With the information pertaining to the degrees of each gene at ps, we return to the point pm and calculate the mean degree of genes of each cluster. We find that the lethal cluster has the largest mean degree.

Dose Estimating Application Software Modification: Additional Function of a Size-Specific Effective Dose Calculator and Auto Exposure Control.

PubMed

Kobayashi, Masanao; Asada, Yasuki; Matsubara, Kosuke; Suzuki, Shouichi; Matsunaga, Yuta; Haba, Tomonobu; Kawaguchi, Ai; Daioku, Tomihiko; Toyama, Hiroshi; Kato, Ryoichi

2017-05-01

Adequate dose management during computed tomography is important. In the present study, the dosimetric application software ImPACT was added to a functional calculator of the size-specific dose estimate and was part of the scan settings for the auto exposure control (AEC) technique. This study aimed to assess the practicality and accuracy of the modified ImPACT software for dose estimation. We compared the conversion factors identified by the software with the values reported by the American Association of Physicists in Medicine Task Group 204, and we noted similar results. Moreover, doses were calculated with the AEC technique and a fixed-tube current of 200 mA for the chest-pelvis region. The modified ImPACT software could estimate each organ dose, which was based on the modulated tube current. The ability to perform beneficial modifications indicates the flexibility of the ImPACT software. The ImPACT software can be further modified for estimation of other doses. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

DefenseLink.mil - Special Report - Soldiers Train with Non-lethal Weapons

Science.gov Websites

Training 10th Mountain Division soldiers feel the effects of a Taser during non-lethal weapons training Nov soldiers feel the effects of a Taser during non-lethal weapons training Nov. 19, 2008, at Fort Drum, N.Y situation can be resolved without lethal measures, Army Staff Sgt. Eric Johnson said during training and

A rabies vaccine adjuvanted with saponins from leaves of the soap tree (Quillaja brasiliensis) induces specific immune responses and protects against lethal challenge.

PubMed

Yendo, Anna Carolina A; de Costa, Fernanda; Cibulski, Samuel P; Teixeira, Thais F; Colling, Luana C; Mastrogiovanni, Mauricio; Soulé, Silvia; Roehe, Paulo M; Gosmann, Grace; Ferreira, Fernando A; Fett-Neto, Arthur G

2016-04-29

Quillaja brasiliensis (Quillajaceae) is a saponin producing species native from southern Brazil and Uruguay. Its saponins are remarkably similar to those of Q. saponaria, which provides most of the saponins used as immunoadjuvants in vaccines. The immunostimulating capacities of aqueous extract (AE) and purified saponin fraction (QB-90) obtained from leaves of Q. brasiliensis were favorably comparable to those of a commercial saponin-based adjuvant preparation (Quil-A) in experimental vaccines against bovine herpesvirus type 1 and 5, poliovirus and bovine viral diarrhea virus in mice model. Herein, the immunogenicity and protection efficacy of rabies vaccines adjuvanted with Q. brasiliensis AE and its saponin fractions were compared with vaccines adjuvanted with either commercial Quil-A or Alum. Mice were vaccinated with one or two doses (on days 0 and 14) of one of the different vaccines and serum levels of total IgG, IgG1 and IgG2a were quantified over time. A challenge experiment with a lethal dose of rabies virus was carried out with the formulations. Viral RNA detection in the brain of mice was performed by qPCR, and RNA copy-numbers were quantified using a standard curve of in vitro transcribed RNA. All Q. brasiliensis saponin-adjuvanted vaccines significantly enhanced levels of specific IgG isotypes when compared with the no adjuvant group (P ≤ 0.05). Overall, one or two doses of saponin-based vaccine were efficient to protect against the lethal rabies exposure. Both AE and saponin fractions from Q. brasiliensis leaves proved potent immunological adjuvants in vaccines against a lethal challenge with a major livestock pathogen, hence confirming their value as competitive or complementary sustainable alternatives to saponins of Q. saponaria. Copyright © 2016 Elsevier Ltd. All rights reserved.

The use of tetrahedral mesh geometries in Monte Carlo simulation of applicator based brachytherapy dose distributions

NASA Astrophysics Data System (ADS)

Paiva Fonseca, Gabriel; Landry, Guillaume; White, Shane; D'Amours, Michel; Yoriyaz, Hélio; Beaulieu, Luc; Reniers, Brigitte; Verhaegen, Frank

2014-10-01

Accounting for brachytherapy applicator attenuation is part of the recommendations from the recent report of AAPM Task Group 186. To do so, model based dose calculation algorithms require accurate modelling of the applicator geometry. This can be non-trivial in the case of irregularly shaped applicators such as the Fletcher Williamson gynaecological applicator or balloon applicators with possibly irregular shapes employed in accelerated partial breast irradiation (APBI) performed using electronic brachytherapy sources (EBS). While many of these applicators can be modelled using constructive solid geometry (CSG), the latter may be difficult and time-consuming. Alternatively, these complex geometries can be modelled using tessellated geometries such as tetrahedral meshes (mesh geometries (MG)). Recent versions of Monte Carlo (MC) codes Geant4 and MCNP6 allow for the use of MG. The goal of this work was to model a series of applicators relevant to brachytherapy using MG. Applicators designed for 192Ir sources and 50 kV EBS were studied; a shielded vaginal applicator, a shielded Fletcher Williamson applicator and an APBI balloon applicator. All applicators were modelled in Geant4 and MCNP6 using MG and CSG for dose calculations. CSG derived dose distributions were considered as reference and used to validate MG models by comparing dose distribution ratios. In general agreement within 1% for the dose calculations was observed for all applicators between MG and CSG and between codes when considering volumes inside the 25% isodose surface. When compared to CSG, MG required longer computation times by a factor of at least 2 for MC simulations using the same code. MCNP6 calculation times were more than ten times shorter than Geant4 in some cases. In conclusion we presented methods allowing for high fidelity modelling with results equivalent to CSG. To the best of our knowledge MG offers the most accurate representation of an irregular APBI balloon applicator.

Dosimetric evaluation of internal shielding in a high dose rate skin applicator

PubMed Central

Granero, Domingo; Perez-Calatayud, Jose; Carmona, Vicente; Pujades, M Carmen; Ballester, Facundo

2011-01-01

Purpose The Valencia HDR applicators are accessories of the microSelectron HDR afterloading system (Nucletron) shaped as truncated cones. The base of the cone is either 2 or 3 cm diameter. They are intended to treat skin lesions, being the typical prescription depth 3 mm. In patients with eyelid lesions, an internal shielding is very useful to reduce the dose to the ocular globe. The purpose of this work was to evaluate the dose enhancement from potential backscatter and electron contamination due to the shielding. Material and methods Two methods were used: a) Monte Carlo simulation, performed with the GEANT4 code, 2 cm Valencia applicator was placed on the surface of a water phantom in which 2 mm lead slab was located at 3 mm depth; b) radiochromic EBT films, used to verify the Monte Carlo results, positioning the films at 1.5, 3, 5 and 7 mm depth, inside the phantom. Two irradiations, with and without the lead shielding slab, were carried out. Results The Monte Carlo results showed that due to the backscatter component from the lead, the dose level raised to about 200% with a depth range of 0.5 mm. Under the lead the dose level was enhanced to about 130% with a depth range of 1 mm. Two millimeters of lead reduce the dose under the slab with about 60%. These results agree with film measurements within uncertainties. Conclusions In conclusion, the use of 2 mm internal lead shielding in eyelid skin treatments with the Valencia applicators were evaluated using MC methods and EBT film dosimetry. The minimum bolus thickness that was needed above and below the shielding was 0.5 mm and 1 mm respectively, and the shielding reduced the absorbed dose delivered to the ocular globe by about 60%. PMID:27877198

An Interlaboratory Validation of the Radiation Dose Response Relationship (DRR) for H-ARS in the Rhesus Macaque.

PubMed

Thrall, Karla D; Love, Ruschelle; OʼDonnell, Kyle C; Farese, Ann M; Manning, Ronald; MacVittie, Thomas J

2015-11-01

The Medical Countermeasures against Radiological Threats (MCART) consortium has established a dose response relationship for the hematopoietic acute radiation syndrome (HARS) in the rhesus macaque conducted under an individualized supportive care protocol, including blood transfusions. Application of this animal model as a platform for demonstrating efficacy of candidate medical countermeasures is significantly strengthened when the model is independently validated at multiple institutions. The study reported here describes implementation of standard operating procedures at an institute outside the consortium in order to evaluate the ability to establish an equivalent radiation dose response relationship in a selected species. Validation of the animal model is a significant component for consideration of the model protocol as an FDA-recommended drug development tool in the context of the "Animal Rule." In the current study, 48 male rhesus macaques (4-8 kg) were exposed to total-body irradiation (TBI) using 6 MV photon energy at a dose rate of approximately 0.8 Gy min. Results show that onset and duration of the hematological response, including anemia, neutropenia, and thrombocytopenia, following TBI ranging from 6.25 to 8.75 Gy correlate well with previously reported findings. The lethality values at 60 d following TBI were estimated to be 6.88 Gy (LD30/60), 7.43 Gy (LD50/60), and 7.98 Gy (LD70/60). These values are equivalent to those published previously of 7.06 Gy (LD30/60), 7.52 Gy (LD50/60), and 7.99 Gy (LD70/60); the DRR slope (p = 0.68) and y-intercepts show agreement along the complete dose range for HARS. The ability to replicate the previously established institutional lethality profile (PROBIT) and model outcomes through careful implementation of defined procedures is a testament to the robustness of the model and highlights the need for consistency in procedures.

Lethal and sub-lethal effects of cyproconazole on freshwater organisms: a case study with Chironomus riparius and Dugesia tigrina.

PubMed

Saraiva, Althiéris S; Sarmento, Renato A; Golovko, Oksana; Randak, Tomas; Pestana, João L T; Soares, Amadeu M V M

2018-04-01

The fungicide cyproconazole (CPZ) inhibits the biosynthesis of ergosterol, an essential sterol component in fungal cell membrane and can also affect non-target organisms by its inhibitory effects on P450 monooxygenases. The predicted environmental concentration of CPZ is up to 49.05 μg/L and 145.89 μg/kg in surface waters and sediments, respectively, and information about CPZ toxicity towards non-target aquatic organisms is still limited. This study aimed to address the lack of ecotoxicological data for CPZ, and thus, an evaluation of the lethal and sub-lethal effects of CPZ was performed using two freshwater invertebrates (the midge Chironomus riparius and the planarian Dugesia tigrina). The estimated CPZ 48 h LC 50 (95% CI) was 17.46 mg/L for C. riparius and 47.38 mg/L for D. tigrina. The emergence time (EmT 50 ) of C. riparius was delayed by CPZ exposure from 0.76 mg/L. On the other hand, planarians showed higher tolerance to CPZ exposure. Sub-lethal effects of CPZ on planarians included reductions in locomotion (1.8 mg/L), delayed photoreceptors regeneration (from 0.45 mg/L), and feeding inhibition (5.6 mg/L). Our results confirm the moderate toxicity of CPZ towards aquatic invertebrates but sub-lethal effects observed also suggest potential chronic effects of CPZ with consequences for population dynamics.

The lethality test used for estimating the potency of antivenoms against Bothrops asper snake venom: pathophysiological mechanisms, prophylactic analgesia, and a surrogate in vitro assay.

PubMed

Chacón, Francisco; Oviedo, Andrea; Escalante, Teresa; Solano, Gabriela; Rucavado, Alexandra; Gutiérrez, José María

2015-01-01

The potency of antivenoms is assessed by analyzing the neutralization of venom-induced lethality, and is expressed as the Median Effective Dose (ED50). The present study was designed to investigate the pathophysiological mechanisms responsible for lethality induced by the venom of Bothrops asper, in the experimental conditions used for the evaluation of the neutralizing potency of antivenoms. Mice injected with 4 LD50s of venom by the intraperitoneal route died within ∼25 min with drastic alterations in the abdominal organs, characterized by hemorrhage, increment in plasma extravasation, and hemoconcentration, thus leading to hypovolemia and cardiovascular collapse. Snake venom metalloproteinases (SVMPs) play a predominat role in lethality, as judged by partial inhibition by the chelating agent CaNa2EDTA. When venom was mixed with antivenom, there was a venom/antivenom ratio at which hemorrhage was significantly reduced, but mice died at later time intervals with evident hemoconcentration, indicating that other components in addition to SVMPs also contribute to plasma extravasation and lethality. Pretreatment with the analgesic tramadol did not affect the outcome of the neutralization test, thus suggesting that prophylactic (precautionary) analgesia can be introduced in this assay. Neutralization of lethality in mice correlated with neutralization of in vitro coagulant activity in human plasma. Copyright © 2014 Elsevier Ltd. All rights reserved.

Choline intake and risk of lethal prostate cancer: incidence and survival123

PubMed Central

Richman, Erin L; Kenfield, Stacey A; Stampfer, Meir J; Giovannucci, Edward L; Zeisel, Steven H; Willett, Walter C; Chan, June M

2012-01-01

Background: Meat, milk, and eggs have been inconsistently associated with the risk of advanced prostate cancer. These foods are sources of choline—a nutrient that may affect prostate cancer progression through cell membrane function and one-carbon metabolism. No study has examined dietary choline and the risk of lethal prostate cancer. Objective: Our objective was to examine whether dietary choline, choline-containing compounds, and betaine (a choline metabolite) increase the risk of lethal prostate cancer. Design: We prospectively examined the intake of these nutrients and the risk of lethal prostate cancer among 47,896 men in the Health Professionals Follow-Up Study. In a case-only survival analysis, we examined the postdiagnostic intake of these nutrients and the risk of lethal prostate cancer among 4282 men with an initial diagnosis of nonmetastatic disease during follow-up. Diet was assessed with a validated questionnaire 6 times during 22 y of follow-up. Results: In the incidence analysis, we observed 695 lethal prostate cancers during 879,627 person-years. Men in the highest quintile of choline intake had a 70% increased risk of lethal prostate cancer (HR: 1.70; 95% CI: 1.18, 2.45; P-trend = 0.005). In the case-only survival analysis, we observed 271 lethal cases during 33,679 person-years. Postdiagnostic choline intake was not statistically significantly associated with the risk of lethal prostate cancer (HR for quintile 5 compared with quintile 1: 1.69; 95% CI: 0.93, 3.09; P-trend = 0.20). Conclusion: Of the 47,896 men in our study population, choline intake was associated with an increased risk of lethal prostate cancer. PMID:22952174

Energy crop (Sida hermaphrodita) fertilization using digestate under marginal soil conditions: A dose-response experiment

NASA Astrophysics Data System (ADS)

Nabel, Moritz; Bueno Piaz Barbosa, Daniela; Horsch, David; Jablonowski, Nicolai David

2014-05-01

The global demand for energy security and the mitigation of climate change are the main drivers pushing energy-plant production in Germany. However, the cultivation of these plants can cause land use conflicts since agricultural soil is mostly used for plant production. A sustainable alternative to the conventional cultivation of food-based energy-crops is the cultivation of special adopted energy-plants on marginal lands. To further increase the sustainability of energy-plant cultivation systems the dependency on synthetic fertilizers needs to be reduced via closed nutrient loops. In the presented study the energy-plant Sida hermaphrodita (Malvaceae) will be used to evaluate the potential to grow this high potential energy-crop on a marginal sandy soil in combination with fertilization via digestate from biogas production. With this dose-response experiment we will further identify an optimum dose, which will be compared to equivalent doses of NPK-fertilizer. Further, lethal doses and deficiency doses will be observed. Two weeks old Sida seedlings were transplanted to 1L pots and fertilized with six doses of digestate (equivalent to a field application of 5, 10, 20, 40, 80, 160t/ha) and three equivalent doses of NPK-fertilizer. Control plants were left untreated. Sida plants will grow for 45 days under greenhouse conditions. We hypothesize that the nutrient status of the marginal soil can be increased and maintained by defined digestate applications, compared to control plants suffering of nutrient deficiency due to the low nutrient status in the marginal substrate. The dose of 40t/ha is expected to give a maximum biomass yield without causing toxicity symptoms. Results shall be used as basis for further experiments on the field scale in a field trial that was set up to investigate sustainable production systems for energy crop production under marginal soil conditions.

Non-Lethal Chemical Weapons

DTIC Science & Technology

2003-04-01

effects include stupor, confusion, and confabulation with concrete and panoramic illusions and hallucinations , and regression to automatic “phantom...scientifically feasible.” (Federation of American Scientists Article, 2) Opponents of non-lethal weapons contend that because certain individuals...3000.3) According to the Federation of American Scientists , these weapons can be placed into two main categories: incapacitants (including military

Delayed Hippocampal Effects From a Single Exposure of Prepubertal Guinea Pigs to sub-lethal dose of Chlorpyrifos: A Magnetic Resonance Imaging and Spectroscopy Study

PubMed Central

Mullins, Roger J.; Xu, Su; Pereira, Edna F.R.; Mamczarz, Jacek; Albuquerque, Edson X.; Gullapalli, Rao P.

2013-01-01

This study was designed to test the hypothesis that in vivo Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS) can detect in adulthood the neurotoxic effects of a single exposure of prepubertal guinea pigs to the organophosphorus pesticide chlorpyrifos. Twelve female guinea pigs were given either a single dose of chlorpyrifos (0.6xLD50 or 300 mg/kg, sc) or peanut oil (vehicle; 0.5 ml/kg, sc) at 35–40 days of age. One year after the exposure, the animals were tested in the Morris water maze. Three days after the end of the behavioral testing, the metabolic and structural integrity of the brain of the animals was examined by means of MRI/MRS. In the Morris water maze, the chlorpyrifos-exposed guinea pigs showed significant memory deficit. Although no significant anatomical differences were found between the chlorpyrifos-exposed guinea pigs and the control animals by in vivo MRI, the chlorpyrifos-exposed animals showed significant decreases in hippocampal myo-inositol concentration using MRS. The present results indicate that a single sub-lethal exposure of prepubertal guinea pigs to the organophosphorus pesticide chlorpyrifos can lead to long-term memory deficits that are accompanied by significant reductions in the levels of hippocampal myo-inositol. PMID:23411083

Terrorist Attacks Escalate in Frequency and Fatalities Preceding Highly Lethal Attacks

PubMed Central

Martens, Andy; Sainudiin, Raazesh; Sibley, Chris G.; Schimel, Jeff; Webber, David

2014-01-01

Highly lethal terrorist attacks, which we define as those killing 21 or more people, account for 50% of the total number of people killed in all terrorist attacks combined, yet comprise only 3.5% of terrorist attacks. Given the disproportionate influence of these incidents, uncovering systematic patterns in attacks that precede and anticipate these highly lethal attacks may be of value for understanding attacks that exact a heavy toll on life. Here we examined whether the activity of terrorist groups escalates–both in the number of people killed per attack and in the frequency of attacks–leading up to highly lethal attacks. Analyses of terrorist attacks drawn from a state-of-the-art international terrorism database (The Global Terrorism Database) showed evidence for both types of escalation leading up to highly lethal attacks, though complexities to the patterns emerged as well. These patterns of escalation do not emerge among terrorist groups that never commit a highly lethal attack. PMID:24755753

Plasma Doping—Enabling Technology for High Dose Logic and Memory Applications

NASA Astrophysics Data System (ADS)

Miller, T.; Godet, L.; Papasouliotis, G. D.; Singh, V.

2008-11-01

As logic and memory device dimensions shrink with each generation, there are more high dose implants at lower energies. Examples include dual poly gate (also referred to as counter-doped poly), elevated source drain and contact plug implants. Plasma Doping technology throughput and dopant profile benefits at these ultra high dose and lower energy conditions have been well established [1,2,3]. For the first time a production-worthy plasma doping implanter, the VIISta PLAD tool, has been developed with unique architecture suited for precise and repeatable dopant placement. Critical elements of the architecture include pulsed DC wafer bias, closed-loop dosimetry and a uniform low energy, high density plasma source. In this paper key performance metrics such as dose uniformity, dose repeatability and dopant profile control will be presented that demonstrate the production-worthiness of the VIISta PLAD tool for several high dose applications.

Minimal In Vivo Efficacy of Iminosugars in a Lethal Ebola Virus Guinea Pig Model

PubMed Central

Dowall, Stuart D.; Taylor, Irene; Rule, Antony; Alonzi, Dominic S.; Sayce, Andrew C.; Wright, Edward; Bentley, Emma M.; Thom, Ruth; Hall, Graham; Dwek, Raymond A.; Hewson, Roger; Zitzmann, Nicole

2016-01-01

The antiviral properties of iminosugars have been reported previously in vitro and in small animal models against Ebola virus (EBOV); however, their effects have not been tested in larger animal models such as guinea pigs. We tested the iminosugars N-butyl-deoxynojirimycin (NB-DNJ) and N-(9-methoxynonyl)-1deoxynojirimycin (MON-DNJ) for safety in uninfected animals, and for antiviral efficacy in animals infected with a lethal dose of guinea pig adapted EBOV. 1850 mg/kg/day NB-DNJ and 120 mg/kg/day MON-DNJ administered intravenously, three times daily, caused no adverse effects and were well tolerated. A pilot study treating infected animals three times within an 8 hour period was promising with 1 of 4 infected NB-DNJ treated animals surviving and the remaining three showing improved clinical signs. MON-DNJ showed no protective effects when EBOV-infected guinea pigs were treated. On histopathological examination, animals treated with NB-DNJ had reduced lesion severity in liver and spleen. However, a second study, in which NB-DNJ was administered at equally-spaced 8 hour intervals, could not confirm drug-associated benefits. Neither was any antiviral effect of iminosugars detected in an EBOV glycoprotein pseudotyped virus assay. Overall, this study provides evidence that NB-DNJ and MON-DNJ do not protect guinea pigs from a lethal EBOV-infection at the dose levels and regimens tested. However, the one surviving animal and signs of improvements in three animals of the NB-DNJ treated cohort could indicate that NB-DNJ at these levels may have a marginal beneficial effect. Future work could be focused on the development of more potent iminosugars. PMID:27880800

Measurement of radiation dose with BeO dosimeters using optically stimulated luminescence technique in radiotherapy applications.

PubMed

Şahin, Serdar; Güneş Tanır, A; Meriç, Niyazi; Aydınkarahaliloğlu, Ercan

2015-09-01

The radiation dose delivered to the target by using different radiotherapy applications has been measured with the help of beryllium oxide (BeO) dosimeters to be placed inside the rando phantom. Three-Dimensional Conformal Radiotherapy (3DCRT), Intensity-Modulated Radiotherapy (IMRT) and Intensity-Modulated Arc Therapy (IMAT) have been used as radiotherapy application. Individual treatment plans have been made for the three radiotherapy applications of rando phantom. The section 4 on the phantom was selected as target and 200 cGy doses were delivered. After the dosimeters placed on section 4 (target) and the sections 2 and 6 (non-target) were irradiated, the result was read through the OSL technique on the Risø TL/OSL system. This procedure was repeated three times for each radiotherapy application. The doses delivered to the target and the non-target sections as a result of the 3DCRT, IMRT and IMAT plans were analyzed. The doses received by the target were measured as 204.71 cGy, 204.76 cGy and 205.65 cGy, respectively. The dose values obtained from treatment planning system (TPS) were compared to the dose values obtained using the OSL technique. It has been concluded that, the radiation dose can be measured with the OSL technique by using BeO dosimeters in medical practices. Copyright © 2015 Elsevier Ltd. All rights reserved.

INTERACTION OF X AND ULTRAVIOLET RADIATION IN PRODUCTION OF RECESSIVE LETHALS IN DROSOPHILA MELANOGASTER (in Italian)

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

Nicoletti, B.; Olivieri, G.

1962-01-01

The possibility that uv rays given to different biological systems before or after x rays could modify genetic or cytological effects is reviewed and discussed. Kaufmann and Hollaender's conclusions about the recovering effect of uv rays on chromosomal damage induced in Drosophila sperms by a pre-treatment of x rays are discussed and analyzed taking into accourt some general considerations. Preliminary results of similar experiments on the frequency of sex-linked recessive lethals induced after single and combined x + uv treatments in Drosophila sperms are reported. All our experiments indicate no effect of the uv treatment (at the given wave lengthsmore » and doses) in lowering the frequency of the x-ray-induced recessive lethals. On the contrary, there are some indications for a synergistic action between the two radiations. These results not in agreement with the generally accepted theory that uv rays do recover X-ray- induced chromosomal damages, could be expiained With the well established correlation between chromosomal rejoined breaks and genic mutations. (auth)« less

Acute oral toxicity and brine shrimp lethality of Elaeis guineensis Jacq., (oil palm leaf) methanol extract.

PubMed

Syahmi, Abdul Rani Muhamad; Vijayarathna, Soundararajan; Sasidharan, Sreenivasan; Latha, Lachimanan Yoga; Kwan, Yuet Ping; Lau, Yee Ling; Shin, Lai Ngit; Chen, Yeng

2010-11-10

Elaeis guineensis (Arecaceae) is widely used in West African traditional medicine for treating various ailments. An evaluation on the toxicity of extracts of this plant is crucial to support the therapeutic claims. The acute oral toxicity and brine shrimp lethality of a methanolic extract of this plant was tested. Oral administration of crude extract at the highest dose of 5,000 mg/kg resulted in no mortalities or evidence of adverse effects, implying that E. guineensis is nontoxic. Normal behavioral pattern, clinical signs and histology of vital organs confirm this evidence. The E. guineensis extracts screened for toxicity against brine shrimp had 50% lethal concentration (LC₅₀) values of more than 1.0 mg/mL (9.00 and 3.87 mg/mL, at 6 and 24 h, respectively), confirming that the extract was not toxic. Maximum mortalities occurred at 100 mg/mL concentration while the least mortalities happened to be at 0.195 mg/mL concentration. The results of both tests confirm that E. guineensis is nontoxic and hence safe for commercial utilization.

Lethal Interpersonal Violence in the Middle Pleistocene

PubMed Central

Sala, Nohemi; Arsuaga, Juan Luis; Pantoja-Pérez, Ana; Pablos, Adrián; Martínez, Ignacio; Quam, Rolf M.; Gómez-Olivencia, Asier; Bermúdez de Castro, José María; Carbonell, Eudald

2015-01-01

Evidence of interpersonal violence has been documented previously in Pleistocene members of the genus Homo, but only very rarely has this been posited as the possible manner of death. Here we report the earliest evidence of lethal interpersonal violence in the hominin fossil record. Cranium 17 recovered from the Sima de los Huesos Middle Pleistocene site shows two clear perimortem depression fractures on the frontal bone, interpreted as being produced by two episodes of localized blunt force trauma. The type of injuries, their location, the strong similarity of the fractures in shape and size, and the different orientations and implied trajectories of the two fractures suggest they were produced with the same object in face-to-face interpersonal conflict. Given that either of the two traumatic events was likely lethal, the presence of multiple blows implies an intention to kill. This finding shows that the lethal interpersonal violence is an ancient human behavior and has important implications for the accumulation of bodies at the site, supporting an anthropic origin. PMID:26018668

Lethal interpersonal violence in the Middle Pleistocene.

PubMed

Sala, Nohemi; Arsuaga, Juan Luis; Pantoja-Pérez, Ana; Pablos, Adrián; Martínez, Ignacio; Quam, Rolf M; Gómez-Olivencia, Asier; Bermúdez de Castro, José María; Carbonell, Eudald

2015-01-01

Evidence of interpersonal violence has been documented previously in Pleistocene members of the genus Homo, but only very rarely has this been posited as the possible manner of death. Here we report the earliest evidence of lethal interpersonal violence in the hominin fossil record. Cranium 17 recovered from the Sima de los Huesos Middle Pleistocene site shows two clear perimortem depression fractures on the frontal bone, interpreted as being produced by two episodes of localized blunt force trauma. The type of injuries, their location, the strong similarity of the fractures in shape and size, and the different orientations and implied trajectories of the two fractures suggest they were produced with the same object in face-to-face interpersonal conflict. Given that either of the two traumatic events was likely lethal, the presence of multiple blows implies an intention to kill. This finding shows that the lethal interpersonal violence is an ancient human behavior and has important implications for the accumulation of bodies at the site, supporting an anthropic origin.

Maternal-Effect Lethal Mutations on Linkage Group II of Caenorhabditis Elegans

PubMed Central

Kemphues, K. J.; Kusch, M.; Wolf, N.

1988-01-01

We have analyzed a set of linkage group (LG) II maternal-effect lethal mutations in Caenorhabditis elegans isolated by a new screening procedure. Screens of 12,455 F(1) progeny from mutagenized adults resulted in the recovery of 54 maternal-effect lethal mutations identifying 29 genes. Of the 54 mutations, 39 are strict maternal-effect mutations defining 17 genes. These 17 genes fall into two classes distinguished by frequency of mutation to strict maternal-effect lethality. The smaller class, comprised of four genes, mutated to strict maternal-effect lethality at a frequency close to 5 X 10(-4), a rate typical of essential genes in C. elegans. Two of these genes are expressed during oogenesis and required exclusively for embryogenesis (pure maternal genes), one appears to be required specifically for meiosis, and the fourth has a more complex pattern of expression. The other 13 genes were represented by only one or two strict maternal alleles each. Two of these are identical genes previously identified by nonmaternal embryonic lethal mutations. We interpret our results to mean that although many C. elegans genes can mutate to strict maternal-effect lethality, most genes mutate to that phenotype rarely. Pure maternal genes, however, are among a smaller class of genes that mutate to maternal-effect lethality at typical rates. If our interpretation is correct, we are near saturation for pure maternal genes in the region of LG II balanced by mnC1. We conclude that the number of pure maternal genes in C. elegans is small, being probably not much higher than 12. PMID:3224814

Comparison between beta radiation dose distribution due to LDR and HDR ocular brachytherapy applicators using GATE Monte Carlo platform.

PubMed

Mostafa, Laoues; Rachid, Khelifi; Ahmed, Sidi Moussa

2016-08-01

Eye applicators with 90Sr/90Y and 106Ru/106Rh beta-ray sources are generally used in brachytherapy for the treatment of eye diseases as uveal melanoma. Whenever, radiation is used in treatment, dosimetry is essential. However, knowledge of the exact dose distribution is a critical decision-making to the outcome of the treatment. The Monte Carlo technique provides a powerful tool for calculation of the dose and dose distributions which helps to predict and determine the doses from different shapes of various types of eye applicators more accurately. The aim of this work consisted in using the Monte Carlo GATE platform to calculate the 3D dose distribution on a mathematical model of the human eye according to international recommendations. Mathematical models were developed for four ophthalmic applicators, two HDR 90Sr applicators SIA.20 and SIA.6, and two LDR 106Ru applicators, a concave CCB model and a flat CCB model. In present work, considering a heterogeneous eye phantom and the chosen tumor, obtained results with the use of GATE for mean doses distributions in a phantom and according to international recommendations show a discrepancy with respect to those specified by the manufacturers. The QC of dosimetric parameters shows that contrarily to the other applicators, the SIA.20 applicator is consistent with recommendations. The GATE platform show that the SIA.20 applicator present better results, namely the dose delivered to critical structures were lower compared to those obtained for the other applicators, and the SIA.6 applicator, simulated with MCNPX generates higher lens doses than those generated by GATE. Copyright © 2016 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Exposure to low UVA doses increases KatA and KatB catalase activities, and confers cross-protection against subsequent oxidative injuries in Pseudomonas aeruginosa.

PubMed

Pezzoni, Magdalena; Tribelli, Paula M; Pizarro, Ramón A; López, Nancy I; Costa, Cristina S

2016-05-01

Solar UVA radiation is one of the main environmental stress factors for Pseudomonas aeruginosa. Exposure to high UVA doses produces lethal effects by the action of the reactive oxygen species (ROS) it generates. P. aeruginosa has several enzymes, including KatA and KatB catalases, which provide detoxification of ROS. We have previously demonstrated that KatA is essential in defending P. aeruginosa against high UVA doses. In order to analyse the mechanisms involved in the adaptation of this micro-organism to UVA, we investigated the effect of exposure to low UVA doses on KatA and KatB activities, and the physiological consequences. Exposure to UVA induced total catalase activity; assays with non-denaturing polyacrylamide gels showed that both KatA and KatB activities were increased by radiation. This regulation occurred at the transcriptional level and depended, at least partly, on the increase in H2O2 levels. We demonstrated that exposure to low UVA produced a protective effect against subsequent lethal doses of UVA, sodium hypochlorite and H2O2. Protection against lethal UVA depends on katA, whilst protection against sodium hypochlorite depends on katB, demonstrating that different mechanisms are involved in the defence against these oxidative agents, although both genes can be involved in the global cellular response. Conversely, protection against lethal doses of H2O2 could depend on induction of both genes and/or (an)other defensive factor(s). A better understanding of the adaptive response of P. aeruginosa to UVA is relevant from an ecological standpoint and for improving disinfection strategies that employ UVA or solar irradiation.

Passive dosing of polycyclic aromatic hydrocarbon (PAH) mixtures to terrestrial springtails: linking mixture toxicity to chemical activities, equilibrium lipid concentrations, and toxic units.

PubMed

Schmidt, Stine N; Holmstrup, Martin; Smith, Kilian E C; Mayer, Philipp

2013-07-02

A 7-day mixture toxicity experiment with the terrestrial springtail Folsomia candida was conducted, and the effects were linked to three different mixture exposure parameters. Passive dosing from silicone was applied to tightly control exposure levels and compositions of 12 mixture treatments, containing the polycyclic aromatic hydrocarbons (PAHs) naphthalene, phenanthrene, and pyrene. Springtail lethality was then linked to sum chemical activities (∑a), sum equilibrium lipid concentrations (∑C(lipid eq.)), and sum toxic units (∑TU). In each case, the effects of all 12 mixture treatments could be fitted to one sigmoidal exposure-response relationship. The effective lethal chemical activity (La50) of 0.027 was well within the expected range for baseline toxicity of 0.01-0.1. Linking the effects to the lipid-based exposure parameter yielded an effective lethal concentration (LC(lipid eq 50)) of 133 mmol kg(-1) lipid in good correspondence with the lethal membrane burden for baseline toxicity (40-160 mmol kg(-1) lipid). Finally, the effective lethal toxic unit (LTU50) of 1.20 was rather close to the expected value of 1. Altogether, passive dosing provided tightly controlled mixture exposure in terms of both level and composition, while ∑a, ∑C(lipid eq.), and ∑TU allowed baseline toxicity to be linked to mixture exposure.

Acute, Sub-lethal Cyanide Poisoning in Mice is Ameliorated by Nitrite Alone: Complications Arising from Concomitant Administration of Nitrite and Thiosulfate as an Antidotal Combination

PubMed Central

Cambal, Leah K.; Swanson, Megan R.; Yuan, Quan; Weitz, Andrew C.; Li, Hui-Hua; Pitt, Bruce R.; Pearce, Linda L.; Peterson, Jim

2011-01-01

Sodium nitrite alone is shown to ameliorate sub-lethal cyanide toxicity in mice when given from ~1 hour before until 20 minutes after the toxic dose as demonstrated by the recovery of righting ability. An optimum dose (12 mg/kg) was determined to significantly relieve cyanide toxicity (5.0 mg/kg) when administered to mice intraperitoneally. Nitrite so administered was shown to rapidly produce NO in the bloodsteam as judged by the dose dependent appearance of EPR signals attributable to nitrosylhemoglobin and methemoglobin. It is argued that antagonism of cyanide inhibition of cytochrome c oxidase by NO is the crucial antidotal activity rather than the methemoglobin-forming action of nitrite. Concomitant addition of sodium thiosulfate to nitrite-treated blood resulted in the detection of sulfidomethemoblobin by EPR spectroscopy. Sulfide is a product of thiosulfate hydrolysis and, like cyanide, is known to be a potent inhibitor of cytochrome c oxidase; the effects of the two inhibitors being essentially additive under standard assay conditions, rather than dominated by either one. The findings afford a plausible explanation for an observed detrimental effect in mice associated with the use of the standard nitrite-thiosulfate combination therapy at sub-lethal levels of cyanide intoxication. PMID:21534623

Induction of Immune Mediators in Glioma and Prostate Cancer Cells by Non-Lethal Photodynamic Therapy

PubMed Central

Kammerer, Robert; Buchner, Alexander; Palluch, Patrick; Pongratz, Thomas; Oboukhovskij, Konstantin; Beyer, Wolfgang; Johansson, Ann; Stepp, Herbert; Baumgartner, Reinhold; Zimmermann, Wolfgang

2011-01-01

Background Photodynamic therapy (PDT) uses the combination of photosensitizing drugs and harmless light to cause selective damage to tumor cells. PDT is therefore an option for focal therapy of localized disease or for otherwise unresectable tumors. In addition, there is increasing evidence that PDT can induce systemic anti-tumor immunity, supporting control of tumor cells, which were not eliminated by the primary treatment. However, the effect of non-lethal PDT on the behavior and malignant potential of tumor cells surviving PDT is molecularly not well defined. Methodology/Principal Findings Here we have evaluated changes in the transcriptome of human glioblastoma (U87, U373) and human (PC-3, DU145) and murine prostate cancer cells (TRAMP-C1, TRAMP-C2) after non-lethal PDT in vitro and in vivo using oligonucleotide microarray analyses. We found that the overall response was similar between the different cell lines and photosensitizers both in vitro and in vivo. The most prominently upregulated genes encoded proteins that belong to pathways activated by cellular stress or are involved in cell cycle arrest. This response was similar to the rescue response of tumor cells following high-dose PDT. In contrast, tumor cells dealing with non-lethal PDT were found to significantly upregulate a number of immune genes, which included the chemokine genes CXCL2, CXCL3 and IL8/CXCL8 as well as the genes for IL6 and its receptor IL6R, which can stimulate proinflammatory reactions, while IL6 and IL6R can also enhance tumor growth. Conclusions Our results indicate that PDT can support anti-tumor immune responses and is, therefore, a rational therapy even if tumor cells cannot be completely eliminated by primary phototoxic mechanisms alone. However, non-lethal PDT can also stimulate tumor growth-promoting autocrine loops, as seen by the upregulation of IL6 and its receptor. Thus the efficacy of PDT to treat tumors may be improved by controlling unwanted and potentially deleterious

Lethal mechanisms in gastric volvulus.

PubMed

Omond, Kimberley J; Byard, Roger W

2017-01-01

A 55-year-old wheelchair-bound woman with severe cerebral palsy was found at autopsy to have marked distention of the stomach due to a volvulus. The stomach was viable, and filled with air and fluid and had pushed the left dome of the diaphragm upwards causing marked compression of the left lung with a mediastinal shift to the right (including the heart). There was no evidence of gastric perforation, ischaemic necrosis or peritonitis. Removal of the organ block revealed marked kyphoscoliosis. Histology confirmed the viability of the stomach and biochemistry showed no dehydration. Death in cases of acute gastric volvulus usually occurs because of compromise of the gastric blood supply resulting in ischaemic necrosis with distention from swallowed air and fluid resulting in perforation with lethal peritonitis. Hypovolaemic shock may also occur. However, the current case demonstrates an alternative lethal mechanism, that of respiratory compromise due to marked thoracic organ compression.

Clinical application of a OneDose MOSFET for skin dose measurements during internal mammary chain irradiation with high dose rate brachytherapy in carcinoma of the breast.

PubMed

Kinhikar, Rajesh A; Sharma, Pramod K; Tambe, Chandrashekhar M; Mahantshetty, Umesh M; Sarin, Rajiv; Deshpande, Deepak D; Shrivastava, Shyam K

2006-07-21

In our earlier study, we experimentally evaluated the characteristics of a newly designed metal oxide semiconductor field effect transistor (MOSFET) OneDose in-vivo dosimetry system for Ir-192 (380 keV) energy and the results were compared with thermoluminescent dosimeters (TLDs). We have now extended the same study to the clinical application of this MOSFET as an in-vivo dosimetry system. The MOSFET was used during high dose rate brachytherapy (HDRBT) of internal mammary chain (IMC) irradiation for a carcinoma of the breast. The aim of this study was to measure the skin dose during IMC irradiation with a MOSFET and a TLD and compare it with the calculated dose with a treatment planning system (TPS). The skin dose was measured for ten patients. All the patients' treatment was planned on a PLATO treatment planning system. TLD measurements were performed to compare the accuracy of the measured results from the MOSFET. The mean doses measured with the MOSFET and the TLD were identical (0.5392 Gy, 15.85% of the prescribed dose). The mean dose was overestimated by the TPS and was 0.5923 Gy (17.42% of the prescribed dose). The TPS overestimated the skin dose by 9% as verified by the MOSFET and TLD. The MOSFET provides adequate in-vivo dosimetry for HDRBT. Immediate readout after irradiation, small size, permanent storage of dose and ease of use make the MOSFET a viable alternative for TLDs.

The lethal injection quandary: how medicine has dismantled the death penalty.

PubMed

Denno, Deborah W

2007-10-01

On February 20, 2006, Michael Morales was hours away from execution in California when two anesthesiologists declined to participate in his lethal injection procedure, thereby halting all state executions. The events brought to the surface the long-running schism between law and medicine, raising the question of whether any beneficial connection between the professions ever existed in the execution context. History shows it seldom did. Decades of botched executions prove it. This Article examines how states ended up with such constitutionally vulnerable lethal injection procedures, suggesting that physician participation in executions, though looked upon with disdain, is more prevalent--and perhaps more necessary--than many would like to believe. The Article also reports the results of this author's unique nationwide study of lethal injection protocols and medical participation. The study demonstrates that states have continued to produce grossly inadequate protocols that severely restrict sufficient understanding of how executions are performed and heighten the likelihood of unconstitutionality. The analysis emphasizes in particular the utter lack of medical or scientific testing of lethal injection despite the early and continuous involvement of doctors but ongoing detachment of medical societies. Lastly, the Article discusses the legal developments that led up to the current rush of lethal injection lawsuits as well as the strong and rapid reverberations that followed, particularly with respect to medical involvement. This Article concludes with two recommendations. First, much like what occurred in this country when the first state switched to electrocution, there should be a nationwide study of proper lethal injection protocols. An independent commission consisting of a diverse group of qualified individuals, including medical personnel, should conduct a thorough assessment of lethal injection, especially the extent of physician participation. Second, this

Application of TL dosemeters for dose distribution measurements at high temperatures in nuclear reactors.

PubMed

Osvay, M; Deme, S

2006-01-01

Al2O3:Mg,Y ceramic thermoluminescence dosemeters were developed at the Institute of Isotopes for high dose applications at room temperatures. The glow curve of Al2O3:Mg,Y exhibits two peaks--one at 250 degrees C (I) and another peak at approximately 400 degrees C (II). In order to extend the application of these dosemeters to high temperatures, the effect of irradiation temperature was investigated using temperature controlled heating system during high dose irradiation at various temperatures (20-100 degrees C). The new calibration and measuring method has been successfully applied for dose mapping within the hermetic zone of the Paks Nuclear Power Plant even at high temperature parts of blocks.

Evaluating the formulae for integrated lethality in ethylene oxide sterilization using six different endospore forming strains of bacteria, and comparisons of integrated lethality for ethylene oxide and steam systems.

PubMed

Mosley, Gregg A; Gillis, John R; Krushefski, Garrett

2005-01-01

Bacterial endospores from six different species of bacteria were exposed to a spectrum of ethylene oxide (EtO) sterilizing conditions. Temperature was varied from 40 to 60 degrees C and the ethylene oxide concentration was varied from 300 to 750 mg/L. Relative humidity was maintained at 60+/-10% RH. The fraction negative procedure was used to determine the D value for each of the test conditions. Bacterial species tested included Bacillus atrophaeus ATCC # 9372, Bacillus smithii ATCC # 51232, Bacillus subtilis "5230" ATCC # 35021, Bacillus subtilis, DSM # 4181, Bacillus pumilus ATCC # 27142, and Geobacillus stearothermophilus ATCC # 7953. All spore preparations were inoculated on filter paper strips packaged in blue, sterilizable glassine pouches. G. stearothermophilus was the least resistant organism tested. The most resistant organisms tested were B. atrophaeus and B. subtilis "5230". The B. subtilis "5230" strain was slightly more resistant than B. atrophaeus at conditions of 54C and EtO concentrations of 400, 600, and 750 mg/L, as well as at 60C/750mg/L EtO. The other species were between these extremes. This empirical data allowed the application of the recently published formula for converting D values from one set of conditions to another and evaluations of accuracy. The measured D values also allowed the determination of Z values based on temperature variations. These formulae, when applied to process temperatures independent of gas concentration, result in a Z value of approximately 32 degrees C that appears to be similar for all species tested. These data support the application of the previously published formulae 1-6 and allow the same approach to integrated lethality for ethylene oxide processes as is commonly applied to steam sterilization. A review of steam sterilization and related principles was conducted for comparison of integrated lethality for these two methods of sterilization. Errors associated with D values, Z values, extrapolation, and

Calcium-Sensing Receptor Tumor Expression and Lethal Prostate Cancer Progression.

PubMed

Ahearn, Thomas U; Tchrakian, Nairi; Wilson, Kathryn M; Lis, Rosina; Nuttall, Elizabeth; Sesso, Howard D; Loda, Massimo; Giovannucci, Edward; Mucci, Lorelei A; Finn, Stephen; Shui, Irene M

2016-06-01

Prostate cancer metastases preferentially target bone, and the calcium-sensing receptor (CaSR) may play a role in promoting this metastatic progression. We evaluated the association of prostate tumor CaSR expression with lethal prostate cancer. A validated CaSR immunohistochemistry assay was performed on tumor tissue microarrays. Vitamin D receptor (VDR) expression and phosphatase and tensin homolog tumor status were previously assessed in a subset of cases by immunohistochemistry. Cox proportional hazards models adjusting for age and body mass index at diagnosis, Gleason grade, and pathological tumor node metastasis stage were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of CaSR expression with lethal prostate cancer. The investigation was conducted in the Health Professionals Follow-up Study and Physicians' Health Study. We studied 1241 incident prostate cancer cases diagnosed between 1983 and 2009. Participants were followed up or cancer-specific mortality or development of metastatic disease. On average, men were followed up 13.6 years, during which there were 83 lethal events. High CaSR expression was associated with lethal prostate cancer independent of clinical and pathological variables (HR 2.0; 95% CI 1.2-3.3). Additionally, there was evidence of effect modification by VDR expression; CaSR was associated with lethal progression among men with low tumor VDR expression (HR 3.2; 95% CI 1.4-7.3) but not in cases with high tumor VDR expression (HR 0.8; 95% CI 0.2-3.0). Tumor CaSR expression is associated with an increased risk of lethal prostate cancer, particularly in tumors with low VDR expression. These results support further investigating the mechanism linking CaSR with metastases.

Characterization and Demonstration of the Value of a Lethal Mouse Model of Middle East Respiratory Syndrome Coronavirus Infection and Disease.

PubMed

Tao, Xinrong; Garron, Tania; Agrawal, Anurodh Shankar; Algaissi, Abdullah; Peng, Bi-Hung; Wakamiya, Maki; Chan, Teh-Sheng; Lu, Lu; Du, Lanying; Jiang, Shibo; Couch, Robert B; Tseng, Chien-Te K

2016-01-01

Characterized animal models are needed for studying the pathogenesis of and evaluating medical countermeasures for persisting Middle East respiratory syndrome-coronavirus (MERS-CoV) infections. Here, we further characterized a lethal transgenic mouse model of MERS-CoV infection and disease that globally expresses human CD26 (hCD26)/DPP4. The 50% infectious dose (ID50) and lethal dose (LD50) of virus were estimated to be <1 and 10 TCID50 of MERS-CoV, respectively. Neutralizing antibody developed in the surviving mice from the ID50/LD50 determinations, and all were fully immune to challenge with 100 LD50 of MERS-CoV. The tissue distribution and histopathology in mice challenged with a potential working dose of 10 LD50 of MERS-CoV were subsequently evaluated. In contrast to the overwhelming infection seen in the mice challenged with 10(5) LD50 of MERS-CoV, we were able to recover infectious virus from these mice only infrequently, although quantitative reverse transcription-PCR (qRT-PCR) tests indicated early and persistent lung infection and delayed occurrence of brain infection. Persistent inflammatory infiltrates were seen in the lungs and brain stems at day 2 and day 6 after infection, respectively. While focal infiltrates were also noted in the liver, definite pathology was not seen in other tissues. Finally, using a receptor binding domain protein vaccine and a MERS-CoV fusion inhibitor, we demonstrated the value of this model for evaluating vaccines and antivirals against MERS. As outcomes of MERS-CoV infection in patients differ greatly, ranging from asymptomatic to overwhelming disease and death, having available both an infection model and a lethal model makes this transgenic mouse model relevant for advancing MERS research. Fully characterized animal models are essential for studying pathogenesis and for preclinical screening of vaccines and drugs against MERS-CoV infection and disease. When given a high dose of MERS-CoV, our transgenic mice expressing h

Blue light induced reactive oxygen species from flavin mononucleotide and flavin adenine dinucleotide on lethality of HeLa cells.

PubMed

Yang, Ming-Yeh; Chang, Chih-Jui; Chen, Liang-Yü

2017-08-01

Photodynamic therapy (PDT) is a safe and non-invasive treatment for cancers and microbial infections. Various photosensitizers and light sources have been developed for clinical cancer therapies. Flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) are the cofactor of enzymes and are used as photosensitizers in this study. Targeting hypoxia and light-triggering reactive oxygen species (ROS) are experimental strategies for poisoning tumor cells in vitro. HeLa cells are committed to apoptosis when treated with FMN or FAD and exposed to visible blue light (the maximum emitted wavelength of blue light is 462nm). Under blue light irradiation at 3.744J/cm 2 (=0.52mW/cm 2 irradiated for 2h), the minimal lethal dose is 3.125μM and the median lethal doses (LD 50 ) for FMN and FAD are 6.5μM and 7.2μM, respectively. Individual exposure to visible blue light irradiation or riboflavin photosensitizers does not produce cytotoxicity and no side effects are observed in this study. The western blotting results also show that an intrinsic apoptosis pathway is activated by the ROS during photolysis of riboflavin analogues. Blue light triggers the cytotoxicity of riboflavins on HeLa cells in vitro. Based on these results, this is a feasible and efficient of PDT with an intrinsic photosensitizer for cancer research. Copyright © 2017 Elsevier B.V. All rights reserved.

28 CFR 552.25 - Use of less-than-lethal weapons, including chemical agents.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 28 Judicial Administration 2 2014-07-01 2014-07-01 false Use of less-than-lethal weapons... Use of less-than-lethal weapons, including chemical agents. (a) The Warden may authorize the use of less-than-lethal weapons, including those containing chemical agents, only when the situation is such...

28 CFR 552.25 - Use of less-than-lethal weapons, including chemical agents.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 28 Judicial Administration 2 2012-07-01 2012-07-01 false Use of less-than-lethal weapons... Use of less-than-lethal weapons, including chemical agents. (a) The Warden may authorize the use of less-than-lethal weapons, including those containing chemical agents, only when the situation is such...

28 CFR 552.25 - Use of less-than-lethal weapons, including chemical agents.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 28 Judicial Administration 2 2013-07-01 2013-07-01 false Use of less-than-lethal weapons... Use of less-than-lethal weapons, including chemical agents. (a) The Warden may authorize the use of less-than-lethal weapons, including those containing chemical agents, only when the situation is such...

[Adequate anti-infective treatment : Importance of individual dosing and application].

PubMed

Brinkmann, A; Röhr, A C; Köberer, A; Fuchs, T; Krüger, W A; König, C; Richter, D; Weigand, M A; Frey, O R

2018-05-15

Sepsis-induced changes in pharmacokinetic parameters are a well-known problem in intensive care medicine. Dosing of antibiotics in this setting is therefore challenging. Alterations to the substance-specific kinetics of anti-infective substances have an effect on the distribution and excretion processes in the body. Increased clearance and an increased distribution volume (V d ) and particularly compromized organ function with reduced antibiotic elimination are often encountered in patients with sepsis. Renal replacement treatment, which is frequently used in intensive care medicine, represents a substantial intervention in this system. Current international guidelines recommend individualized dosing strategies and adaptation of doses according to measured serum levels and pharmacokinetic/pharmacodynamic (PK/PD) parameters as concepts to optimize anti-infective therapy in the critically ill. Likewise, the recommendation to adjust the administration form of beat-lactam antibiotics to prolonged or continuous infusion can be found increasingly more often in the literature. This article reviews the background of the individual dosing in intensive care patients and their applicability to the clinical routine.

Effect of lethality on the extinction and on the error threshold of quasispecies.

PubMed

Tejero, Hector; Marín, Arturo; Montero, Francisco

2010-02-21

In this paper the effect of lethality on error threshold and extinction has been studied in a population of error-prone self-replicating molecules. For given lethality and a simple fitness landscape, three dynamic regimes can be obtained: quasispecies, error catastrophe, and extinction. Using a simple model in which molecules are classified as master, lethal and non-lethal mutants, it is possible to obtain the mutation rates of the transitions between the three regimes analytically. The numerical resolution of the extended model, in which molecules are classified depending on their Hamming distance to the master sequence, confirms the results obtained in the simple model and shows how an error catastrophe regime changes when lethality is taken in account. (c) 2009 Elsevier Ltd. All rights reserved.

The population genetics of human disease: The case of recessive, lethal mutations

PubMed Central

Gao, Ziyue; Baker, Zachary; Diesel, José Francisco; Simons, Yuval B.; Haque, Imran S.; Pickrell, Joseph; Przeworski, Molly

2017-01-01

Do the frequencies of disease mutations in human populations reflect a simple balance between mutation and purifying selection? What other factors shape the prevalence of disease mutations? To begin to answer these questions, we focused on one of the simplest cases: recessive mutations that alone cause lethal diseases or complete sterility. To this end, we generated a hand-curated set of 417 Mendelian mutations in 32 genes reported to cause a recessive, lethal Mendelian disease. We then considered analytic models of mutation-selection balance in infinite and finite populations of constant sizes and simulations of purifying selection in a more realistic demographic setting, and tested how well these models fit allele frequencies estimated from 33,370 individuals of European ancestry. In doing so, we distinguished between CpG transitions, which occur at a substantially elevated rate, and three other mutation types. Intriguingly, the observed frequency for CpG transitions is slightly higher than expectation but close, whereas the frequencies observed for the three other mutation types are an order of magnitude higher than expected, with a bigger deviation from expectation seen for less mutable types. This discrepancy is even larger when subtle fitness effects in heterozygotes or lethal compound heterozygotes are taken into account. In principle, higher than expected frequencies of disease mutations could be due to widespread errors in reporting causal variants, compensation by other mutations, or balancing selection. It is unclear why these factors would have a greater impact on disease mutations that occur at lower rates, however. We argue instead that the unexpectedly high frequency of disease mutations and the relationship to the mutation rate likely reflect an ascertainment bias: of all the mutations that cause recessive lethal diseases, those that by chance have reached higher frequencies are more likely to have been identified and thus to have been included in

[Clinical application of iodine 123 with special consideration of radionuclide purity, measuring accuracy and radiation dose(author's dose)].

PubMed

Hermann, H J; Ammon, J; Winkel, K z; Haubold, U

1975-05-01

Iodine 123 is a nearly "ideal" radionuclide for thyroid imaging. The production of Iodine 123 requires cyclotrons or accelerators. The production of multicurie amounts of Iodine 123 has been suggested through the use of high-energy accelerators (less than 60 MeV). Most of the methods for the production of Iodine 123 using a compact cyclotron result in contamination with f.e. Iodine 124 which reduces the spatial resolution af imagining procedures and increases the radiation dose to the patient. The radiation dose has been calculated for three methods of production. The various contamination with Iodine 124, Iodine 125, and Iodine 126 result in comparable radiation dose of Iodine 131, provided that the time between production and application is more than four half-live-times of Iodine 123.

Lethality of firearms relative to other suicide methods: a population based study.

PubMed

Shenassa, E D; Catlin, S N; Buka, S L

2003-02-01

(1) To quantify lethality of firearms relative to other suicide methods, (2) to quantify the extent to which suicide mortality may be reduced by limiting access to firearms. Data on suicides and hospitalised para-suicides that occurred in the state of Illinois from 1990 to 1997 were combined. Total number of episodes for each suicide method was estimated as the sum of the number of suicides and the number of para-suicides for that method. Gender and suicide method were used as proxies for intention to die, and estimated lethality of suicide methods within method-gender groups (for example, male firearm users). Logistic regression was used to quantify the lethality of firearms relative to other suicide methods. Excess mortality associated with the use of firearms was estimated by conservatively assuming that in the absence of firearms the next most lethal suicide method would be used. From January 1990 to December 1997, among individuals 10 years or older in the state of Illinois, there were 37,352 hospital admissions for para-suicide and 10,287 completed suicides. Firearms are the most lethal suicide method. Episodes involving firearms are 2.6 times (95% CI 2.1 to 3.1) more lethal than those involving suffocation-the second most lethal suicide method. Preventing access to firearms can reduce the proportion of fatal firearms related suicides by 32% among minors, and 6.5% among adults. Limiting access to firearms is a potentially effective means of reducing suicide mortality.

Suicide Intent and Accurate Expectations of Lethality: Predictors of Medical Lethality of Suicide Attempts

ERIC Educational Resources Information Center

Brown, Gregory K.; Henriques, Gregg R.; Sosdjan, Daniella; Beck, Aaron T.

2004-01-01

The degree of intent to commit suicide and the severity of self-injury were examined in individuals (N = 180) who had recently attempted suicide. Although a minimal association was found between the degree of suicide intent and the degree of lethality of the attempt, the accuracy of expectations about the likelihood of dying was found to moderate…

Preliminary assessment of the relative toxicity of 1,5-diazido-3-nitrazapentane 90-day dermal application male and female rabbits study number 75-51-y809-90, May 1990 - June 1992. Phase 2. Final report, May 1990-June 1992

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

Haight, E.A.; Harvey, J.G.; Beall, P.

1992-06-01

A 90-day application of DANPE has the potential to cause testicular hypospermatogenesis in male rabbits and an apparent inhibition of mature ovarian follicles formation in female rabbits. A no-observed-adverse-effect-level was not achieved in the male rabbits but was achieved in female rabbits at 27.3 mg/kg dose level.... 1,5-Diazido-3-Nitrazapentane, Dermal, Approximate Lethal Dose (ALD), Testicular hypospermatogenesis, Ovarian follicle No-observed-adverse-effect-level (NOAEL).

Conflict Without Casualties: Non-Lethal Weapons in Irregular Warfare

DTIC Science & Technology

2007-09-01

the body,” and the Geneva Protocol of 1925, bans the use of chemical and biological weapons .11 On 8 April 1975, President Ford issued Executive...E Funding – PE 63851M) (accessed 15 December 2006). The American Journal of Bioethics . “Medical Ethics and Non-Lethal Weapons .” Bioethics.net...CASUALTIES: NON-LETHAL WEAPONS IN IRREGULAR WARFARE by Richard L. Scott September 2007 Thesis Advisor: Robert McNab Second Reader

Testicular trauma secondary to less-lethal kinetic energy munitions.

PubMed

Kavoussi, Parviz K; Hermans, Michael R

2006-06-01

Many cases of testicular trauma secondary to munitions have been reported. We report a case of a 37-year-old man who suffered testicular trauma as a result of a less-lethal munition projectile. With the advent, and increased use, of less-lethal munitions by the military and law enforcement agencies, more of these new subsets of genitourinary trauma patients who will require care are sure to result.

Dosimetric impact of applicator displacement during high dose rate (HDR) Cobalt-60 brachytherapy for cervical cancer: A planning study

NASA Astrophysics Data System (ADS)

Yong, J. S.; Ung, N. M.; Jamalludin, Z.; Malik, R. A.; Wong, J. H. D.; Liew, Y. M.; Ng, K. H.

2016-02-01

We investigated the dosimetric impact of applicator displacement on dose specification during high dose rate (HDR) Cobalt-60 (Co-60) brachytherapy for cervical cancer through a planning study. Eighteen randomly selected HDR full insertion plans were restrospectively studied. The tandem and ovoids were virtually shifted translationally and rotationally in the x-, y- and z-axis directions on the treatment planning system. Doses to reference points and volumes of interest in the plans with shifted applicators were compared with the original plans. The impact of dose displacement on 2D (point-based) and 3D (volume-based) treatment planning techniques was also assessed. A ±2 mm translational y-axis applicator shift and ±4° rotational x-axis applicator shift resulted in dosimetric changes of more than 5% to organs at risk (OAR) reference points. Changes to the maximum doses to 2 cc of the organ (D2cc) in 3D planning were statistically significant and higher than the reference points in 2D planning for both the rectum and bladder (p<0.05). Rectal D2cc was observed to be the most sensitive to applicator displacement among all dose metrics. Applicator displacement that is greater than ±2 mm translational y-axis and ±4° rotational x-axis resulted in significant dose changes to the OAR. Thus, steps must be taken to minimize the possibility of applicator displacement during brachytherapy.

Impact of acute alcohol consumption on lethality of suicide methods.

PubMed

Park, C Hyung Keun; Yoo, Seong Ho; Lee, Jaewon; Cho, Sung Joon; Shin, Min-Sup; Kim, Eun Young; Kim, Se Hyun; Ham, Keunsoo; Ahn, Yong Min

2017-05-01

The influence of acute alcohol consumption on the factors related to suicide remains understudied. Thus, the present study investigated the relationship between blood alcohol content (BAC) and the lethality of suicide methods. Autopsy data on 315 South Korean suicide completers with a positive BAC were collected from a nationwide pool between May 2015 and November 2015, and the methods were dichotomised as suicide methods of low lethality (SMLL; drug/chemical overdose and sharp objects, n=67) and suicide methods of high lethality (SMHL; everything else, n=243). BAC at the time of autopsy and various suicide-related factors of these two groups were compared with logistic regression analyses. Compared to suicide completers with a BAC in the lowest range of 0.011-0.049%, suicide completers with a BAC in the range of 0.150-0.199% were more likely to use SMHL (odds ratio [OR]: 3.644, 95% confidence interval [CI]: 1.221-10.874). Additionally, the adoption of SMHL was significantly associated with the absence of a psychiatric illness (OR: 0.433, 95% CI: 0.222-0.843) and a younger age; the OR for high BAC among subjects in their 40s was 0.266 (95% CI: 0.083-0.856); in their 50s, 0.183 (95% CI: 0.055-0.615); and in their 60s, 0.057 (95% CI: 0.015-0.216). The relationship between BAC and suicide method lethality was represented by a bell-shaped pattern in which suicide methods of high lethality were more likely to be used by suicide completers with mid-range BAC levels. The increased impulsivity and impairments in particular executive functions, including planning and organization, associated with acute alcohol use may influence the selection of a particular suicide method based on its lethality. Copyright © 2017 Elsevier Inc. All rights reserved.

High dose rate brachytherapy with customized applicators for malignant facial skin lesions.

PubMed

Jumeau, R; Renard-Oldrini, S; Courrech, F; Buchheit, I; Oldrini, G; Vogin, G; Peiffert, D

2016-07-01

Brachytherapy is a well-known treatment in the management of skin tumors. For facial or scalp lesions, applicators have been developed to deliver non-invasive treatment. We present cases treated with customized applicators with high dose rate system. Patients with poor performance status treated for malignant skin lesions of the scalp or the facial skin between 2011 and 2014 were studied. Afterloading devices were chosen between Freiburg(®) Flap, silicone-mold or wax applicators. The clinical target volume (CTV) was created by adding margins to lesions (10mm to 20mm). The dose schedules were 25Gy in five fractions for postoperative lesions, 30Gy in six fractions for exclusive treatments and a single session of 8Gy could be considered for palliative treatments. In 30 months, 11 patients received a treatment for a total of 12 lesions. The median age was 80 years. The median follow-up was 17 months and the 2-year local control rate was 91%. The mean CTV surface was 41.1cm(2) with a mean thickness of 6.1mm. We conceived three wax applicators, used our silicone-mold eight times and the Freiburg(®) Flap one time. We observed only low-grade radiodermitis (grade I: 50%, grade II: 33%), and no high-grade skin toxicity. High dose rate brachytherapy with customized applicators for facial skin and scalp lesions is efficient and safe. It is a good modality to treat complex lesions in patients unfit for invasive treatment. Copyright © 2016 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

Brachytherapy Application With In Situ Dose Painting Administered by Gold Nanoparticle Eluters

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

Sinha, Neeharika; Cifter, Gizem; Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts

Purpose: Recent studies show promise that administering gold nanoparticles (GNP) to tumor cells during brachytherapy could significantly enhance radiation damage to the tumor. A new strategy proposed for sustained administration of the GNP in prostate tumors is to load them into routinely used brachytherapy spacers for customizable in situ release after implantation. This in silico study investigated the intratumor biodistribution and corresponding dose enhancement over time due to GNP released from such GNP-loaded brachytherapy spacers (GBS). Method and Materials: An experimentally determined intratumoral diffusion coefficient (D) for 10-nm nanoparticles was used to estimate D for other sizes by using themore » Stokes-Einstein equation. GNP concentration profiles, obtained using D, were then used to calculate the corresponding dose enhancement factor (DEF) for each tumor voxel, using dose painting-by-numbers approach, for times relevant to the considered brachytherapy sources' lifetimes. The investigation was carried out as a function of GNP size for the clinically applicable low-dose-rate brachytherapy sources iodine-125 (I-125), palladium-103 (Pd-103), and cesium-131 (Cs-131). Results: Results showed that dose enhancement to tumor voxels and subvolumes during brachytherapy can be customized by varying the size of GNP released or eluted from the GBS. For example, using a concentration of 7 mg/g GNP, significant DEF (>20%) could be achieved 5 mm from a GBS after 5, 12, 25, 46, 72, 120, and 195 days, respectively, for GNP sizes of 2, 5, 10, 20, 30, and 50 nm and for 80 nm when treating with I-125. Conclusions: Analyses showed that using Cs-131 provides the highest dose enhancement to tumor voxels. However, given its relatively longer half-life, I-125 presents the most flexibility for customizing the dose enhancement as a function of GNP size. These findings provide a useful reference for further work toward development of potential new brachytherapy

Sticky foam as a less-than-lethal technology

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

Scott, S.H.

1996-12-31

Sandia National Labs (SNL) in 1994 completed a project funded by the National Institute of Justice (NIJ) to determine the applicability of sticky foam for correctional applications. Sticky foam is an extremely tacky, tenacious material used to block, entangle, and impair individuals. The NIJ project developed a gun capable of firing multiple shots of sticky foam, tested the gun and sticky foam effectiveness on SNL volunteers acting out prison and law enforcement scenarios, and had the gun and sticky foam evaluated by correctional representatives. Based on the NIJ project work, SNL supported the Marine Corps Mission, Operation United Shield, withmore » sticky foam guns and supporting equipment to assist in the withdrawal of UN Peacekeepers from Somalia. Prior to the loan of the equipment, the Marines were given training in sticky foam characterization, toxicology, safety issues, cleanup and waste disposal, use limitations, use protocol and precautions, emergency facial clean-up, skin cleanup, gun filling, targeting and firing, and gun cleaning. The Marine Corps successfully used the sticky foam guns as part of that operation. This paper describes these recent developments of sticky foam for non-lethal uses and some of the lessons learned from scenario and application testing.« less

O-chromosome lethal frequencies in Serbian and Montenegrin Drosophila subobscura populations.

PubMed

Zivanovic, G; Arenas, C; Mestres, F

2011-10-01

Lethal chromosomal frequencies were obtained from three Drosophila subobscura samples from the Mt. Avala (Serbia) population in September 2003 (0.218), June 2004 (0.204) and September 2004 (0.250). These values and those from other Balkan populations studied previously (Petnica, Kamariste, Zanjic and Djerdap) were used to analyze the possible effect of population, year, month and altitude above sea level on lethal chromosomal frequencies. According to ANOVAS no effect were observed. Furthermore, the lethal frequencies of the Balkan populations did not vary according to latitude. This is probably due to the relative proximity and high gene flow between these populations. From a joint study of all the Palearctic D. subobscura populations so far analyzed, it can be deduced that the Balkan populations are located in the central area of the species distribution. Finally, it seems that lethal chromosomal frequencies are a consequence of the genetic structure of the populations.

Effective lethal mutagenesis of influenza virus by three nucleoside analogs.

PubMed

Pauly, Matthew D; Lauring, Adam S

2015-04-01

Lethal mutagenesis is a broad-spectrum antiviral strategy that exploits the high mutation rate and low mutational tolerance of many RNA viruses. This approach uses mutagenic drugs to increase viral mutation rates and burden viral populations with mutations that reduce the number of infectious progeny. We investigated the effectiveness of lethal mutagenesis as a strategy against influenza virus using three nucleoside analogs, ribavirin, 5-azacytidine, and 5-fluorouracil. All three drugs were active against a panel of seasonal H3N2 and laboratory-adapted H1N1 strains. We found that each drug increased the frequency of mutations in influenza virus populations and decreased the virus' specific infectivity, indicating a mutagenic mode of action. We were able to drive viral populations to extinction by passaging influenza virus in the presence of each drug, indicating that complete lethal mutagenesis of influenza virus populations can be achieved when a sufficient mutational burden is applied. Population-wide resistance to these mutagenic agents did not arise after serial passage of influenza virus populations in sublethal concentrations of drug. Sequencing of these drug-passaged viral populations revealed genome-wide accumulation of mutations at low frequency. The replicative capacity of drug-passaged populations was reduced at higher multiplicities of infection, suggesting the presence of defective interfering particles and a possible barrier to the evolution of resistance. Together, our data suggest that lethal mutagenesis may be a particularly effective therapeutic approach with a high genetic barrier to resistance for influenza virus. Influenza virus is an RNA virus that causes significant morbidity and mortality during annual epidemics. Novel therapies for RNA viruses are needed due to the ease with which these viruses evolve resistance to existing therapeutics. Lethal mutagenesis is a broad-spectrum strategy that exploits the high mutation rate and the low

Heterochromatin position effects on circularized sex chromosomes cause filicidal embryonic lethality in Drosophila melanogaster.

PubMed

Ferree, Patrick M; Gomez, Karina; Rominger, Peter; Howard, Dagnie; Kornfeld, Hannah; Barbash, Daniel A

2014-04-01

Some circularized X-Y chromosomes in Drosophila melanogaster are mitotically unstable and induce early embryonic lethality, but the genetic basis is unknown. Our experiments suggest that a large region of X-linked satellite DNA causes anaphase bridges and lethality when placed into a new heterochromatic environment within certain circularized X-Y chromosomes. These results reveal that repetitive sequences can be incompatible with one another in cis. The lethal phenotype also bears a remarkable resemblance to a case of interspecific hybrid lethality.

Non-Lethal Endotoxin Injection: A Rat Model of Hypercoagulability.

PubMed

Brooks, Marjory B; Turk, James R; Guerrero, Abraham; Narayanan, Padma K; Nolan, John P; Besteman, Elizabeth G; Wilson, Dennis W; Thomas, Roberta A; Fishman, Cindy E; Thompson, Karol L; Ellinger-Ziegelbauer, Heidrun; Pierson, Jennifer B; Paulman, April; Chiang, Alan Y; Schultze, Albert E

2017-01-01

Systemic inflammation co-activates coagulation, which unchecked culminates in a lethal syndrome of multi-organ microvascular thrombosis known as disseminated intravascular coagulation (DIC). We studied an endotoxin-induced inflammatory state in rats to identify biomarkers of hemostatic imbalance favoring hypercoagulability. Intraperitoneal injection of LPS at 15 mg/kg body weight resulted in peripheral leukopenia and widespread neutrophilic sequestration characteristic of an acute systemic inflammatory response. Early indicators of hemostatic pathway activation developed within 4 hours, including increased circulating concentrations of procoagulant extracellular vesicles (EVs), EVs expressing endothelial cell and platelet membrane markers, and high concentration of soluble intercellular adhesion molecule-1 (sICAM-1), plasminogen activator inhibitor-1 (PAI-1), and D-dimers. Inflammation persisted throughout the 48-hour observation period; however, increases were found in a subset of serum microRNA (miRNA) that coincided with gradual resolution of hemostatic protein abnormalities and reduction in EV counts. Dose-adjusted LPS treatment in rats provides a time-course model to develop biomarker profiles reflecting procoagulant imbalance and rebalance under inflammatory conditions.

Application of TXRF for ion implanter dose matching experiments

NASA Astrophysics Data System (ADS)

Frost, M. R.; French, M.; Harris, W.

2004-06-01

Secondary ion mass spectrometry (SIMS) has been utilized for many years to measure the dose of ion implants in silicon for the purpose of verifying the ability of ion implantation equipment to accurately and reproducibly implant the desired species at the target dose. The development of statistically and instrumentally rigorous protocols has lead to high confidence levels, particularly with regard to accuracy and short-term repeatability. For example, high-dose, high-energy B implant dosimetry can be targeted to within ±1%. However, performing dose determination experiments using SIMS does have undesirable aspects, such as being highly labor intensive and sample destructive. Modern total reflection X-ray fluorescence (TXRF) instruments are equipped with capabilities for full 300 mm wafer handling, automated data acquisition software and intense X-ray sources. These attributes enable the technique to overcome the SIMS disadvantages listed above, as well as provide unique strengths that make it potentially highly amenable to implanter dose matching. In this paper, we report on data collected to date that provides confidence that TXRF is an effective and economical method to perform these measurements within certain limitations. We have investigated a number of ion implanted species that are within the "envelope" of TXRF application. This envelope is defined by a few important parameters. Species: For the anode materials used in the more common X-ray sources on the market, each has its own set of elements that can be detected. We have investigated W and Mo X-ray sources, which are the most common in use in commercial instrumentation. Implant energy: In general, if the energy of the implanted species is too high (or more specifically, the distribution of the implanted species is too deep), the amount of dopant not detected by TXRF may be significant, increasing the error of the measurement. Therefore, for each species investigated, the implant energy cannot exceed a

Low doses of a neonicotinoid insecticide modify pheromone response thresholds of central but not peripheral olfactory neurons in a pest insect

PubMed Central

Rabhi, Kaouther K.; Deisig, Nina; Demondion, Elodie; Le Corre, Julie; Robert, Guillaume; Tricoire-Leignel, Hélène; Lucas, Philippe; Gadenne, Christophe; Anton, Sylvia

2016-01-01

Insect pest management relies mainly on neurotoxic insecticides, including neonicotinoids, leaving residues in the environment. There is now evidence that low doses of insecticides can have positive effects on pest insects by enhancing various life traits. Because pest insects often rely on sex pheromones for reproduction, and olfactory synaptic transmission is cholinergic, neonicotinoid residues could modify chemical communication. We recently showed that treatments with different sublethal doses of clothianidin could either enhance or decrease behavioural sex pheromone responses in the male moth, Agrotis ipsilon. We investigated now effects of the behaviourally active clothianidin doses on the sensitivity of the peripheral and central olfactory system. We show with extracellular recordings that both tested clothianidin doses do not influence pheromone responses in olfactory receptor neurons. Similarly, in vivo optical imaging does not reveal any changes in glomerular response intensities to the sex pheromone after clothianidin treatments. The sensitivity of intracellularly recorded antennal lobe output neurons, however, is upregulated by a lethal dose 20 times and downregulated by a dose 10 times lower than the lethal dose 0. This correlates with the changes of behavioural responses after clothianidin treatment and suggests the antennal lobe as neural substrate involved in clothianidin-induced behavioural changes. PMID:26842577

Defeat mutant KRAS with synthetic lethality

PubMed Central

Pang, Xiufeng; Liu, Mingyao

2017-01-01

ABSTRACT Ras proteins are considered as the founding members of a large superfamily of small GTPases that control fundamental cellular functions. Mutationally activated RAS genes were discovered in human cancer cells more than 3 decades ago, but intensive efforts on Ras structure, biochemistry, function and signaling continue even now. Because mutant Ras proteins are inherently difficult to inhibit and have yet been therapeutically conquered, it was designated as “the Everest of oncogenes” in the cancer genome landscape, further promoting a “renaissance” in RAS research. Different paths to directly or indirectly targeting mutant Ras signaling are currently under investigation in the hope of finding an efficacious regimen. Inhibitors directly binding to KRASG12C to block its downstream signaling have been revealed, supporting the notion of Ras' druggability. An alternative indirect approach by targeting synthetic lethal interactors of mutant RAS is underway. We recently employed a synthetic lethal drug screen plus a combinatorial strategy using a panel of clinical agents and discovered that KRAS-mutant cancers were fragile to the combined inhibition of polo-like kinase 1 (Plk1) and RhoA/Rho kinase (ROCK). The combined regimen of BI-2536 (a Plk1 inhibitor) and fasudil (a ROCK inhibitor) promoted a significant inhibition of patient-derived lung cancer xenografts and prolonged the survival of LSL-KRASG12D mice. In this commentary, we will summarize the state-of-the art for the direction of synthetic lethality, and also speculate on the future development of this approach. PMID:27463838

A Multivariate Model of Stakeholder Preference for Lethal Cat Management

PubMed Central

Wald, Dara M.; Jacobson, Susan K.

2014-01-01

Identifying stakeholder beliefs and attitudes is critical for resolving management conflicts. Debate over outdoor cat management is often described as a conflict between two groups, environmental advocates and animal welfare advocates, but little is known about the variables predicting differences among these critical stakeholder groups. We administered a mail survey to randomly selected stakeholders representing both of these groups (n = 1,596) in Florida, where contention over the management of outdoor cats has been widespread. We used a structural equation model to evaluate stakeholder intention to support non-lethal management. The cognitive hierarchy model predicted that values influenced beliefs, which predicted general and specific attitudes, which in turn, influenced behavioral intentions. We posited that specific attitudes would mediate the effect of general attitudes, beliefs, and values on management support. Model fit statistics suggested that the final model fit the data well (CFI = 0.94, RMSEA = 0.062). The final model explained 74% of the variance in management support, and positive attitudes toward lethal management (humaneness) had the largest direct effect on management support. Specific attitudes toward lethal management and general attitudes toward outdoor cats mediated the relationship between positive (p<0.05) and negative cat-related impact beliefs (p<0.05) and support for management. These results supported the specificity hypothesis and the use of the cognitive hierarchy to assess stakeholder intention to support non-lethal cat management. Our findings suggest that stakeholders can simultaneously perceive both positive and negative beliefs about outdoor cats, which influence attitudes toward and support for non-lethal management. PMID:24736744

A multivariate model of stakeholder preference for lethal cat management.

PubMed

Wald, Dara M; Jacobson, Susan K

2014-01-01

Identifying stakeholder beliefs and attitudes is critical for resolving management conflicts. Debate over outdoor cat management is often described as a conflict between two groups, environmental advocates and animal welfare advocates, but little is known about the variables predicting differences among these critical stakeholder groups. We administered a mail survey to randomly selected stakeholders representing both of these groups (n=1,596) in Florida, where contention over the management of outdoor cats has been widespread. We used a structural equation model to evaluate stakeholder intention to support non-lethal management. The cognitive hierarchy model predicted that values influenced beliefs, which predicted general and specific attitudes, which in turn, influenced behavioral intentions. We posited that specific attitudes would mediate the effect of general attitudes, beliefs, and values on management support. Model fit statistics suggested that the final model fit the data well (CFI=0.94, RMSEA=0.062). The final model explained 74% of the variance in management support, and positive attitudes toward lethal management (humaneness) had the largest direct effect on management support. Specific attitudes toward lethal management and general attitudes toward outdoor cats mediated the relationship between positive (p<0.05) and negative cat-related impact beliefs (p<0.05) and support for management. These results supported the specificity hypothesis and the use of the cognitive hierarchy to assess stakeholder intention to support non-lethal cat management. Our findings suggest that stakeholders can simultaneously perceive both positive and negative beliefs about outdoor cats, which influence attitudes toward and support for non-lethal management.

Lethal Trap Trees and Semiochemical Repellents as Area Host Protection Strategies for Spruce Beetle (Coleoptera: Curculionidae, Scolytinae) in Utah.

PubMed

Matthew Hansen, E; Steven Munson, A; Blackford, Darren C; Wakarchuk, David; Scott Baggett, L

2016-10-01

We tested lethal trap trees and repellent semiochemicals as area treatments to protect host trees from spruce beetle (Dendroctonus rufipennis Kirby) attacks. Lethal trap tree treatments ("spray treatment") combined a spruce beetle bait with carbaryl treatment of the baited spruce. Repellent treatments ("spray-repellent") combined a baited lethal trap tree within a 16-m grid of MCH (3-methylcyclohex-2-en-1-one) and two novel spruce beetle repellents. After beetle flight, we surveyed all trees within 50 m of plot center, stratified by 10-m radius subplots, and compared attack rates to those from baited and unbaited control plots. Compared to the baited controls, spruce in the spray treatment had significantly reduced likelihood of a more severe attack classification (e.g., mass-attacked over strip-attacked or unsuccessful-attacked over unattacked). Because spruce in the spray treatment also had significantly heightened probability of more severe attack classification than those in the unbaited controls, however, we do not recommend lethal trap trees as a stand-alone beetle suppression strategy for epidemic beetle populations. Spruce in the spray-repellent treatment were slightly more likely to be classified as more severely attacked within 30 m of plot center compared to unbaited controls but, overall, had reduced probabilities of beetle attack over the entire 50-m radius plots. The semiochemical repellents deployed in this study were effective at reducing attacks on spruce within treated plots despite the presence of a centrally located spruce beetle bait. Further testing will be required to clarify operational protocols such as dose, elution rate, and release device spacing. Published by Oxford University Press on behalf of Entomological Society of America 2016. This work is written by US Government employees and is in the public domain in the US.

Sensitivity of seven PCRs for early detection of koi herpesvirus in experimentally infected carp, Cyprinus carpio L., by lethal and non-lethal sampling methods.

PubMed

Monaghan, S J; Thompson, K D; Adams, A; Bergmann, S M

2015-03-01

Koi herpesvirus (KHV) causes an economically important, highly infectious disease in common carp and koi, Cyprinus carpio L. Since the occurrence of mass mortalities worldwide, highly specific and sensitive molecular diagnostic methods have been developed for KHV detection. The sensitivity and reliability of these assays have essentially focused at the detection of low viral DNA copy numbers during latent or persistent infections. However, the efficacy of these assays has not been investigated with regard to low-level viraemia during acute infection stages. This study was conducted to compare the sensitivity of seven different polymerase chain reaction (PCR) assays to detect KHV during the first hours and days post-infection (hpi; dpi), using lethal and non-lethal sampling methods. The results highlight the limitations of the assays for detecting virus during the first 4 dpi despite rapid mortality in experimentally infected carp. False-negative results were associated with time post-infection and the tissue sampled. Non-lethal sampling appears effective for KHV screening, with efficient detection in mucus samples obtained from external swabs during this early infection period (<5 dpi), while biopsies from gills and kidney were negative using the same PCR assays. Non-lethal sampling may improve the reliability of KHV detection in subclinical, acutely infected carp. © 2014 John Wiley & Sons Ltd.

Practical applications of internal dose calculations

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

Carbaugh, E.H.

1994-06-01

Accurate estimates of intake magnitude and internal dose are the goal for any assessment of an actual intake of radioactivity. When only one datum is available on which to base estimates, the choices for internal dose assessment become straight-forward: apply the appropriate retention or excretion function, calculate the intake, and calculate the dose. The difficulty comes when multiple data and different types of data become available. Then practical decisions must be made on how to interpret conflicting data, or how to adjust the assumptions and techniques underlying internal dose assessments to give results consistent with the data. This article describesmore » nine types of adjustments which can be incorporated into calculations of intake and internal dose, and then offers several practical insights to dealing with some real-world internal dose puzzles.« less

Lethal effects of short-wavelength visible light on insects.

PubMed

Hori, Masatoshi; Shibuya, Kazuki; Sato, Mitsunari; Saito, Yoshino

2014-12-09

We investigated the lethal effects of visible light on insects by using light-emitting diodes (LEDs). The toxic effects of ultraviolet (UV) light, particularly shortwave (i.e., UVB and UVC) light, on organisms are well known. However, the effects of irradiation with visible light remain unclear, although shorter wavelengths are known to be more lethal. Irradiation with visible light is not thought to cause mortality in complex animals including insects. Here, however, we found that irradiation with short-wavelength visible (blue) light killed eggs, larvae, pupae, and adults of Drosophila melanogaster. Blue light was also lethal to mosquitoes and flour beetles, but the effective wavelength at which mortality occurred differed among the insect species. Our findings suggest that highly toxic wavelengths of visible light are species-specific in insects, and that shorter wavelengths are not always more toxic. For some animals, such as insects, blue light is more harmful than UV light.

Lethal effects of short-wavelength visible light on insects

NASA Astrophysics Data System (ADS)

Hori, Masatoshi; Shibuya, Kazuki; Sato, Mitsunari; Saito, Yoshino

2014-12-01

We investigated the lethal effects of visible light on insects by using light-emitting diodes (LEDs). The toxic effects of ultraviolet (UV) light, particularly shortwave (i.e., UVB and UVC) light, on organisms are well known. However, the effects of irradiation with visible light remain unclear, although shorter wavelengths are known to be more lethal. Irradiation with visible light is not thought to cause mortality in complex animals including insects. Here, however, we found that irradiation with short-wavelength visible (blue) light killed eggs, larvae, pupae, and adults of Drosophila melanogaster. Blue light was also lethal to mosquitoes and flour beetles, but the effective wavelength at which mortality occurred differed among the insect species. Our findings suggest that highly toxic wavelengths of visible light are species-specific in insects, and that shorter wavelengths are not always more toxic. For some animals, such as insects, blue light is more harmful than UV light.

Skin penetration assessment of less lethal kinetic energy munitions.

PubMed

Bir, Cynthia A; Stewart, Shelby J; Wilhelm, Marianne

2005-11-01

The development of less-lethal technologies has provided law enforcement personnel with an alternative to lethal force. Although the less lethal projectile was produced to engender non-penetrating wounds, case studies show that there have been a number of reported penetrating injuries ranging from minor to significant in morbidity. The objective of this study was to determine the energy per unit area required to penetrate various regions of the body. Eight unembalmed postmortem human specimens were procured for this testing. Each specimen sustained a maximum of 25 impacts consisting of shots to the anterior and posterior thorax, abdomen, and legs. A 12-gauge, fin-stabilized, rubber rocket round was used as the impactor for all of the conducted tests. The energy density required for 50% risk of penetration varied from 23.99 J/cm2 for the location on the anterior rib (p = 0.000) to 52.74 J/cm2 for the location on the posterior rib (p = 0.001).

Phytochemistry, Brine shrimp lethality and mice acute oral toxicity studies on seed extracts of Vernonia anthelmintica.

PubMed

Jamil, Subia; Khan, Rafeeq Alam; Afroz, Syeda; Ahmed, Shadab

2016-11-01

Despite the widespread use of Vernonia anthelmintica seeds in traditional medicine, the need to establish the safety of the Vernonia anthelmintica is required to ascertain the safe use of this herbal medicine. The aim of the present study is to establish the acute toxicity profile of different extracts of Vernonia anthelmintica. Hexane and ethanol extract of Vernonia Anthelmintica has been studied for its brine shrimp lethality potential. Water decoction (WDVA), Hexane (HEVA) and Ethanol (EEVA) extracts of Vernonia anthelmintica has also been evaluated for their in-vivo acute oral toxicity in mice by Lorke's method. Phytochemistry of all three extracts was also evaluated for the presence of their secondary metabolites. All three extracts showed the presence of flavonoids and terpenoids, while alkaloids, tannins and fixed oils were present in HEVA and EEVA. Furthermore EEVA also showed presence of carbohydrates and HEVA also showed the presence of cardiac glycosides. Ethanol and hexane extracts of Vernonia anthelmintica showed a positive cytotoxicity in brine shrimp lethality test at 24 hours with LC50 104.16 (224.0-48.05)μg/ml and 216.11μg/ml (378.2-128.7) respectively as compared to standard drug etoposide LC50 7.46μg/ml. The oral LD50 for EEVA, HEVA and WDVA in mice by Lorke's method was greater than 5000mg/kg. The result of brine shrimp lethality test clearly exhibited the presence of bioactive compounds with cytotoxic potential; however seems to be safe for oral use since LD50 was higher than 5000mg/kg and thus safety of acute dosing in vivo practices is justified.

Sub-lethal exposure of cockroaches to boric acid pesticide contributes to increased Bla g 2 excretion.

PubMed

Zhang, Y C; Perzanowski, M S; Chew, G L

2005-07-01

Several epidemiology studies have found an increase in the major cockroach allergen Bla g 2 with reported pesticide use. Our aim was to investigate the effect on the excretion of Bla g 1 and Bla g 2 allergens by cockroaches exposed to sub-lethal doses of the pesticides, boric acid and hydramethylnon gel. German cockroaches in separate colonies were fed either boric acid or hydramethylnon gel at concentrations of 0.2, 0.1 and 0.01% in their water supply over a 2 week period. Ten colonies were exposed to each treatment concentration. Bla g 1 and Bla g 2 in fecal pellets were measured by ELISA. Cockroaches exposed to boric acid excreted fecal pellets with significantly higher concentrations of Bla g 2 (35,400 U/g) than did controls (12,700 U/g) (P = 0.001). Bla g 1 concentrations were not significantly different. There was no difference in either Bla g 1 or Bla g 2 concentrations between cockroaches that ingested hydramethylnon gel and those in the controls colonies. The application of boric acid, a common pesticide, appears to paradoxically increase the production of Bla g 2, a major allergen, by the surviving cockroaches. This may have important implications in avoidance strategies.

Lethal Dietary Toxicities of Environmental Contaminants and Pesticides to Coturnix

USGS Publications Warehouse

Hill, E.F.; Camardese, M.B.

1986-01-01

Five-day subacute dietary toxicity tests of 193 potential environmental contaminants, pesticides, organic solvents, and various adjuvants are presented for young coturnix (Japanese quail, Coturnix japonica Temminck and Schlegel). The report provides the most comprehensive data base available for avian subacute dietary toxicity tests and is primarily intended for use in ranking toxicities by a standard method that has a reasonable degree of environmental relevance. Findings are presented in two parts: Part I is a critique of selected drugs that includes discussion of subacute toxicity in relation to chemical class and structure, pesticide formulation, and age of animals; Part II is a summary of toxicologic findings for each test substance and provides a statistically basis for comparing toxicities. Data presented include the median lethal concentration (LC50), slope of the probit regression curve (dose-response curve), response chronology, and food consumption. We observed that: 1) fewer than 15% of the compounds were classed 'very' or 'highly' toxic (i.e, LC50 < 200 ppm) and all of these were either chlorinated hydrocarbons, organophosphates, or organometallics; 2) subacute toxicity may vary widely among structurally similar chemicals and between different formulations of the same chemical; therefore, conclusions about lethal hazard must be made cautiously until the actual formulation of inset has been tested: 3) inclusion of a general standard in each battery of tests is useful for detection of atypical trials and monitoring population changes but should not be used indiscriminantly for adjusting LC50's for intertest differences unless the chemicals of concern and the standard elicit their toxicities through the same action; 4) although other species have been tested effectively under the subacute protocol, coturnix were ideal for the stated purpose of this research because they are inexpensive, well-adapted to the laboratory environment, and yield good intertest

Lethal and sublethal effects of seven insecticides on three beneficial insects in laboratory assays and field trials.

PubMed

Fernandes, Maria E S; Alves, Flávia M; Pereira, Renata C; Aquino, Leonardo A; Fernandes, Flávio L; Zanuncio, José C

2016-08-01

Lethal and sublethal effects of insecticides on target and non-target arthropods are a concern of pest management programs. Cycloneda sanguinea, Orius insidiosus and Chauliognathus flavipes are important biological control agents for aphids, whitefly, lepidopterus eggs, thrips and mites. All three test species were subjected to a toxicity study using the insecticides acephate, bifenthrin, chlorantraniliprole, chlorpyrifos, deltamethrin, imidacloprid, and thiamethoxam. Experiments were done in the lab and field. In the laboratory we evaluated the mortality and sublethal effects of the concentration that killed 20% of the population (LC20) on feeding, repellence and reproduction of the species tested. The lethal effects of these insecticides at the recommended doses was evaluated in the field. Concentration-response bioassays indicated chlorantraniliprole had the lowest toxicity, while chlorpyrifos and acephate were the most toxic. Test species exposed to filter paper surfaces treated with pyrethroids, neonicotinoids and organophosphates were repelled. On the other hand, test species were not repelled from surfaces treated with chlorantraniliprole. Chlorantraniliprole therefore seemed to be the least dangerous insecticide for these three beneficial arthropod test species. Copyright © 2016 Elsevier Ltd. All rights reserved.

Rescue of bilirubin-induced neonatal lethality in a mouse model of Crigler-Najjar syndrome type I by AAV9-mediated gene transfer

PubMed Central

Bortolussi, Giulia; Zentilin, Lorena; Baj, Gabriele; Giraudi, Pablo; Bellarosa, Cristina; Giacca, Mauro; Tiribelli, Claudio; Muro, Andrés F.

2012-01-01

Crigler-Najjar type I (CNI) syndrome is a recessively inherited disorder characterized by severe unconjugated hyperbilirubinemia caused by uridine diphosphoglucuronosyltransferase 1A1 (UGT1A1) deficiency. The disease is lethal due to bilirubin-induced neurological damage unless phototherapy is applied from birth. However, treatment becomes less effective during growth, and liver transplantation is required. To investigate the pathophysiology of the disease and therapeutic approaches in mice, we generated a mouse model by introducing a premature stop codon in the UGT1a1 gene, which results in an inactive enzyme. Homozygous mutant mice developed severe jaundice soon after birth and died within 11 d, showing significant cerebellar alterations. To rescue neonatal lethality, newborns were injected with a single dose of adeno-associated viral vector 9 (AAV9) expressing the human UGT1A1. Gene therapy treatment completely rescued all AAV-treated mutant mice, accompanied by lower plasma bilirubin levels and normal brain histology and motor coordination. Our mouse model of CNI reproduces genetic and phenotypic features of the human disease. We have shown, for the first time, the full recovery of the lethal effects of neonatal hyperbilirubinemia. We believe that, besides gene-addition-based therapies, our mice could represent a very useful model to develop and test novel technologies based on gene correction by homologous recombination.—Bortolussi, G., Zentilin, L., Baj, G., Giraudi, P., Bellarosa, C., Giacca, M., Tiribelli, C., Muro, A. F. Rescue of bilirubin-induced neonatal lethality in a mouse model of Crigler-Najjar syndrome type I by AAV9-mediated gene transfer. PMID:22094718

Intraguild relationships between sympatric predators exposed to lethal control: predator manipulation experiments

PubMed Central

2013-01-01

populations of native prey fauna at lower trophic levels are unlikely to be negatively affected by contemporary dingo control practices through the release of mesopredators. We conclude that contemporary lethal control practices used on some top-predator populations do not produce the conditions required to generate positive responses from mesopredators. Functional relationships between sympatric terrestrial predators may not be altered by exposure to spatially and temporally sporadic application of non-selective lethal control. PMID:23842144

Intraguild relationships between sympatric predators exposed to lethal control: predator manipulation experiments.

PubMed

Allen, Benjamin L; Allen, Lee R; Engeman, Richard M; Leung, Luke K-P

2013-07-10

at lower trophic levels are unlikely to be negatively affected by contemporary dingo control practices through the release of mesopredators. We conclude that contemporary lethal control practices used on some top-predator populations do not produce the conditions required to generate positive responses from mesopredators. Functional relationships between sympatric terrestrial predators may not be altered by exposure to spatially and temporally sporadic application of non-selective lethal control.

[Toxicity study of cefmatilen hydrochloride hydrate (S-1090) (1)--Single oral and intravenous dose toxicity studies in rats].

PubMed

Yahara, I; Furukawa, H; Sato, K; Nishimura, K; Harihara, A; Yabuuchi, K; Miyauchi, H; Kii, Y; Muraoka, Y; Kitamura, T; Kato, I

2001-05-01

A single oral dose toxicity study of Cefmatilen hydrochloride hydrate (S-1090) and a single intravenous dose toxicity study of its sodium salt (S-1090-Na) were conducted in rats. One dose level of 2000 mg potency/kg was set in both studies. Single oral dose toxicity study of S-1090 No deaths occurred. Diarrhea occurred on the dosing day and slightly soft feces lasted until 6 days after administration. These changes were considered to result from changes of intestinal flora induced by the antibiotic activity of S-1090. Reddish-brown feces (due to chelated products of S-1090 or its decomposition products with Fe3+ in the diet) were also observed until the next day after administration. Body weights increased favorably, and no S-1090-related pathological changes were observed. The oral lethal dose of S-1090 was estimated to be more than 2000 mg potency/kg. Single intravenous dose toxicity study of S-1090-Na No deaths occurred. The rats showed characteristic clinical signs such as hypoactivity, abnormal gait and hypopnea immediately after dosing, and some rats showed prone position or paleness of eyeballs and ear auricles in due course. These signs disappeared by 4 hr after administration. Slightly soft feces and reddish-brown feces were observed much the same as in the orally-treated rats. Body weights increased favorably. In the pathological examinations, slight cecal enlargement and increased basophilia, dilatation and calcification of the renal tubules in the kidney were observed. The intravenous lethal dose of S-1090-Na was estimated to be more than 2000 mg potency/kg.

Application of the ELDO approach to assess cumulative eye lens doses for interventional cardiologists.

PubMed

Farah, J; Struelens, L; Auvinen, A; Jacob, S; Koukorava, C; Schnelzer, M; Vanhavere, F; Clairand, I

2015-04-01

In preparation of a large European epidemiological study on the relation between eye lens dose and the occurrence of lens opacities, the European ELDO project focused on the development of practical methods to estimate retrospectively cumulative eye lens dose for interventional medical professionals exposed to radiation. The present paper applies one of the ELDO approaches, correlating eye lens dose to whole-body doses, to assess cumulative eye lens dose for 14 different Finnish interventional cardiologists for whom annual whole-body dose records were available for their entire working period. The estimated cumulative left and right eye lens dose ranged from 8 to 264 mSv and 6 to 225 mSv, respectively. In addition, calculations showed annual eye lens doses sometimes exceeding the new ICRP annual limit of 20 mSv. The work also highlights the large uncertainties associated with the application of such an approach proving the need for dedicated dosimetry systems in the routine monitoring of the eye lens dose. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

TU-AB-207A-03: Image Quality, Dose, and Clinical Applications

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

Dong, F.

Practicing medical physicists are often time charged with the tasks of evaluating and troubleshooting complex image quality issues related to CT scanners. This course will equip them with a solid and practical understanding of common CT imaging chain and its major components with emphasis on acquisition physics and hardware, reconstruction, artifacts, image quality, dose, and advanced clinical applications. The core objective is to explain the effects of these major system components on the image quality. This course will not focus on the rapid-changing advanced technologies given the two-hour time limit, but the fundamental principles discussed in this course may facilitatemore » better understanding of those more complicated technologies. The course will begin with an overview of CT acquisition physics and geometry. X-ray tube and CT detector are important acquisition hardware critical to the overall image quality. Each of these two subsystems consists of several major components. An in-depth description of the function and failure modes of these components will be provided. Examples of artifacts related to these failure modes will be presented: off-focal radiation, tube arcing, heel effect, oil bubble, offset drift effect, cross-talk effect, and bad pixels. The fundamentals of CT image reconstruction will first be discussed on an intuitive level. Approaches that do not require rigorous derivation of mathematical formulations will be presented. This is followed by a detailed derivation of the Fourier slice theorem: the foundation of the FBP algorithm. FBP for parallel-beam, fan-beam, and cone-beam geometries will be discussed. To address the issue of radiation dose related to x-ray CT, recent advances in iterative reconstruction, their advantages, and clinical applications will also be described. Because of the nature of fundamental physics and mathematics, limitations in data acquisition, and non-ideal conditions of major system components, image artifact

Deadly Lessons: Understanding Lethal School Violence.

ERIC Educational Resources Information Center

Moore, Mark H., Ed.; Petrie, Carol V., Ed.; Braga, Anthony A., Ed.; McLaughlin, Brenda L., Ed.

This collection of papers is the outcome of the National Academies' effort to glean information from six different case studies of student-perpetrated school shootings. Part 1, "Case Studies of Lethal School Violence," includes: "The Copycat Factor: Mental Illness, Guns, and the Shooting Incident at Heritage High School, Rockdale…

Theoretical models and simulation codes to investigate bystander effects and cellular communication at low doses

NASA Astrophysics Data System (ADS)

Ballarini, F.; Alloni, D.; Facoetti, A.; Mairani, A.; Nano, R.; Ottolenghi, A.

Astronauts in space are continuously exposed to low doses of ionizing radiation from Galactic Cosmic Rays During the last ten years the effects of low radiation doses have been widely re-discussed following a large number of observations on the so-called non targeted effects in particular bystander effects The latter consist of induction of cytogenetic damage in cells not directly traversed by radiation most likely as a response to molecular messengers released by directly irradiated cells Bystander effects which are observed both for lethal endpoints e g clonogenic inactivation and apoptosis and for non-lethal ones e g mutations and neoplastic transformation tend to show non-linear dose responses This might have significant consequences in terms of low-dose risk which is generally calculated on the basis of the Linear No Threshold hypothesis Although the mechanisms underlying bystander effects are still largely unknown it is now clear that two types of cellular communication i e via gap junctions and or release of molecular messengers into the extracellular environment play a fundamental role Theoretical models and simulation codes can be of help in elucidating such mechanisms In the present paper we will review different available modelling approaches including one that is being developed at the University of Pavia The focus will be on the different assumptions adopted by the various authors and on the implications of such assumptions in terms of non-targeted radiobiological damage and more generally low-dose

Resveratrol Antagonizes Antimicrobial Lethality and Stimulates Recovery of Bacterial Mutants

PubMed Central

Liu, Yuanli; Zhou, Jinan; Qu, Yilin; Yang, Xinguang; Shi, Guojing; Wang, Xiuhong; Hong, Yuzhi; Drlica, Karl; Zhao, Xilin

2016-01-01

Reactive oxygen species (ROS; superoxide, peroxide, and hydroxyl radical) are thought to contribute to the rapid bactericidal activity of diverse antimicrobial agents. The possibility has been raised that consumption of antioxidants in food may interfere with the lethal action of antimicrobials. Whether nutritional supplements containing antioxidant activity are also likely to interfere with antimicrobial lethality is unknown. To examine this possibility, resveratrol, a popular antioxidant dietary supplement, was added to cultures of Escherichia coli and Staphylococcus aureus that were then treated with antimicrobial and assayed for bacterial survival and the recovery of mutants resistant to an unrelated antimicrobial, rifampicin. Resveratrol, at concentrations likely to be present during human consumption, caused a 2- to 3-fold reduction in killing during a 2-hr treatment with moxifloxacin or kanamycin. At higher, but still subinhibitory concentrations, resveratrol reduced antimicrobial lethality by more than 3 orders of magnitude. Resveratrol also reduced the increase in reactive oxygen species (ROS) characteristic of treatment with quinolone (oxolinic acid). These data support the general idea that the lethal activity of some antimicrobials involves ROS. Surprisingly, subinhibitory concentrations of resveratrol promoted (2- to 6-fold) the recovery of rifampicin-resistant mutants arising from the action of ciprofloxacin, kanamycin, or daptomycin. This result is consistent with resveratrol reducing ROS to sublethal levels that are still mutagenic, while the absence of resveratrol allows ROS levels to high enough to kill mutagenized cells. Suppression of antimicrobial lethality and promotion of mutant recovery by resveratrol suggests that the antioxidant may contribute to the emergence of resistance to several antimicrobials, especially if new derivatives and/or formulations of resveratrol markedly increase bioavailability. PMID:27045517

Lethal and sub-lethal effects of elevated CO2 concentrations on marine benthic invertebrates and fish.

PubMed

Lee, Changkeun; Hong, Seongjin; Kwon, Bong-Oh; Lee, Jung-Ho; Ryu, Jongseong; Park, Young-Gyu; Kang, Seong-Gil; Khim, Jong Seong

2016-08-01

Concern about leakage of carbon dioxide (CO2) from deep-sea storage in geological reservoirs is increasing because of its possible adverse effects on marine organisms locally or at nearby coastal areas both in sediment and water column. In the present study, we examined how elevated CO2 affects various intertidal epibenthic (benthic copepod), intertidal endobenthic (Manila clam and Venus clam), sub-tidal benthic (brittle starfish), and free-living (marine medaka) organisms in areas expected to be impacted by leakage. Acute lethal and sub-lethal effects were detected in the adult stage of all test organisms exposed to varying concentrations of CO2, due to the associated decline in pH (8.3 to 5.2) during 96-h exposure. However, intertidal organisms (such as benthic copepods and clams) showed remarkable resistance to elevated CO2, with the Venus clam being the most tolerant (LpH50 = 5.45). Sub-tidal species (such as brittle starfish [LpH50 = 6.16] and marine medaka [LpH50 = 5.91]) were more sensitive to elevated CO2 compared to intertidal species, possibly because they have fewer defensive capabilities. Of note, the exposure duration might regulate the degree of acute sub-lethal effects, as evidenced by the Venus clam, which showed a time-dependent effect to elevated CO2. Finally, copper was chosen as a model toxic element to find out the synergistic or antagonistic effects between ocean acidification and metal pollution. Combination of CO2 and Cu exposure enhances the adverse effects to organisms, generally supporting a synergistic effect scenario. Overall, the significant variation in the degree to which CO2 adversely affected organisms (viz., working range and strength) was clearly observed, supporting the general concept of species-dependent effects of elevated CO2.

Multi-locus phylogeny of lethal amanitas: Implications for species diversity and historical biogeography

PubMed Central

2014-01-01

Background Lethal amanitas (Amanita section Phalloideae) are a group of wild, fatal mushrooms causing many poisoning cases worldwide. However, the diversity and evolutionary history of these lethal mushrooms remain poorly known due to the limited sampling and insufficient gene fragments employed for phylogenetic analyses. In this study, five gene loci (nrLSU, ITS, rpb2, ef1-α and β-tubulin) with a widely geographic sampling from East and South Asia, Europe, North and Central America, South Africa and Australia were analysed with maximum-likelihood, maximum-parsimony and Bayesian inference methods. Biochemical analyses were also conducted with intention to detect amatoxins and phalloidin in 14 representative samples. Result Lethal amanitas were robustly supported to be a monophyletic group after excluding five species that were provisionally defined as lethal amanitas based on morphological studies. In lethal amanitas, 28 phylogenetic species were recognised by integrating molecular phylogenetic analyses with morphological studies, and 14 of them represented putatively new species. The biochemical analyses indicated a single origin of cyclic peptide toxins (amatoxins and phalloidin) within Amanita and suggested that this kind of toxins seemed to be a synapomorphy of lethal amanitas. Molecular dating through BEAST and biogeographic analyses with LAGRANGE and RASP indicated that lethal amanitas most likely originated in the Palaeotropics with the present crown group dated around 64.92 Mya in the early Paleocene, and the East Asia–eastern North America or Eurasia–North America–Central America disjunct distribution patterns were primarily established during the middle Oligocene to Miocene. Conclusion The cryptic diversity found in this study indicates that the species diversity of lethal amanitas is strongly underestimated under the current taxonomy. The intercontinental sister species or sister groups relationships among East Asia and eastern North America or

Lethal effect of dehydroleucodine (DhL) on amphibian Bufo arenarum embryos.

PubMed

Moreno, Liliana Elizabeth; Juárez, Américo Osvaldo; Pelzer, Lilian Eugenia

2012-03-01

The dehydroleucodine is a sesquiterpene lactone isolated from Artemisia douglasiana Besser which is used in popular medicine. Toxicity tests using embryos of amphibian have been widely used in order to predict toxic effects of different compounds. However, to our knowledge, there are not studies focussed on the toxic effects of dehydroleucodine on Bufo arenarum, which is an anuran widely distributed in South America. The effect of dehydroleucodine on the survival of embryos was evaluated in an acute test during the early life stage of B. arenarum embryos. Lethality and the degree of adverse effects were dehydroleucodine dose-dependent. Overall, amphibian early life stages appeared to be more susceptible to the embryotoxicity associated with exposure to dehydroleucodine, especially at concentration greater that 3mM. This increased susceptibility may result from the relatively high rate of cellular differentiation and morphogenesis that occurs at this early stage of development. Copyright © 2012 Elsevier Ltd. All rights reserved.

Attacks on German public figures, 1968-2004: warning behaviors, potentially lethal and non-lethal acts, psychiatric status, and motivations.

PubMed

Hoffmann, Jens; Meloy, J Reid; Guldimann, Angela; Ermer, Anneliese

2011-01-01

Fourteen non-terrorist attackers of public figures in Germany between 1968 and 2004 were intensively studied, with a particular focus on warning behaviors, attack behaviors, and the relationship between psychiatric diagnosis, symptoms, and motivations for the assault. A large proportion of the attackers were severely mentally ill, and most likely to be in the potentially lethal rather than the non-lethal group. A new typology of seven warning behaviors was applied to the data, and all were present, most frequently fixation and pathway warning behavior, and least frequently a direct threat. Psychiatric diagnosis could be closely linked to motivation when analyzed at the level of symptom and content of thought, often delusional. Most of the attacks were directed at political figures, and the majority occurred after 1995. Copyright © 2011 John Wiley & Sons, Ltd.

Impulsivity, aggression and brain structure in high and low lethality suicide attempters with borderline personality disorder.

PubMed

Soloff, Paul; White, Richard; Diwadkar, Vaibhav A

2014-06-30

Impulsivity and aggressiveness are trait dispositions associated with the vulnerability to suicidal behavior across diagnoses. They are associated with structural and functional abnormalities in brain networks involved in regulation of mood, impulse and behavior. They are also core characteristics of borderline personality disorder (BPD), a disorder defined, in part, by recurrent suicidal behavior. We assessed the relationships between personality traits, brain structure and lethality of suicide attempts in 51 BPD attempters using multiple regression analyses on structural MRI data. BPD was diagnosed by the Diagnostic Interview for Borderline Patients-revised, impulsivity by the Barratt Impulsiveness Scale (BIS), aggression by the Brown-Goodwin Lifetime History of Aggression (LHA), and high lethality by a score of 4 or more on the Lethality Rating Scale (LRS). Sixteen High Lethality attempters were compared to 35 Low Lethality attempters, with no significant differences noted in gender, co-morbidity, childhood abuse, BIS or LHA scores. Degree of medical lethality (LRS) was negatively related to gray matter volumes across multiple fronto-temporal-limbic regions. Effects of impulsivity and aggression on gray matter volumes discriminated High from Low Lethality attempters and differed markedly within lethality groups. Lethality of suicide attempts in BPD may be related to the mediation of these personality traits by specific neural networks. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Genetics Home Reference: Amish lethal microcephaly

MedlinePlus

... occurs in approximately 1 in 500 newborns in the Old Order Amish population of Pennsylvania. It has not been found outside this population. Related Information What information about a genetic condition can statistics provide? Why ... in the SLC25A19 gene cause Amish lethal microcephaly . The SLC25A19 ...

A DNA vaccine for Crimean-Congo hemorrhagic fever protects against disease and death in two lethal mouse models

PubMed Central

Fitzpatrick, Collin J.; Suschak, John J.; Richards, Michelle J.; Badger, Catherine V.; Six, Carolyn M.; Martin, Jacqueline D.; Hannaman, Drew; Zivcec, Marko; Bergeron, Eric; Koehler, Jeffrey W.; Schmaljohn, Connie S.

2017-01-01

Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne virus capable of causing a severe hemorrhagic fever disease in humans. There are currently no licensed vaccines to prevent CCHFV-associated disease. We developed a DNA vaccine expressing the M-segment glycoprotein precursor gene of CCHFV and assessed its immunogenicity and protective efficacy in two lethal mouse models of disease: type I interferon receptor knockout (IFNAR-/-) mice; and a novel transiently immune suppressed (IS) mouse model. Vaccination of mice by muscle electroporation of the M-segment DNA vaccine elicited strong antigen-specific humoral immune responses with neutralizing titers after three vaccinations in both IFNAR-/- and IS mouse models. To compare the protective efficacy of the vaccine in the two models, groups of vaccinated mice (7–10 per group) were intraperitoneally (IP) challenged with a lethal dose of CCHFV strain IbAr 10200. Weight loss was markedly reduced in CCHFV DNA-vaccinated mice as compared to controls. Furthermore, whereas all vector-control vaccinated mice succumbed to disease by day 5, the DNA vaccine protected >60% of the animals from lethal disease. Mice from both models developed comparable levels of antibodies, but the IS mice had a more balanced Th1/Th2 response to vaccination. There were no statistical differences in the protective efficacies of the vaccine in the two models. Our results provide the first comparison of these two mouse models for assessing a vaccine against CCHFV and offer supportive data indicating that a DNA vaccine expressing the glycoprotein genes of CCHFV elicits protective immunity against CCHFV. PMID:28922426

A DNA vaccine for Crimean-Congo hemorrhagic fever protects against disease and death in two lethal mouse models.

PubMed

Garrison, Aura R; Shoemaker, Charles J; Golden, Joseph W; Fitzpatrick, Collin J; Suschak, John J; Richards, Michelle J; Badger, Catherine V; Six, Carolyn M; Martin, Jacqueline D; Hannaman, Drew; Zivcec, Marko; Bergeron, Eric; Koehler, Jeffrey W; Schmaljohn, Connie S

2017-09-01

Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne virus capable of causing a severe hemorrhagic fever disease in humans. There are currently no licensed vaccines to prevent CCHFV-associated disease. We developed a DNA vaccine expressing the M-segment glycoprotein precursor gene of CCHFV and assessed its immunogenicity and protective efficacy in two lethal mouse models of disease: type I interferon receptor knockout (IFNAR-/-) mice; and a novel transiently immune suppressed (IS) mouse model. Vaccination of mice by muscle electroporation of the M-segment DNA vaccine elicited strong antigen-specific humoral immune responses with neutralizing titers after three vaccinations in both IFNAR-/- and IS mouse models. To compare the protective efficacy of the vaccine in the two models, groups of vaccinated mice (7-10 per group) were intraperitoneally (IP) challenged with a lethal dose of CCHFV strain IbAr 10200. Weight loss was markedly reduced in CCHFV DNA-vaccinated mice as compared to controls. Furthermore, whereas all vector-control vaccinated mice succumbed to disease by day 5, the DNA vaccine protected >60% of the animals from lethal disease. Mice from both models developed comparable levels of antibodies, but the IS mice had a more balanced Th1/Th2 response to vaccination. There were no statistical differences in the protective efficacies of the vaccine in the two models. Our results provide the first comparison of these two mouse models for assessing a vaccine against CCHFV and offer supportive data indicating that a DNA vaccine expressing the glycoprotein genes of CCHFV elicits protective immunity against CCHFV.

Comparing biomarker responses during thermal acclimation: A lethal vs non-lethal approach in a tropical reef clownfish.

PubMed

Madeira, Carolina; Madeira, Diana; Diniz, Mário S; Cabral, Henrique N; Vinagre, Catarina

2017-02-01

Knowledge of thermal stress biology for most tropical fish species in reef ecosystems under climate change is still quite limited. Thus, the objective of this study was to measure the time-course changes of thermal stress biomarkers in the commercially exploited coral reef fish Amphiprion ocellaris, during a laboratory simulated event of increased temperature. Heat shock protein 70kDa (Hsp70) and total ubiquitin (Ub) were determined in the muscle (lethal method) and in the fin (non-lethal alternative method) under two temperature treatments (control - 26°C and elevated temperature - 30°C) throughout one month with weekly samplings. Results suggest that biomarker basal levels are tissue-specific and influence the degree of response under temperature exposure. Responses were highly inducible in the muscle but not in fin tissue, indicating that the latter is not reliable for monitoring purposes. Thermal stress was observed in the muscle after one week of exposure (both biomarkers increased significantly) and Ub levels then decreased, suggesting the animals were able to acclimate by maintaining high levels of Hsp70 and through an effective protein turnover. In addition, the results show that mortality rates did not differ between treatments. This indicates that A. ocellaris is capable of displaying a plastic response to elevated temperature by adjusting the protein quality control system to protect cell functions, without decreasing survival. Thus, this coral reef fish species presents a significant acclimation potential under ocean warming scenarios of +4°C. Monitoring of thermal stress through a non-lethal method, fin-clipping, although desirable proved to be inadequate for this species. Copyright © 2016 Elsevier Inc. All rights reserved.

Relative Risks for Lethal Prostate Cancer Based on Complete Family History of Prostate Cancer Death.

PubMed

Albright, Frederick S; Stephenson, Robert A; Agarwal, Neeraj; Cannon-Albright, Lisa A

2017-01-01

There are few published familial relative risks (RR) for lethal prostate cancer. This study estimates RRs for lethal prostate cancer based on comprehensive family history data, with the goal of improving identification of those men at highest risk of dying from prostate cancer. We used a population-based genealogical resource linked to a statewide electronic SEER cancer registry and death certificates to estimate relative risks (RR) for death from prostate cancer based upon family history. Over 600,000 male probands were analyzed, representing a variety of family history constellations of lethal prostate cancer. RR estimates were based on the ratio of the observed to the expected number of lethal prostate cancer cases using internal rates. RRs for lethal prostate cancer based on the number of affected first-degree relatives (FDR) ranged from 2.49 (95% CI: 2.27, 2.73) for exactly 1 FDR to 5.30 (2.13, 10.93) for ≥3 affected FDRs. In an absence of affected FDRs, increased risk was also significant for increasing numbers of affected second-degree or third degree relatives. Equivalent risks were observed for similar maternal and paternal family history. This study provides population-based estimates of lethal prostate cancer risk based on lethal prostate cancer family history. Many family history constellations associated with two to greater than five times increased risk for lethal prostate cancer were identified. These lethal prostate cancer risk estimates hold potential for use in identification, screening, early diagnosis, and treatment of men at high risk for death from prostate cancer. Prostate77:41-48, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Monochloroacetic acid lethality in the rat in relation to lactic acid accumulation in the cerebrospinal fluid

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

Mitroka, J.G.

1989-01-01

Potential antidotes for human exposure to monochloroacetic acid (MCA) were evaluated using a rodent model. Dichloroacetic acid (DCA) and phenobarbital (PB) but not ethanol or phenytoin, were found to be effective antidotes to monochloroacetic acid (MCA) in rats. DCA (110 mg/kg, ip), administered to rats 15 minutes after a LD-80 of MCA (80 mg/kg, iv), consistently reduced mortality to 0%, while PB reduced mortality to less than 20%. Both DCA and PB were found to be similarly effective in mice. The hypothesis that PB reduces mortality in MCA treated rats by altering the metabolic disposition of MCA was evaluated andmore » rejected. Administration of PB to rats treated with a lethal dose of ({sup 14}C)MCA did not alter the concentrations of MCA or its metabolites in plasma or cerebrospinal fluid (CSF), or the extent of covalent binding between radioactivity equivalent to ({sup 14}C)MCA and brain proteins. The relationship between altered blood-brain barrier permeability and death in MCA treated rats was investigated. Treatment with MCA (80 mg/kg, iv) was associated with a significant (50%) increase in the permeability of the rat blood-brain barrier to ({sup 125}I)BSA. The effect was not altered by treatment with PB, however, suggesting that altered blood-brain barrier permeability does not have an important role in the lethal effect of MCA in rats. The effect of MCA on brain carbohydrate metabolism in vivo was investigated. CSF and blood lactic acid concentrations increased in MCA treated rats, and the increase in CSF levels was dose related. In individual MCA treated rats, CSF lactate concentrations paralleled the time course of ataxia and a discrete threshold for death (18 mmol/L) was observed. The relationship between excess brain lactate levels and death in MCA treated rats was investigated further.« less

Kunjin Virus Replicon-Based Vaccines Expressing Ebola Virus Glycoprotein GP Protect the Guinea Pig Against Lethal Ebola Virus Infection

PubMed Central

Reynard, O.; Mokhonov, V.; Mokhonova, E.; Leung, J.; Page, A.; Mateo, M.; Pyankova, O.; Georges-Courbot, M. C.; Raoul, H.; Khromykh, A. A.

2011-01-01

Pre- or postexposure treatments against the filoviral hemorrhagic fevers are currently not available for human use. We evaluated, in a guinea pig model, the immunogenic potential of Kunjin virus (KUN)–derived replicons as a vaccine candidate against Ebola virus (EBOV). Virus like particles (VLPs) containing KUN replicons expressing EBOV wild-type glycoprotein GP, membrane anchor-truncated GP (GP/Ctr), and mutated GP (D637L) with enhanced shedding capacity were generated and assayed for their protective efficacy. Immunization with KUN VLPs expressing full-length wild-type and D637L-mutated GPs but not membrane anchor–truncated GP induced dose-dependent protection against a challenge of a lethal dose of recombinant guinea pig-adapted EBOV. The surviving animals showed complete clearance of the virus. Our results demonstrate the potential for KUN replicon vectors as vaccine candidates against EBOV infection. PMID:21987742

Lethality of First Contact Dysentery Epidemics on Pacific Islands

PubMed Central

Shanks, G. Dennis

2016-01-01

Infectious diseases depopulated many isolated Pacific islands when they were first exposed to global pathogen circulation from the 18th century. Although the mortality was great, the lack of medical observers makes determination of what happened during these historical epidemics largely speculative. Bacillary dysentery caused by Shigella is the most likely infection causing some of the most lethal island epidemics. The fragmentary historical record is reviewed to gain insight into the possible causes of the extreme lethality that was observed during first-contact epidemics in the Pacific. Immune aspects of the early dysentery epidemics and postmeasles infection resulting in subacute inflammatory enteric disease suggest that epidemiologic isolation was the major lethality risk factor on Pacific islands in the 19th century. Other possible risk factors include human leukocyte antigen homogeneity from a founder effect and pathogen-induced derangement of immune tolerance to gut flora. If this analysis is correct, then Pacific islands are currently at no greater risk of emerging disease epidemics than other developing countries despite their dark history. PMID:27185765

Lethality of First Contact Dysentery Epidemics on Pacific Islands.

PubMed

Shanks, G Dennis

2016-08-03

Infectious diseases depopulated many isolated Pacific islands when they were first exposed to global pathogen circulation from the 18th century. Although the mortality was great, the lack of medical observers makes determination of what happened during these historical epidemics largely speculative. Bacillary dysentery caused by Shigella is the most likely infection causing some of the most lethal island epidemics. The fragmentary historical record is reviewed to gain insight into the possible causes of the extreme lethality that was observed during first-contact epidemics in the Pacific. Immune aspects of the early dysentery epidemics and postmeasles infection resulting in subacute inflammatory enteric disease suggest that epidemiologic isolation was the major lethality risk factor on Pacific islands in the 19th century. Other possible risk factors include human leukocyte antigen homogeneity from a founder effect and pathogen-induced derangement of immune tolerance to gut flora. If this analysis is correct, then Pacific islands are currently at no greater risk of emerging disease epidemics than other developing countries despite their dark history. © The American Society of Tropical Medicine and Hygiene.

A decade of Australian methotrexate dosing errors.

PubMed

Cairns, Rose; Brown, Jared A; Lynch, Ann-Maree; Robinson, Jeff; Wylie, Carol; Buckley, Nicholas A

2016-06-06

Accidental daily dosing of methotrexate can result in life-threatening toxicity. We investigated methotrexate dosing errors reported to the National Coronial Information System (NCIS), the Therapeutic Goods Administration Database of Adverse Event Notifications (TGA DAEN) and Australian Poisons Information Centres (PICs). A retrospective review of coronial cases in the NCIS (2000-2014), and of reports to the TGA DAEN (2004-2014) and Australian PICs (2004-2015). Cases were included if dosing errors were accidental, with evidence of daily dosing on at least 3 consecutive days. Events per year, dose, consecutive days of methotrexate administration, reasons for the error, clinical features. Twenty-two deaths linked with methotrexate were identified in the NCIS, including seven cases in which erroneous daily dosing was documented. Methotrexate medication error was listed in ten cases in the DAEN, including two deaths. Australian PIC databases contained 92 cases, with a worrying increase seen during 2014-2015. Reasons for the errors included patient misunderstanding and incorrect packaging of dosette packs by pharmacists. The recorded clinical effects of daily dosage were consistent with those previously reported for methotrexate toxicity. Dosing errors with methotrexate can be lethal and continue to occur despite a number of safety initiatives in the past decade. Further strategies to reduce these preventable harms need to be implemented and evaluated. Recent suggestions include further changes in packet size, mandatory weekly dosing labelling on packaging, improving education, and including alerts in prescribing and dispensing software.

Immobilized Hydrolytic Enzymes Exhibit Antibiofilm Activity Against Escherichia coli at Sub-Lethal Concentrations.

PubMed

Villa, Federica; Secundo, Francesco; Polo, Andrea; Cappitelli, Francesca

2015-07-01

The effects of two commercially available immobilized enzymes (namely the glycosidase pectinase and the protease subtilisin A) at sub-lethal concentrations were investigated in terms of their influence on biofilm genesis, on the composition of the biofilm matrix, and their antibiotic synergy against Escherichia coli biofilm, used as a model system of bacterial biofilms. The best antibiofilm performance of solid-supported hydrolases was obtained at the surface concentration of 0.022 and 0.095 U/cm(2) with a reduction of 1.2 and 2.3 log CFU/biofilm for pectinase and subtilisin, respectively. At these enzyme surface concentrations, the biocatalysts affected the structural composition of the biofilm matrix, impacting biofilm thickness. Finally, the immobilized hydrolases enhanced biofilm sensitivity to a clinically relevant concentration of the antibiotic ampicillin. At the final antibiotic concentration of 0.1 mg/ml, a reduction of 2 and 3.5 log10 units in presence of 0.022 Upectinase/cm(2) and 0.095 Usubtilisin/cm(2) was obtained, respectively, in comparison the antibiotic alone. Immobilized pectinase and subtilisin at sub-lethal concentrations demonstrated a great potential for antibiofilm applications.

Suitability of non-lethal marker and marker-free systems for development of transgenic crop plants: present status and future prospects.

PubMed

Manimaran, P; Ramkumar, G; Sakthivel, K; Sundaram, R M; Madhav, M S; Balachandran, S M

2011-01-01

Genetically modified crops are one of the prudent options for enhancing the production and productivity of crop plants by safeguarding from the losses due to biotic and abiotic stresses. Agrobacterium-mediated and biolistic transformation methods are used to develop transgenic crop plants in which selectable marker genes (SMG) are generally deployed to identify 'true' transformants. The commonly used SMG obtained from prokaryotic sources when employed in transgenic plants pose risks due to their lethal nature during selection process. In the recent past, some non-lethal SMGs have been identified and used for selection of transformants with increased precision and high selection efficiency. Considering the concerns related to bio-safety of the environment, it is desirable to remove the SMG in order to maximize the commercial success through wide adoption and public acceptance of genetically modified (GM) food crops. In this review, we examine the availability, and the suitability of wide range of non-lethal selection markers and elimination of SMG methods to develop marker-free transgenics for achieving global food security. As the strategies for marker-free plants are still in proof-of-concept stage, adaptation of new genomics tools for identification of novel non-lethal marker systems and its application for developing marker-free transgenics would further strengthen the crop improvement program. Copyright © 2011 Elsevier Inc. All rights reserved.

Annotating novel genes by integrating synthetic lethals and genomic information

PubMed Central

Schöner, Daniel; Kalisch, Markus; Leisner, Christian; Meier, Lukas; Sohrmann, Marc; Faty, Mahamadou; Barral, Yves; Peter, Matthias; Gruissem, Wilhelm; Bühlmann, Peter

2008-01-01

Background Large scale screening for synthetic lethality serves as a common tool in yeast genetics to systematically search for genes that play a role in specific biological processes. Often the amounts of data resulting from a single large scale screen far exceed the capacities of experimental characterization of every identified target. Thus, there is need for computational tools that select promising candidate genes in order to reduce the number of follow-up experiments to a manageable size. Results We analyze synthetic lethality data for arp1 and jnm1, two spindle migration genes, in order to identify novel members in this process. To this end, we use an unsupervised statistical method that integrates additional information from biological data sources, such as gene expression, phenotypic profiling, RNA degradation and sequence similarity. Different from existing methods that require large amounts of synthetic lethal data, our method merely relies on synthetic lethality information from two single screens. Using a Multivariate Gaussian Mixture Model, we determine the best subset of features that assign the target genes to two groups. The approach identifies a small group of genes as candidates involved in spindle migration. Experimental testing confirms the majority of our candidates and we present she1 (YBL031W) as a novel gene involved in spindle migration. We applied the statistical methodology also to TOR2 signaling as another example. Conclusion We demonstrate the general use of Multivariate Gaussian Mixture Modeling for selecting candidate genes for experimental characterization from synthetic lethality data sets. For the given example, integration of different data sources contributes to the identification of genetic interaction partners of arp1 and jnm1 that play a role in the same biological process. PMID:18194531

Computed radiography as a gamma ray detector—dose response and applications

NASA Astrophysics Data System (ADS)

O'Keeffe, D. S.; McLeod, R. W.

2004-08-01

Computed radiography (CR) can be used for imaging the spatial distribution of photon emissions from radionuclides. Its wide dynamic range and good response to medium energy gamma rays reduces the need for long exposure times. Measurements of small doses can be performed without having to pre-sensitize the computed radiography plates via an x-ray exposure, as required with screen-film systems. Cassette-based Agfa MD30 and Kodak GP25 CR plates were used in applications involving the detection of gamma ray emissions from technetium-99m and iodine-131. Cassette entrance doses as small as 1 µGy (140 keV gamma rays) produce noisy images, but the images are suitable for applications such as the detection of breaks in radiation protection barriers. A consequence of the gamma ray sensitivity of CR plates is the possibility that some nuclear medicine patients may fog their x-rays if the x-ray is taken soon after their radiopharmaceutical injection. The investigation showed that such fogging is likely to be diffuse.

Clostridium sordellii lethal toxin kills mice by inducing a major increase in lung vascular permeability.

PubMed

Geny, Blandine; Khun, Huot; Fitting, Catherine; Zarantonelli, Leticia; Mazuet, Christelle; Cayet, Nadège; Szatanik, Marek; Prevost, Marie-Christine; Cavaillon, Jean-Marc; Huerre, Michel; Popoff, Michel R

2007-03-01

When intraperitoneally injected into Swiss mice, Clostridium sordellii lethal toxin reproduces the fatal toxic shock syndrome observed in humans and animals after natural infection. This animal model was used to study the mechanism of lethal toxin-induced death. Histopathological and biochemical analyses identified lung and heart as preferential organs targeted by lethal toxin. Massive extravasation of blood fluid in the thoracic cage, resulting from an increase in lung vascular permeability, generated profound modifications such as animal dehydration, increase in hematocrit, hypoxia, and finally, cardiorespiratory failure. Vascular permeability increase induced by lethal toxin resulted from modifications of lung endothelial cells as evidenced by electron microscopy. Immunohistochemical analysis demonstrated that VE-cadherin, a protein participating in intercellular adherens junctions, was redistributed from membrane to cytosol in lung endothelial cells. No major sign of lethal toxin-induced inflammation was observed that could participate in the toxic shock syndrome. The main effect of the lethal toxin is the glucosylation-dependent inactivation of small GTPases, in particular Rac, which is involved in actin polymerization occurring in vivo in lungs leading to E-cadherin junction destabilization. We conclude that the cells most susceptible to lethal toxin are lung vascular endothelial cells, the adherens junctions of which were altered after intoxication.

Clostridium sordellii Lethal Toxin Kills Mice by Inducing a Major Increase in Lung Vascular Permeability

PubMed Central

Geny, Blandine; Khun, Huot; Fitting, Catherine; Zarantonelli, Leticia; Mazuet, Christelle; Cayet, Nadège; Szatanik, Marek; Prevost, Marie-Christine; Cavaillon, Jean-Marc; Huerre, Michel; Popoff, Michel R.

2007-01-01

When intraperitoneally injected into Swiss mice, Clostridium sordellii lethal toxin reproduces the fatal toxic shock syndrome observed in humans and animals after natural infection. This animal model was used to study the mechanism of lethal toxin-induced death. Histopathological and biochemical analyses identified lung and heart as preferential organs targeted by lethal toxin. Massive extravasation of blood fluid in the thoracic cage, resulting from an increase in lung vascular permeability, generated profound modifications such as animal dehydration, increase in hematocrit, hypoxia, and finally, cardiorespiratory failure. Vascular permeability increase induced by lethal toxin resulted from modifications of lung endothelial cells as evidenced by electron microscopy. Immunohistochemical analysis demonstrated that VE-cadherin, a protein participating in intercellular adherens junctions, was redistributed from membrane to cytosol in lung endothelial cells. No major sign of lethal toxin-induced inflammation was observed that could participate in the toxic shock syndrome. The main effect of the lethal toxin is the glucosylation-dependent inactivation of small GTPases, in particular Rac, which is involved in actin polymerization occurring in vivo in lungs leading to E-cadherin junction destabilization. We conclude that the cells most susceptible to lethal toxin are lung vascular endothelial cells, the adherens junctions of which were altered after intoxication. PMID:17322384

Differential antagonism of tetramethylenedisulfotetramine-induced seizures by agents acting at NMDA and GABAA receptors

PubMed Central

Shakarjian, Michael P.; Velíšková, Jana; Stanton, Patric K.; Velíšek, Libor

2012-01-01

Tetramethylenedisulfotetramine (TMDT) is a highly lethal neuroactive rodenticide responsible for many accidental and intentional poisonings in mainland China. Ease of synthesis, water solubility, potency, and difficulty to treat make TMDT a potential weapon for terrorist activity. We characterized TMDT-induced convulsions and mortality in male C57BL/6 mice. TMDT (ip) produced a continuum of twitches, clonic, and tonic-clonic seizures decreasing in onset latency and increasing in severity with increasing dose; 0.4 mg/kg was 100% lethal. The NMDA antagonist, ketamine (35 mg/kg) injected ip immediately after the first TMDT-induced seizure, did not change number of tonic-clonic seizures or lethality, but increased the number of clonic seizures. Doubling the ketamine dose decreased tonic-clonic seizures and eliminated lethality through a 60 min observation period. Treating mice with another NMDA antagonist, MK-801, 0.5 or 1 mg/kg ip, showed similar effects as low and high doses of ketamine, respectively, and prevented lethality, converting status epilepticus EEG activity to isolated interictal discharges. Treatment with these agents 15 min prior to TMDT administration did not increase their effectiveness. Post-treatment with the GABAA receptor allosteric enhancer diazepam (5 mg/kg) greatly reduced seizure manifestations and prevented lethality 60 min post-TMDT, but ictal events were evident in EEG recordings and, hours post-treatment, mice experienced status epilepticus and died. Thus, TMDT is a highly potent and lethal convulsant for which single-dose benzodiazepine treatment is inadequate in managing electrographic seizures or lethality. Repeated benzodiazepine dosing or combined application of benzodiazepines and NMDA receptor antagonists are more likely to be effective in treating TMDT poisoning. PMID:23022509

Evaluating the Predictive Validity of Suicidal Intent and Medical Lethality in Youth

ERIC Educational Resources Information Center

Sapyta, Jeffrey; Goldston, David B.; Erkanli, Alaattin; Daniel, Stephanie S.; Heilbron, Nicole; Mayfield, Andrew; Treadway, S. Lyn

2012-01-01

Objectives: To examine whether suicidal intent and medical lethality of past suicide attempts are predictive of future attempts, the association between intent and lethality, and the consistency of these characteristics across repeated attempts among youth. Method: Suicide attempts in a 15-year prospective study of 180 formerly psychiatrically…

Introduction of novel 3D-printed superficial applicators for high-dose-rate skin brachytherapy.

PubMed

Jones, Emma-Louise; Tonino Baldion, Anna; Thomas, Christopher; Burrows, Tom; Byrne, Nick; Newton, Victoria; Aldridge, Sarah

Custom-made surface mold applicators often allow more flexibility when carrying out skin brachytherapy, particularly for small treatment areas with high surface obliquity. They can, however, be difficult to manufacture, particularly if there is a lack of experience in superficial high-dose-rate brachytherapy techniques or with limited resources. We present a novel method of manufacturing superficial brachytherapy applicators utilizing three-dimensional (3D)-printing techniques. We describe the treatment planning process and the process of applicator manufacture. The treatment planning process, with the introduction of a pre-plan, allows for an "ideal" catheter arrangement within an applicator to be determined, exploiting varying catheter orientations, heights, and curvatures if required. The pre-plan arrangement is then 3D printed to the exact specifications of the pre-plan applicator design. This results in improved target volume coverage and improved sparing of organs at risk. Using a pre-plan technique for ideal catheter placement followed by automated 3D-printed applicator manufacture has greatly improved the entire process of superficial high-dose-rate brachytherapy treatment. We are able to design and manufacture flexible, well-fitting, superior quality applicators resulting in a more efficient and improved patient pathway and patient experience. Copyright © 2016 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

The H-ARS Dose Response Relationship (DRR): Validation and Variables.

PubMed

Plett, P Artur; Sampson, Carol H; Chua, Hui Lin; Jackson, William; Vemula, Sasidhar; Sellamuthu, Rajendran; Fisher, Alexa; Feng, Hailin; Wu, Tong; MacVittie, Thomas J; Orschell, Christie M

2015-11-01

Manipulations of lethally-irradiated animals, such as for administration of pharmaceuticals, blood sampling, or other laboratory procedures, have the potential to induce stress effects that may negatively affect morbidity and mortality. To investigate this in a murine model of the hematopoietic acute radiation syndrome, 20 individual survival efficacy studies were grouped based on the severity of the administration (Admn) schedules of their medical countermeasure (MCM) into Admn 1 (no injections), Admn 2 (1-3 injections), or Admn 3 (29 injections or 6-9 oral gavages). Radiation doses ranged from LD30/30 to LD95/30. Thirty-day survival of vehicle controls in each group was used to construct radiation dose lethality response relationship (DRR) probit plots, which were compared statistically to the original DRR from which all LDXX/30 for the studies were obtained. The slope of the Admn 3 probit was found to be significantly steeper (5.190) than that of the original DRR (2.842) or Admn 2 (2.009), which were not significantly different. The LD50/30 for Admn 3 (8.43 Gy) was less than that of the original DRR (8.53 Gy, p < 0.050), whereas the LD50/30 of other groups were similar. Kaplan-Meier survival curves showed significantly worse survival of Admn 3 mice compared to the three other groups (p = 0.007). Taken together, these results show that stressful administration schedules of MCM can negatively impact survival and that dosing regimens should be considered when constructing DRR to use in survival studies.

A lethal ovitrap-based mass trapping scheme for dengue control in Australia: I. Public acceptability and performance of lethal ovitraps.

PubMed

Ritchie, S A; Rapley, L P; Williams, C; Johnson, P H; Larkman, M; Silcock, R M; Long, S A; Russell, R C

2009-12-01

We report on the first field evaluation of the public acceptability and performance of two types of lethal ovitrap (LO) in three separate trials in Cairns, Australia. Health workers were able to set standard lethal ovitraps (SLOs) in 75 and 71% of premise yards in the wet and dry season, respectively, and biodegradable lethal ovitraps (BLOs) in 93% of yards. Public acceptance, measured as retention of traps by residents, was high for both trap types, with <9% of traps missing after 4 weeks. Traps retaining water after 4 weeks were 78 and 34% for the two SLO trials and 58% for the BLOs. The 'failure rate' in the 535 BLOs set in the field for 4 weeks was 47%, of which 19% were lost, 51% had holes from probable insect chewing, 23% were knocked over, 7% had dried by evaporation and 1% were split. There was no significant difference in the failure rate of BLOs set on porous (grass, soil and mulch) versus solid (tiles, concrete, wood and stone) substrates. The SLOs and the BLOs were readily acceptable to ovipositing Aedes aegypti L. (Diptera: Culicidae); the mean number of eggs/trap was 6 and 15, for the dry season and wet season SLO trial, respectively, and 15 for the BLO wet season trial. Indeed, 84-94% of premise yards had egg positive SLOs or BLOs. A high percentage of both wet and dry season SLOs (29 and 70%, respectively) and BLOs (62%) that were dry after 4 weeks were egg positive, indicating the traps had functioned. Lethal strips from SLOs and BLOs that had been exposed for 4 weeks killed 83 and 74%, respectively, of gravid Ae. aegypti in laboratory assays. These results indicate that mass trapping schemes using SLOs and BLOs are not rejected by the public and effectively target gravid Ae. aegypti. The impact of the interventions on mosquito populations is described in a companion paper.

Dosimetric characterizations of GZP6 60Co high dose rate brachytherapy sources: application of superimposition method

PubMed Central

Bahreyni Toossi, Mohammad Taghi; Ghorbani, Mahdi; Mowlavi, Ali Asghar; Meigooni, Ali Soleimani

2012-01-01

Background Dosimetric characteristics of a high dose rate (HDR) GZP6 Co-60 brachytherapy source have been evaluated following American Association of Physicists in MedicineTask Group 43U1 (AAPM TG-43U1) recommendations for their clinical applications. Materials and methods MCNP-4C and MCNPX Monte Carlo codes were utilized to calculate dose rate constant, two dimensional (2D) dose distribution, radial dose function and 2D anisotropy function of the source. These parameters of this source are compared with the available data for Ralstron 60Co and microSelectron192Ir sources. Besides, a superimposition method was developed to extend the obtained results for the GZP6 source No. 3 to other GZP6 sources. Results The simulated value for dose rate constant for GZP6 source was 1.104±0.03 cGyh-1U-1. The graphical and tabulated radial dose function and 2D anisotropy function of this source are presented here. The results of these investigations show that the dosimetric parameters of GZP6 source are comparable to those for the Ralstron source. While dose rate constant for the two 60Co sources are similar to that for the microSelectron192Ir source, there are differences between radial dose function and anisotropy functions. Radial dose function of the 192Ir source is less steep than both 60Co source models. In addition, the 60Co sources are showing more isotropic dose distribution than the 192Ir source. Conclusions The superimposition method is applicable to produce dose distributions for other source arrangements from the dose distribution of a single source. The calculated dosimetric quantities of this new source can be introduced as input data to the GZP6 treatment planning system (TPS) and to validate the performance of the TPS. PMID:23077455

Lethal Zika Virus Disease Models in Young and Older Interferon α/β Receptor Knock Out Mice.

PubMed

Marzi, Andrea; Emanuel, Jackson; Callison, Julie; McNally, Kristin L; Arndt, Nicolette; Chadinha, Spencer; Martellaro, Cynthia; Rosenke, Rebecca; Scott, Dana P; Safronetz, David; Whitehead, Stephen S; Best, Sonja M; Feldmann, Heinz

2018-01-01

The common small animal disease models for Zika virus (ZIKV) are mice lacking the interferon responses, but infection of interferon receptor α/β knock out (IFNAR -/- ) mice is not uniformly lethal particularly in older animals. Here we sought to advance this model in regard to lethality for future countermeasure efficacy testing against more recent ZIKV strains from the Asian lineage, preferably the American sublineage. We first infected IFNAR -/- mice subcutaneously with the contemporary ZIKV-Paraiba strain resulting in predominantly neurological disease with ~50% lethality. Infection with ZIKV-Paraiba by different routes established a uniformly lethal model only in young mice (4-week old) upon intraperitoneal infection. However, intraperitoneal inoculation of ZIKV-French Polynesia resulted in uniform lethality in older IFNAR -/- mice (10-12-weeks old). In conclusion, we have established uniformly lethal mouse disease models for efficacy testing of antivirals and vaccines against recent ZIKV strains representing the Asian lineage.

The Decline of the Military Ethos and Profession of Arms: An Argument Against Autonomous Lethal Engagements

DTIC Science & Technology

2012-10-01

very limited to support near-term, clear-cut, small-scale tactical objectives avoiding mass applications which could compromise long term strategic...principles of double effect and double intent factor into the calculus of the use of force as well.26 The professional community is divided on the...lethal force and those who prosecute it and a lack of empathy for those who it is waged upon.54 Finally, Hartle writes that one purpose of professional

The evolution of lethal intergroup violence.

PubMed

Kelly, Raymond C

2005-10-25

Recent findings and analyses in evolutionary biology, archaeology, and ethnology provide a favorable conjuncture for examining the evolution of lethal intergroup violence among hominids during the 2.9-million-year Paleolithic time span. Here, I seek to identify and investigate the main turning points in this evolutionary trajectory and to delineate the periodization that follows from this inquiry.

Sci-Thur PM – Brachytherapy 06: 3D Printed Surface Applicators for High Dose Rate Brachytherapy

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

Clarke, Scott; Yewondwossen, Mammo; Robar, James

Purpose: The purpose of this work is to develop a new applicator for administering high dose rate (HDR) brachytherapy using 3D printing technology. Primary advantages of using a 3D printed applicator will be to offer a more streamlined approach for therapists and patients while achieving better conformity, reproducibility, and patient specific applicators. Methods: A phantom study was conducted to measure the effectiveness of a 3D printed surface applicator by analyzing tumours on three locations of the body: the foot, nose, and scalp. The applicator was designed using Eclipse and further modified using Blender to create the catheter tunnels before beingmore » printed on a Lulzbot Taz 5 3D printer. A radiation plan was made using Oncentra Brachytherapy for a control treatment option using Freiburg Flaps and one with the novel method of a 3D printed applicator. A comparative analysis was made using D90, D100, V100, V150, and V200 Results: The 3D printed applicator showed comparable dose coverage with significant improvements on highly irregular surfaces when analyzed against a plan made using Freiburg Flaps. Although both plans exhibited complete tumour coverage, the 3D applicator showed improvements in D90 and V150 and the 3D applicator had a dose homogeneity index (DHI) of 0.99 compared to a DHI of 0.97 for the control. Therapist prep time also dropped significantly due to the lack of need for a thermoplastic mesh. Conclusions: 3D printed applicators for treatment of superficial sites proved to offer more patient convenience, less prep time, better conformity and tighter margins.« less

SU-E-T-352: Effects of Skull Attenuation and Missing Backscatter On Brain Dose in HDR Treatment of the Head with Surface Applicators

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

Cifter, F; Dhou, S; Lewis, J

2015-06-15

Purpose: To calculate the effect of lack of backscatter from air and attenuation of bone on dose distributions in brachytherapy surface treatment of head. Existing treatment planning systems based on TG43 do not account for heterogeneities, and thus may overestimate the dose to the brain. While brachytherapy generally has rapid dose falloff, the dose to the deeper tissues (in this case, the brain) can become significant when treating large curved surfaces. Methods: Applicator geometries representing a range of clinical cases were simulated in MCNP5. An Ir-192 source was modeled using the energy spectrum presented by TG-43. The head phantom wasmore » modeled as a 7.5-cm radius water sphere, with a 7 -mm thick skull embedded 5-mm beneath the surface. Dose values were calculated at 20 points inside the head, in which 10 of them were on the central axis and the other 10 on the axis connecting the central of the phantom with the second to last source from the applicator edge. Results: Central and peripheral dose distributions for a range of applicator and head sizes are presented. The distance along the central axis at which the dose falls to 80% of the prescribed dose (D80) was 7 mm for a representative small applicator and 9 mm for a large applicator. Corresponding D50 and D30 for the same small applicator were 17 mm and 32 mm respectively. D50 and D30 for the larger applicator were 32 mm and 60 mm respectively. These results reflect the slower falloff expected for larger applicators on a curved surface. Conclusion: Our results can provide guidance for clinicians to calculate the dose reduction effect due to bone attenuation and the lack of backscatter from air to estimate the brain dose for the HDR treatments of surface lesions.« less

Antiviral treatment is more effective than smallpox vaccination upon lethal monkeypox virus infection.

PubMed

Stittelaar, Koert J; Neyts, Johan; Naesens, Lieve; van Amerongen, Geert; van Lavieren, Rob F; Holý, Antonin; De Clercq, Erik; Niesters, Hubert G M; Fries, Edwin; Maas, Chantal; Mulder, Paul G H; van der Zeijst, Ben A M; Osterhaus, Albert D M E

2006-02-09

There is concern that variola virus, the aetiological agent of smallpox, may be used as a biological weapon. For this reason several countries are now stockpiling (vaccinia virus-based) smallpox vaccine. Although the preventive use of smallpox vaccination has been well documented, little is known about its efficacy when used after exposure to the virus. Here we compare the effectiveness of (1) post-exposure smallpox vaccination and (2) antiviral treatment with either cidofovir (also called HPMPC or Vistide) or with a related acyclic nucleoside phosphonate analogue (HPMPO-DAPy) after lethal intratracheal infection of cynomolgus monkeys (Macaca fascicularis) with monkeypox virus (MPXV). MPXV causes a disease similar to human smallpox and this animal model can be used to measure differences in the protective efficacies of classical and new-generation candidate smallpox vaccines. We show that initiation of antiviral treatment 24 h after lethal intratracheal MPXV infection, using either of the antiviral agents and applying various systemic treatment regimens, resulted in significantly reduced mortality and reduced numbers of cutaneous monkeypox lesions. In contrast, when monkeys were vaccinated 24 h after MPXV infection, using a standard human dose of a currently recommended smallpox vaccine (Elstree-RIVM), no significant reduction in mortality was observed. When antiviral therapy was terminated 13 days after infection, all surviving animals had virus-specific serum antibodies and antiviral T lymphocytes. These data show that adequate preparedness for a biological threat involving smallpox should include the possibility of treating exposed individuals with antiviral compounds such as cidofovir or other selective anti-poxvirus drugs.

Cancer radiotherapy based on femtosecond IR laser-beam filamentation yielding ultra-high dose rates and zero entrance dose.

PubMed

Meesat, Ridthee; Belmouaddine, Hakim; Allard, Jean-François; Tanguay-Renaud, Catherine; Lemay, Rosalie; Brastaviceanu, Tiberius; Tremblay, Luc; Paquette, Benoit; Wagner, J Richard; Jay-Gerin, Jean-Paul; Lepage, Martin; Huels, Michael A; Houde, Daniel

2012-09-18

Since the invention of cancer radiotherapy, its primary goal has been to maximize lethal radiation doses to the tumor volume while keeping the dose to surrounding healthy tissues at zero. Sadly, conventional radiation sources (γ or X rays, electrons) used for decades, including multiple or modulated beams, inevitably deposit the majority of their dose in front or behind the tumor, thus damaging healthy tissue and causing secondary cancers years after treatment. Even the most recent pioneering advances in costly proton or carbon ion therapies can not completely avoid dose buildup in front of the tumor volume. Here we show that this ultimate goal of radiotherapy is yet within our reach: Using intense ultra-short infrared laser pulses we can now deposit a very large energy dose at unprecedented microscopic dose rates (up to 10(11) Gy/s) deep inside an adjustable, well-controlled macroscopic volume, without any dose deposit in front or behind the target volume. Our infrared laser pulses produce high density avalanches of low energy electrons via laser filamentation, a phenomenon that results in a spatial energy density and temporal dose rate that both exceed by orders of magnitude any values previously reported even for the most intense clinical radiotherapy systems. Moreover, we show that (i) the type of final damage and its mechanisms in aqueous media, at the molecular and biomolecular level, is comparable to that of conventional ionizing radiation, and (ii) at the tumor tissue level in an animal cancer model, the laser irradiation method shows clear therapeutic benefits.

Differential antagonism of tetramethylenedisulfotetramine-induced seizures by agents acting at NMDA and GABA{sub A} receptors

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

Shakarjian, Michael P., E-mail: michael_shakarjian@nymc.edu; Department of Medicine, Division of Pulmonary and Critical Care Medicine, UMDNJ–Robert Wood Johnson Medical School, Piscataway, NJ 08854; Velíšková, Jana, E-mail: jana_veliskova@nymc.edu

Tetramethylenedisulfotetramine (TMDT) is a highly lethal neuroactive rodenticide responsible for many accidental and intentional poisonings in mainland China. Ease of synthesis, water solubility, potency, and difficulty to treat make TMDT a potential weapon for terrorist activity. We characterized TMDT-induced convulsions and mortality in male C57BL/6 mice. TMDT (ip) produced a continuum of twitches, clonic, and tonic–clonic seizures decreasing in onset latency and increasing in severity with increasing dose; 0.4 mg/kg was 100% lethal. The NMDA antagonist, ketamine (35 mg/kg) injected ip immediately after the first TMDT-induced seizure, did not change number of tonic–clonic seizures or lethality, but increased the numbermore » of clonic seizures. Doubling the ketamine dose decreased tonic–clonic seizures and eliminated lethality through a 60 min observation period. Treating mice with another NMDA antagonist, MK-801, 0.5 or 1 mg/kg ip, showed similar effects as low and high doses of ketamine, respectively, and prevented lethality, converting status epilepticus EEG activity to isolated interictal discharges. Treatment with these agents 15 min prior to TMDT administration did not increase their effectiveness. Post-treatment with the GABA{sub A} receptor allosteric enhancer diazepam (5 mg/kg) greatly reduced seizure manifestations and prevented lethality 60 min post-TMDT, but ictal events were evident in EEG recordings and, hours post-treatment, mice experienced status epilepticus and died. Thus, TMDT is a highly potent and lethal convulsant for which single-dose benzodiazepine treatment is inadequate in managing electrographic seizures or lethality. Repeated benzodiazepine dosing or combined application of benzodiazepines and NMDA receptor antagonists is more likely to be effective in treating TMDT poisoning. -- Highlights: ► TMDT produces convulsions and lethality at low doses in mice. ► Diazepam pre- or post-treatments inhibit TMDT-induced convulsions

Mitigative Effects of a Combination of Multiple Pharmaceutical Drugs on the Survival of Mice Exposed to Lethal Ionizing Radiation.

PubMed

Hirouchi, Tokuhisa; Ito, Koichi; Nakano, Manabu; Monzen, Satoru; Yoshino, Hironori; Chiba, Mitsuru; Hazawa, Masaharu; Nakano, Akira; Ishikawa, Junya; Yamaguchi, Masaru; Tanaka, Kimio; Kashiwakura, Ikuo

2015-01-01

It is important to establish an easy-to-use therapeutic protocol for the emergency medical care of patients involved in radiation accidents to reduce the radiation-related casualties. The present study aimed to establish an optimum therapeutic protocol using currently approved pharmaceutical drugs to increase the survival of victims exposed to lethal radiation. Different combinations of four drugs-recombinant human erythropoietin (EPO), granulocyte-colony stimulating factor (G-CSF), c-mpl receptor agonist romiplostim (RP) and nandrolone decanoate (ND)-were administered to mice within 2 h after exposure to a lethal 7 Gy dose of γ-irradiation. On day 30 after irradiation, the condition of the mice was analyzed using various hematological parameters, such as the number of peripheral blood cells, bone marrow cells, hematopoietic progenitor cells and the expression of cell surface antigens. Approximately 10% of the untreated irradiated control mice survived for 21 days, but all of the control mice died by day 30. The combined administration of G-CSF, EPO and RP for five days immediately after irradiation led to a complete survival of the irradiated mice until day 30. However, the treatment with G-CSF, EPO and RP with ND led to only 75% survival at day 30. The hematological analyses showed that the numbers of almost all of hematopoietic cells in the surviving mice treated with effective medications recovered to the levels of non-irradiated mice. The present findings show that the combination of G-CSF, EPO and RP may be a useful countermeasure for victims exposed to accidental lethal irradiation.

Zn(2+)-dependence of the synergistic increase in rat thymocyte cell lethality caused by simultaneous application of 4,5-dichloro-2-octyl-4-isothiazolin-3-one (DCOIT) and H2O2.

PubMed

Saitoh, Shohei; Fukunaga, Eri; Ohtani, Hana; Oyama, Yasuo

2015-09-01

4,5-Dichloro-2-octyl-4-isothiazolin-3-one (DCOIT) is an antifouling agent that is an alternative to organotins such as tributyltin (TBT). Because DCOIT decreases catalase activity, it may increase the susceptibility of cells to oxidative stress. We examined the effects of DCOIT on rat thymocytes suffering from oxidative stress induced by H2O2. The simultaneous application of DCOIT and H2O2 induced a synergistic increase in cell lethality that was completely suppressed by chelating intracellular Zn(2+). Intracellular Zn(2+) concentration was increased by DCOIT at concentrations ranging from 0.1 μM to 3 μM. Although the increase in cell lethality produced by DCOIT alone was less than that produced by TBT alone, a synergistic increase was not induced by the combination of TBT and H2O2. Therefore, these results suggest that DCOIT increases vulnerability to oxidative stress and is more cytotoxic than TBT when oxidative stress is induced by H2O2. Copyright © 2014 Elsevier Ltd. All rights reserved.

Direct measurement of the lethal isotherm for radiofrequency ablation of myocardial tissue.

PubMed

Wood, Mark; Goldberg, Scott; Lau, Melissa; Goel, Aneesh; Alexander, Daniel; Han, Frederick; Feinstein, Shawn

2011-06-01

The lethal isotherm for radiofrequency catheter ablation of cardiac myocardium is widely accepted to be 50°C, but this has not been directly measured. The purpose of this study was to directly measure the tissue temperature at the edge of radiofrequency lesions in real time using infrared thermal imaging. Fifteen radiofrequency lesions of 6 to 240 seconds in duration were applied to the left ventricular surface of isolated perfused pig hearts. At the end of radiofrequency delivery, a thermal image of the tissue surface was acquired with an infrared camera. The lesion was then stained and an optical image of the lesion was obtained. The thermal and optical images were electronically merged to allow determination of the tissue temperature at the edge of the lesion at the end of radiofrequency delivery. By adjusting the temperature overlay display to conform with the edge of the radiofrequency lesion, the lethal isotherm was measured to be 60.6°C (interquartile ranges, 59.7° to 62.4°C; range, 58.1° to 64.2°C). The areas encompassed by the lesion border in the optical image and the lethal isotherm in the thermal image were statistically similar and highly correlated (Spearman ρ=0.99, P<0.001). The lethal isotherm temperature was not related to the duration of radiofrequency delivery or to lesion size (both P>0.64). The areas circumscribed by 50°C isotherms were significantly larger than the areas of the lesions on optical imaging (P=0.002). By direct measurement, the lethal isotherm for cardiac myocardium is near 61°C for radiofrequency energy deliveries <240 seconds in duration. A 50°C isotherm overestimates lesion size. Accurate knowledge of the lethal isotherm for radiofrequency ablation is important to clinical practice as well as mathematical modeling of radiofrequency lesions.

Effects of Training with Lethal Chemicals on Job Proficiency and Job Confidence.

ERIC Educational Resources Information Center

Smith, Paula; And Others

A study was designed to determine if soldiers trained to use chemical agents are more proficient in performing their jobs in an environment where lethal chemical agents are used and more confident of their ability to survive. A treatment group, composed of 150 soldiers, knew that their training would involve lethal agents in the Chemical…

Toxicity of Single-dose Intramuscular Injection of Samjeong Pharmacopuncture in Sprague-Dawley Rats.

PubMed

Kwon, Kang; Kim, Chul-Yun; Kim, Nam-Kwen; Sun, Seung-Ho; Seo, Hyung-Sik

2015-06-01

This study was carried out in order to find both the single-dose intramuscular injection toxicity and the approximate lethal dose of samjeong pharmacopuncture (SP) in Sprague-Dawley (SD) rats. The SD rats in this study were divided into four groups, one control group (1.0 mL/animal, normal saline) and three experimental groups (0.25, 0.5, and 1.0 mL/animal, SP). All groups consisted of five male and five female rats. SP was injected as a single-dose intramuscularly at the thigh. After the injection, general symptoms and weight were observed for 14 days. After the observations had ended, hematologic and serum biochemical examinations, necropsy and a local tolerance test at the injection site were performed. The experiments were carried out at the Good Laboratory Practice firm, Biotoxtech Co. (Cheongwon, Chungbuk). Animal experiments were approved by the Ethics Committee (Approval Number: 130379). No deaths occurred in any of the three experimental groups. The injection of SP had no effects on the general symptoms, body weights, results of the hematologic, and serum biochemical examinations, and necropsy findings. In local tolerance tests at the injection sites, mild inflammation was observed in the experimental group, but it did not appear to be a treatment related effect. Under the conditions of this test, the results from the injection of SP suggest that the approximate lethal dose of SP is above 1.0 mL/animal for both male and female SD rats. Therefore, the clinical use of SP is thought to be safe.

Absorbed Dose and Dose Equivalent Calculations for Modeling Effective Dose

NASA Technical Reports Server (NTRS)

Welton, Andrew; Lee, Kerry

2010-01-01

While in orbit, Astronauts are exposed to a much higher dose of ionizing radiation than when on the ground. It is important to model how shielding designs on spacecraft reduce radiation effective dose pre-flight, and determine whether or not a danger to humans is presented. However, in order to calculate effective dose, dose equivalent calculations are needed. Dose equivalent takes into account an absorbed dose of radiation and the biological effectiveness of ionizing radiation. This is important in preventing long-term, stochastic radiation effects in humans spending time in space. Monte carlo simulations run with the particle transport code FLUKA, give absorbed and equivalent dose data for relevant shielding. The shielding geometry used in the dose calculations is a layered slab design, consisting of aluminum, polyethylene, and water. Water is used to simulate the soft tissues that compose the human body. The results obtained will provide information on how the shielding performs with many thicknesses of each material in the slab. This allows them to be directly applicable to modern spacecraft shielding geometries.

Influence of lethal and sublethal exposure to clothianidin on the seven-spotted lady beetle, Coccinella septempunctata L. (Coleoptera: Coccinellidae).

PubMed

Jiang, Jiangong; Zhang, Zhengqun; Yu, Xin; Ma, Dicheng; Yu, Caihong; Liu, Feng; Mu, Wei

2018-06-06

The seven-spotted ladybird beetle, Coccinella septempunctata L., as a dominant predator of aphids, has played a crucial role in integrated pest management (IPM) strategies in agricultural ecosystems. To study the risk of insecticides to C. septempunctata, the neonicotinoid clothianidin was selected for evaluation of its influence on C. septempunctata at lethal and sublethal doses. The LR 50 (application rate causing 50% mortality) in the exposed larvae decreased from 19.94 to 5.91 g a.i. ha -1 , and the daily HQ (hazard quotient) values increased from 3.00 to 10.15, indicating potential intoxication risks. We also determined NOERs (No Observed Effect application Rates) of clothianidin on the total developmental time (10 g a.i. ha -1 ), survival (2.5 g a.i. ha -1 ) and pupation (5 g a.i. ha -1 ). Moreover, clothianidin at a NOER of 2.5 g a.i. ha -1 did not profoundly affect adult emergence, fecundity or egg hatchability. The total effect (E) assessment also showed that clothianidin at 2.5 g a.i. ha -1 was slightly harmful to C. septempunctata. These results suggested that clothianidin would impair C. septempunctata when applied at over 2.5 g a.i. ha -1 in the field. Conservation of this biological control agent in agricultural ecosystems thus requires further measures to decrease the applied dosages of clothianidin. Copyright © 2018 Elsevier Inc. All rights reserved.

77 FR 6548 - Notice of Availability of Ballistic Survivability, Lethality and Vulnerability Analyses

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-08

..., Lethality and Vulnerability Analyses AGENCY: Department of the Army, DoD. ACTION: Notice of availability...) is a leader in ballistic survivability, lethality and vulnerability (SLV) analyses. ARL/SLAD conducts SLV analyses, using the MUVES-S2 vulnerability model, to quantify system, subsystem and/or component...

Improving on Army Field Gauze for Lethal Vascular Injuries: Challenges in Dressing Development

USDA-ARS?s Scientific Manuscript database

Accounting for half of all deaths, uncontrolled hemorrhage remains the leading cause of death on the battlefield. Gaining hemostatic control of lethal vascular injuries sustained in combat using topical agents remains a challenge. Recent animal testing using a lethal arterial injury model compared a...

The efficacy and pharmacokinetics of brincidofovir for the treatment of lethal rabbitpox virus infection: a model of smallpox disease.

PubMed

Trost, Lawrence C; Rose, Michelle L; Khouri, Jody; Keilholz, Laurie; Long, James; Godin, Stephen J; Foster, Scott A

2015-05-01

Brincidofovir (BCV) has broad-spectrum in vitro activity against dsDNA viruses, including smallpox, and is being developed as a treatment for smallpox as well as infections caused by other dsDNA viruses. BCV has previously been shown to be active in multiple animal models of smallpox. Here we present the results of a randomized, blinded, placebo-controlled study of the efficacy and pharmacokinetics of a novel, "humanized" regimen of BCV for treatment of New Zealand White rabbits infected with a highly lethal inoculum of rabbitpox virus, a well characterized model of smallpox. Compared with placebo, a dose-dependent increase in survival was observed in all BCV-treatment groups. Concentrations of cidofovir diphosphate (CDV-PP), the active antiviral, in rabbit peripheral blood mononuclear cells (PBMCs) were determined for comparison to those produced in humans at the dose proposed for treatment of smallpox. CDV-PP exposure in PBMCs from rabbits given BCV scaled to human exposures at the dose proposed for treatment of smallpox, which is also currently under evaluation for other indications. The results of this study demonstrate the activity of BCV in the rabbitpox model of smallpox and the feasibility of scaling doses efficacious in the model to a proposed human dose and regimen for treatment of smallpox. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Effect of temperature and heating rate on apparent lethal concentrations of pyrolysis products

NASA Technical Reports Server (NTRS)

Hilado, C. J.; Solis, A. N.; Marcussen, W. H.; Furst, A.

1976-01-01

The apparent lethal concentrations for 50 percent of the test animals of the pyrolysis products from twelve polymeric materials were studied as a function of temperature and heating rate. The materials were polyethylene, nylon 6, ABS, polycarbonate, polyether sulfone, polyaryl sulfone, wool fabric, aromatic polyamide fabric, polychloroprene foam, polyvinyl fluoride film, Douglas fir, and red oak. The apparent lethal concentration values of most materials vary significantly with temperature and heating rate. The apparent lethal concentration values, based on weight of sample charged, appears to effectively integrate the thermophysical, thermochemical, and physiological responses from a known quantity of material under specified imposed conditions.

Beliefs and attitudes toward lethal management of deer in Cuyahoga Valley National Park

USGS Publications Warehouse

Fulton, D.C.; Skerl, K.; Shank, E.M.; Lime, D.W.

2004-01-01

We used the theory of reasoned action to help understand attitudes and beliefs about lethal management of deer (Odocoileus virginianus) in Cuyahoga Valley National Park (CVNP), Ohio. We used a mail-back survey to collect data from Ohio residents in the surrounding 9-county area. Two strata were defined: residents <10 km from CVNP (near n = 369) and residents =10 km from CVNP (far n = 312). Respondents indicated that lethal control of deer was acceptable (near 71%??4.7%, far 62%??5.5%) and taking no action to reduce deer populations was unacceptable (near 75%??4.5%, far 72%??5.1%). Beliefs about outcomes of lethal control and evaluation of those outcomes proved to be strong predictors of the acceptability of lethal control of deer in CVNP. Lethal control was more acceptable if it was done to prevent severe consequences for humans (e.g., spread of disease, car collisions) or the natural environment (e.g., maintain a healthy deer herd) than to prevent negative aesthetic impacts or personal property damage. Results from the study can be used to assist managers at CVNP as they make decisions regarding alternatives for deer management in the park and to inform others managing abundant deer populations of socially relevant impacts of management actions.

The evolution of lethal intergroup violence

PubMed Central

Kelly, Raymond C.

2005-01-01

Recent findings and analyses in evolutionary biology, archaeology, and ethnology provide a favorable conjuncture for examining the evolution of lethal intergroup violence among hominids during the 2.9-million-year Paleolithic time span. Here, I seek to identify and investigate the main turning points in this evolutionary trajectory and to delineate the periodization that follows from this inquiry. PMID:16129826

Anorexia in rats after protracted whole-body irradiation with low doses (in German)

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

Schraub, A.; Sattler, E.L.; Doell, G.

1975-07-01

In our experiments, carried out hitherto, concerning the effect of incorporated and radioactive substances, weight behaviour and food uptake have proved to be a sensitive test. With regard to these experiments and the half- life of the radionuclides used, it is reported about trial series in Wistar rats. These rats were applied, with Co-60 gamma irradiation, different whole-body doses protracted over 48 hours. A total of 32 groups of experimental animals (20 animals each) was exposed to irradiation doses of lethal, medium lethal, and sublethal ranges, control and pseudo-irradiation series included. The experiments were carried out under observance of constantmore » irradiation and attitude conditions, night and day changes, as conditioned by the season, included. Even in the inferior sublethal range (12 to 24 R), a significant trend of decreased food uptake is registered. This trend remains for a short period after the end of irradiation, but then it returns to normal conditions. Furthermore, a new decrease with subsequent increase seems to become evident - about ten days after termination of the radiotherapy (especially after several hundred R); report about these items will be made later on. (orig.)« less

Protease-deficient herpes simplex virus protects mice from lethal herpesvirus infection.

PubMed Central

Hippenmeyer, P J; Rankin, A M; Luckow, V A; Neises, G R

1997-01-01

Null mutants and attenuated mutants of herpes simplex virus (HSV) have been shown to induce immunity against challenge from wild-type virus. Null viruses with a defect in late gene products would be expected to express more viral genes than viruses with defects in essential early gene products and thus induce a better immune response. Herpesviruses encode a late gene product (serine protease) that is autocatalytic and cleaves the capsid assembly protein during viral replication. To determine whether a virus with a mutation in this gene could induce immunity, we constructed a recombinant virus containing the gusA reporter gene in the protease domain of the HSV type 1 UL26 open reading frame (ORF). Consistent with previous results (M. Gao, L. Matusick-Kumar, W. Hurlburt, S. F. DiTusa, W. W. Newcomb, J. C. Brown, P. J. McCann, I. Deckman, and R. J. Colonno, J. Virol. 68:3702-3712, 1994), recombinant virus could be isolated only from helper cell lines expressing the product of the UL26 ORF. Mice inoculated with the recombinant virus were unaffected by doses of virus that were lethal to mice infected with wild-type virus. Mice which were previously inoculated with the recombinant virus were also protected by a subsequent challenge with wild-type virus in a dose-dependent manner. These results indicate that recombinant viruses lacking the protease gene are avirulent but render protection from subsequent challenge. PMID:8995617

A Translational Murine Model of Sub-Lethal Intoxication with Shiga Toxin 2 Reveals Novel Ultrastructural Findings in the Brain Striatum

PubMed Central

Tironi-Farinati, Carla; Geoghegan, Patricia A.; Cangelosi, Adriana; Pinto, Alipio; Loidl, C. Fabian; Goldstein, Jorge

2013-01-01

Infection by Shiga toxin-producing Escherichia coli causes hemorrhagic colitis, hemolytic uremic syndrome (HUS), acute renal failure, and also central nervous system complications in around 30% of the children affected. Besides, neurological deficits are one of the most unrepairable and untreatable outcomes of HUS. Study of the striatum is relevant because basal ganglia are one of the brain areas most commonly affected in patients that have suffered from HUS and since the deleterious effects of a sub-lethal dose of Shiga toxin have never been studied in the striatum, the purpose of this study was to attempt to simulate an infection by Shiga toxin-producing E. coli in a murine model. To this end, intravenous administration of a sub-lethal dose of Shiga toxin 2 (0.5 ηg per mouse) was used and the correlation between neurological manifestations and ultrastructural changes in striatal brain cells was studied in detail. Neurological manifestations included significant motor behavior abnormalities in spontaneous motor activity, gait, pelvic elevation and hind limb activity eight days after administration of the toxin. Transmission electron microscopy revealed that the toxin caused early perivascular edema two days after administration, as well as significant damage in astrocytes four days after administration and significant damage in neurons and oligodendrocytes eight days after administration. Interrupted synapses and mast cell extravasation were also found eight days after administration of the toxin. We thus conclude that the chronological order of events observed in the striatum could explain the neurological disorders found eight days after administration of the toxin. PMID:23383285

Lifestyle and dietary factors in the prevention of lethal prostate cancer

PubMed Central

Wilson, Kathryn M; Giovannucci, Edward L; Mucci, Lorelei A

2012-01-01

The prevention of lethal prostate cancer is a critical public health challenge that would improve health and reduce suffering from this disease. In this review, we discuss the evidence surrounding specific lifestyle and dietary factors in the prevention of lethal prostate cancer. We present a summary of evidence for the following selected behavioral risk factors: obesity and weight change, physical activity, smoking, antioxidant intake, vitamin D and calcium, and coffee intake. PMID:22504869

Lethal effect of a single dose of rasburicase in a preterm newborn infant.

PubMed

Zaramella, Patrizia; De Salvia, Alessandra; Zaninotto, Martina; Baraldi, Maura; Capovilla, Giovanni; De Leo, Domenico; Chiandetti, Lino

2013-01-01

This case report describes a preterm newborn infant who was treated with a single dose of rasburicase for an increase in uric acid level. He died on the third day as a result of complications of hemolysis, which appeared to be precipitated by rasburicase. The patient's death was preceded by progressive respiratory insufficiency, lactic acidosis, and hyperbilirubinemia, culminating in refractory hypoxia and hypotension. A postmortem assay for glucose-6-phosphate dehydrogenase showed deficiency and the glucose-6-phosphate dehydrogenase Mediterranean genotype.

Variability in mutational fitness effects prevents full lethal transitions in large quasispecies populations

NASA Astrophysics Data System (ADS)

Sardanyés, Josep; Simó, Carles; Martínez, Regina; Solé, Ricard V.; Elena, Santiago F.

2014-04-01

The distribution of mutational fitness effects (DMFE) is crucial to the evolutionary fate of quasispecies. In this article we analyze the effect of the DMFE on the dynamics of a large quasispecies by means of a phenotypic version of the classic Eigen's model that incorporates beneficial, neutral, deleterious, and lethal mutations. By parameterizing the model with available experimental data on the DMFE of Vesicular stomatitis virus (VSV) and Tobacco etch virus (TEV), we found that increasing mutation does not totally push the entire viral quasispecies towards deleterious or lethal regions of the phenotypic sequence space. The probability of finding regions in the parameter space of the general model that results in a quasispecies only composed by lethal phenotypes is extremely small at equilibrium and in transient times. The implications of our findings can be extended to other scenarios, such as lethal mutagenesis or genomically unstable cancer, where increased mutagenesis has been suggested as a potential therapy.

Electroshock weapons can be lethal!

NASA Astrophysics Data System (ADS)

Lundquist, Marjorie

2008-03-01

Electroshock weapons (EWs)-stun guns, tasers, riot shields-are electroconductive devices designed to safely incapacitate healthy men neuromuscularly, so they are called nonlethal or less-lethal. EW firms seeking large nonmilitary markets targeted law enforcement and corrections personnel, who began using EWs in prisons/jails and on public patrol in 1980 in the USA. This shifted the EW-shocked population from healthy soldiers to a heterogeneous mix of both sexes, ages 6-92, in a wide variety of health conditions! An EW operates by disrupting normal physiological processes, producing transient effects in healthy people. But if a person's health is sufficiently compromised, the margin of safety can be lost, resulting in death or permanent health problems. 325 people have died after EW shock since 1980. Did the EW cause these deaths? Evidence indicates that EWs do play a causal role in most such deaths. EWs can be lethal for people in diabetic shock^1 (hypoglycemia), which may be why Robert Dziekanski-a Polish immigrant to Canada-died so quickly after he was tasered at Vancouver Airport: not having eaten for over 10 hours, he likely was severely hypoglycemic. The EW death rate in North America is 30 times higher than need be, because EW users have not been properly trained to use EWs on a heterogeneous population safely! ^1J. Clinical Engineering 30(3):111(2005).

The effect of tandem-ovoid titanium applicator on points A, B, bladder, and rectum doses in gynecological brachytherapy using 192Ir

PubMed Central

Sadeghi, Mohammad Hosein; Mehdizadeh, Amir; Faghihi, Reza; Moharramzadeh, Vahed; Meigooni, Ali Soleimani

2018-01-01

Purpose The dosimetry procedure by simple superposition accounts only for the self-shielding of the source and does not take into account the attenuation of photons by the applicators. The purpose of this investigation is an estimation of the effects of the tandem and ovoid applicator on dose distribution inside the phantom by MCNP5 Monte Carlo simulations. Material and methods In this study, the superposition method is used for obtaining the dose distribution in the phantom without using the applicator for a typical gynecological brachytherapy (superposition-1). Then, the sources are simulated inside the tandem and ovoid applicator to identify the effect of applicator attenuation (superposition-2), and the dose at points A, B, bladder, and rectum were compared with the results of superposition. The exact dwell positions, times of the source, and positions of the dosimetry points were determined in images of a patient and treatment data of an adult woman patient from a cancer center. The MCNP5 Monte Carlo (MC) code was used for simulation of the phantoms, applicators, and the sources. Results The results of this study showed no significant differences between the results of superposition method and the MC simulations for different dosimetry points. The difference in all important dosimetry points was found to be less than 5%. Conclusions According to the results, applicator attenuation has no significant effect on the calculated points dose, the superposition method, adding the dose of each source obtained by the MC simulation, can estimate the dose to points A, B, bladder, and rectum with good accuracy. PMID:29619061

The effect of tandem-ovoid titanium applicator on points A, B, bladder, and rectum doses in gynecological brachytherapy using 192Ir.

PubMed

Sadeghi, Mohammad Hosein; Sina, Sedigheh; Mehdizadeh, Amir; Faghihi, Reza; Moharramzadeh, Vahed; Meigooni, Ali Soleimani

2018-02-01

The dosimetry procedure by simple superposition accounts only for the self-shielding of the source and does not take into account the attenuation of photons by the applicators. The purpose of this investigation is an estimation of the effects of the tandem and ovoid applicator on dose distribution inside the phantom by MCNP5 Monte Carlo simulations. In this study, the superposition method is used for obtaining the dose distribution in the phantom without using the applicator for a typical gynecological brachytherapy (superposition-1). Then, the sources are simulated inside the tandem and ovoid applicator to identify the effect of applicator attenuation (superposition-2), and the dose at points A, B, bladder, and rectum were compared with the results of superposition. The exact dwell positions, times of the source, and positions of the dosimetry points were determined in images of a patient and treatment data of an adult woman patient from a cancer center. The MCNP5 Monte Carlo (MC) code was used for simulation of the phantoms, applicators, and the sources. The results of this study showed no significant differences between the results of superposition method and the MC simulations for different dosimetry points. The difference in all important dosimetry points was found to be less than 5%. According to the results, applicator attenuation has no significant effect on the calculated points dose, the superposition method, adding the dose of each source obtained by the MC simulation, can estimate the dose to points A, B, bladder, and rectum with good accuracy.

Examining the impact of psychiatric diagnosis and comorbidity on the medical lethality of adolescent suicide attempts.

PubMed

McManama O'Brien, Kimberly H; Berzin, Stephanie C

2012-08-01

Specific psychiatric diagnoses and comorbidity patterns were examined to determine if they were related to the medical lethality of suicide attempts among adolescents presenting to an urban general hospital (N=375). Bivariate analysis showed that attempters with substance abuse disorders had higher levels of lethality than attempters without substance abuse. Regression results indicated having depression comorbid with any other diagnosis was not associated with medical lethality. However, having a substance abuse disorder was associated with higher suicide attempt lethality, highlighting the importance of substance abuse as a risk factor for lethal suicide attempts in adolescents. This finding stimulates critical thinking around the understanding of suicidal behavior in youth and the development and implementation of treatment strategies for suicidal adolescents with substance abuse disorders. © 2012 The American Association of Suicidology.

Susceptibility of Marmosets (Callithrix jacchus) to Monkeypox Virus: A Low Dose Prospective Model for Monkeypox and Smallpox Disease.

PubMed

Mucker, Eric M; Chapman, Jennifer; Huzella, Louis M; Huggins, John W; Shamblin, Joshua; Robinson, Camenzind G; Hensley, Lisa E

2015-01-01

Although current nonhuman primate models of monkeypox and smallpox diseases provide some insight into disease pathogenesis, they require a high titer inoculum, use an unnatural route of infection, and/or do not accurately represent the entire disease course. This is a concern when developing smallpox and/or monkeypox countermeasures or trying to understand host pathogen relationships. In our studies, we altered half of the test system by using a New World nonhuman primate host, the common marmoset. Based on dose finding studies, we found that marmosets are susceptible to monkeypox virus infection, produce a high viremia, and have pathological features consistent with smallpox and monkeypox in humans. The low dose (48 plaque forming units) required to elicit a uniformly lethal disease and the extended incubation (preclinical signs) are unique features among nonhuman primate models utilizing monkeypox virus. The uniform lethality, hemorrhagic rash, high viremia, decrease in platelets, pathology, and abbreviated acute phase are reflective of early-type hemorrhagic smallpox.

Susceptibility of Marmosets (Callithrix jacchus) to Monkeypox Virus: A Low Dose Prospective Model for Monkeypox and Smallpox Disease

PubMed Central

Mucker, Eric M.; Chapman, Jennifer; Huzella, Louis M.; Huggins, John W.; Shamblin, Joshua; Robinson, Camenzind G.; Hensley, Lisa E.

2015-01-01

Although current nonhuman primate models of monkeypox and smallpox diseases provide some insight into disease pathogenesis, they require a high titer inoculum, use an unnatural route of infection, and/or do not accurately represent the entire disease course. This is a concern when developing smallpox and/or monkeypox countermeasures or trying to understand host pathogen relationships. In our studies, we altered half of the test system by using a New World nonhuman primate host, the common marmoset. Based on dose finding studies, we found that marmosets are susceptible to monkeypox virus infection, produce a high viremia, and have pathological features consistent with smallpox and monkeypox in humans. The low dose (48 plaque forming units) required to elicit a uniformly lethal disease and the extended incubation (preclinical signs) are unique features among nonhuman primate models utilizing monkeypox virus. The uniform lethality, hemorrhagic rash, high viremia, decrease in platelets, pathology, and abbreviated acute phase are reflective of early-type hemorrhagic smallpox. PMID:26147658

Risks of non-lethal weapon use: case studies of three French victims of stinger grenades.

PubMed

Scolan, V; Herry, C; Carreta, M; Stahl, C; Barret, L; Romanet, J P; Paysant, F

2012-11-30

The development of non-lethal weapons started in the 1960s. In France, they have been used by the police for about 10 years. We relate the cases of three French women, victims of stinger grenades, non-lethal weapons recently adopted by the French law enforcement to distract and disperse crowds. The three victims presented serious injuries requiring emergency surgical care. One lost her eye. Based on these cases, we discuss the lethal character of these weapons and propose measures to be taken to prevent their dramatic consequences. Although the danger is obviously less than for firearms, stinger grenades are nonetheless potentially lethal and cause serious physical injuries. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Inactivation of CDK2 is synthetically lethal to MYCN over-expressing cancer cells

PubMed Central

Molenaar, Jan J.; Ebus, Marli E.; Geerts, Dirk; Koster, Jan; Lamers, Fieke; Valentijn, Linda J.; Westerhout, Ellen M.; Versteeg, Rogier; Caron, Huib N.

2009-01-01

Two genes have a synthetically lethal relationship when the silencing or inhibiting of 1 gene is only lethal in the context of a mutation or activation of the second gene. This situation offers an attractive therapeutic strategy, as inhibition of such a gene will only trigger cell death in tumor cells with an activated second oncogene but spare normal cells without activation of the second oncogene. Here we present evidence that CDK2 is synthetically lethal to neuroblastoma cells with MYCN amplification and over-expression. Neuroblastomas are childhood tumors with an often lethal outcome. Twenty percent of the tumors have MYCN amplification, and these tumors are ultimately refractory to any therapy. Targeted silencing of CDK2 by 3 RNA interference techniques induced apoptosis in MYCN-amplified neuroblastoma cell lines, but not in MYCN single copy cells. Silencing of MYCN abrogated this apoptotic response in MYCN-amplified cells. Inversely, silencing of CDK2 in MYCN single copy cells did not trigger apoptosis, unless a MYCN transgene was activated. The MYCN induced apoptosis after CDK2 silencing was accompanied by nuclear stabilization of P53, and mRNA profiling showed up-regulation of P53 target genes. Silencing of P53 rescued the cells from MYCN-driven apoptosis. The synthetic lethality of CDK2 silencing in MYCN activated neuroblastoma cells can also be triggered by inhibition of CDK2 with a small molecule drug. Treatment of neuroblastoma cells with roscovitine, a CDK inhibitor, at clinically achievable concentrations induced MYCN-dependent apoptosis. The synthetically lethal relationship between CDK2 and MYCN indicates CDK2 inhibitors as potential MYCN-selective cancer therapeutics. PMID:19525400

Dosimetry in radiotherapy using a-Si EPIDs: Systems, methods, and applications focusing on 3D patient dose estimation

NASA Astrophysics Data System (ADS)

McCurdy, B. M. C.

2013-06-01

An overview is provided of the use of amorphous silicon electronic portal imaging devices (EPIDs) for dosimetric purposes in radiation therapy, focusing on 3D patient dose estimation. EPIDs were originally developed to provide on-treatment radiological imaging to assist with patient setup, but there has also been a natural interest in using them as dosimeters since they use the megavoltage therapy beam to form images. The current generation of clinically available EPID technology, amorphous-silicon (a-Si) flat panel imagers, possess many characteristics that make them much better suited to dosimetric applications than earlier EPID technologies. Features such as linearity with dose/dose rate, high spatial resolution, realtime capability, minimal optical glare, and digital operation combine with the convenience of a compact, retractable detector system directly mounted on the linear accelerator to provide a system that is well-suited to dosimetric applications. This review will discuss clinically available a-Si EPID systems, highlighting dosimetric characteristics and remaining limitations. Methods for using EPIDs in dosimetry applications will be discussed. Dosimetric applications using a-Si EPIDs to estimate three-dimensional dose in the patient during treatment will be overviewed. Clinics throughout the world are implementing increasingly complex treatments such as dynamic intensity modulated radiation therapy and volumetric modulated arc therapy, as well as specialized treatment techniques using large doses per fraction and short treatment courses (ie. hypofractionation and stereotactic radiosurgery). These factors drive the continued strong interest in using EPIDs as dosimeters for patient treatment verification.

Linear-quadratic dose kinetics or dose-dependent repair/misrepair

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

Braby, L.A.; Nelson, J.M.

1991-09-01

Models for the response of cells exposed to low LET radiation can be grouped into three general types on the basis of assumptions about the nature of the interaction which results in the shoulder of the survival curve. The three forms of interaction are (1) sublethal damage becoming lethal, (2) potentially lethal damage becoming irreparable, and (3) potentially lethal damage saturating'' a repair system. The effects that these three forms of interaction would have on the results of specific types of experiments are investigated. Comparisons with experimental results indicate that only the second type is significant in determining the responsemore » of typical cultured mammalian cells. 5 refs., 2 figs.« less

Structure-Based Systematic Isolation of Conditional-Lethal Mutations in the Single Yeast Calmodulin Gene

PubMed Central

Ohya, Y.; Botstein, D.

1994-01-01

Conditional-lethal mutations of the single calmodulin gene in Saccharomyces cerevisiae have been very difficult to isolate by random and systematic methods, despite the fact that deletions cause recessive lethality. We report here the isolation of numerous conditional-lethal mutants that were recovered by systematically altering phenylalanine residues. The phenylalanine residues of calmodulin were implicated in function both by structural studies of calmodulin bound to target peptides and by their extraordinary conservation in evolution. Seven single and 26 multiple Phe -> Ala mutations were constructed. Mutant phenotypes were examined in a haploid cmd1 disrupted strain under three conditions: single copy, low copy, and overexpressed. Whereas all but one of the single mutations caused no obvious phenotype, most of the multiple mutations caused obvious growth phenotypes. Five were lethal, 6 were lethal only in synthetic medium, 13 were temperature-sensitive lethal and 2 had no discernible phenotypic consequences. Overexpression of some of the mutant genes restored the phenotype to nearly wild type. Several temperature-sensitive calmodulin mutations were suppressed by elevated concentration of CaCl(2) in the medium. Mutant calmodulin protein was detected at normal levels in extracts of most of the lethal mutant cells, suggesting that the deleterious phenotypes were due to loss of the calmodulin function and not protein instability. Analysis of diploid strains heterozygous for all combinations of cmd1-ts alleles revealed four intragenic complementation groups. The contributions of individual phe->ala changes to mutant phenotypes support the idea of internal functional redundancy in the symmetrical calmodulin protein molecule. These results suggest that the several phenylalanine residues in calmodulin are required to different extents in different combinations in order to carry out each of the several essential tasks. PMID:7896089

Non-lethal sampling of walleye for stable isotope analysis: a comparison of three tissues

USGS Publications Warehouse

Chipps, Steven R.; VanDeHey, J.A.; Fincel, M.J.

2012-01-01

Stable isotope analysis of fishes is often performed using muscle or organ tissues that require sacrificing animals. Non-lethal sampling provides an alternative for evaluating isotopic composition for species of concern or individuals of exceptional value. Stable isotope values of white muscle (lethal) were compared with those from fins and scales (non-lethal) in walleye, Sander vitreus (Mitchill), from multiple systems, size classes and across a range of isotopic values. Isotopic variability was also compared among populations to determine the potential of non-lethal tissues for diet-variability analyses. Muscle-derived isotope values were enriched compared with fins and depleted relative to scales. A split-sample validation technique and linear regression found that isotopic composition of walleye fins and scales was significantly related to that in muscle tissue for both δ13C and δ15N (r2 = 0.79–0.93). However, isotopic variability was significantly different between tissue types in two of six populations for δ15N and three of six populations for δ13C. Although species and population specific, these findings indicate that isotopic measures obtained from non-lethal tissues are indicative of those obtained from muscle.

Non-Lethal Weapons (NLW) Reference Book

DTIC Science & Technology

2012-01-01

Array (DSLA) 7 Navy Anti- Swimmer Grenade 7 CP DEVELOPMENTAL NLW Improved Flash Bang Grenade (IFBG) 8 Airburst Non-Lethal Munitions (ANLM) 8...to take all feasible precautions to avoid the incidence of permanent blindness to unenhanced vision training . Frequently Asked Questions iv v...deliver an electro-muscular disruption charge out to 35 feet to disable resistant individuals. This device enhances force protection and mission

Effect of two doses of urea foliar application on leaves and grape nitrogen composition during two vintages.

PubMed

Pérez-Álvarez, Eva P; Garde-Cerdán, Teresa; García-Escudero, Enrique; Martínez-Vidaurre, José María

2017-06-01

Nitrogen affects grapevine growth and also yeast metabolism, which have a direct influence on fermentation kinetics and the formation of different volatile compounds. Throughout the grapevine cycle, soil nitrogen availability and grape nitrogen composition can vary because of different factors. Nitrogen foliar applications can contribute toward enhancing grapevine nitrogen status and minimize the problem of leaching that traditional nitrogen-soil applications can provoke. The present study aimed to evaluate the influence of urea foliar applications on grapevine nitrogen status and grape amino acid content. Accordingly, two different doses of urea were applied over the leaves of a 'Tempranillo' vineyard. The highest urea doses affected nitrogen content on blade leaf tissues after veraison. Must amino acid profiles were modified by urea application and some of the compounds increased their concentrations. The effect of year on the increase of must total amino acid concentrations was more important than the effect of the doses applied. Urea foliar applications can be an interesting tool for decreasing grapevine nitrogen deficiencies. This method of nitrogen implementation in the vineyard could avoid sluggish fermentation problems during winemaking, enhance must nitrogen composition, and contribute to improving wine quality. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

Crystallographic studies of the Anthrax lethal toxin. Annual report

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

Frederick, C.A.

1996-07-01

The lethal form of Anthrax results from the inhalation of anthrax spores. Death is primarily due to the effects of the lethal toxin (Protective Antigen (PA) + Lethal Factor) from the causative agent, Bacillus anthracis. All the Anthrax vaccines currently in use or under development contain or produce PA, the major antigenic component of anthrax toxin, and there is a clear need for an improved vaccine for human use. In the previous report we described the first atomic resolution structure of PA, revealing that the molecule is composed largely of beta-sheets organized into four domains. This information can be usedmore » in the design. of recombinant PA vaccines. In this report we describe additional features of the full-length PA molecule derived from further crystallographic refinement and careful examination of the structure. We compare two crystal forms of PA grown at different pH values and discuss the functional implications. A complete definition of the function of each domain must await the crystal structure of the PA63 heptamer. We have grown crystals of the heptamer under both detergent and detergent-free conditions, and made substantial progress towards the crystal structure. The mechanism of anthrax intoxication in the light of our results is reviewed.« less

[Toxicity study of cefmatilen hydrochloride hydrate (S-1090) (2)--Single oral dose toxicity study in dogs].

PubMed

Kato, I; Nishimura, K; Ueno, M; Inoue, S; Harihara, A; Yabuuchi, K; Sato, K; Miyauchi, H; Hirata, M; Kimura, Y; Furukawa, H

2001-05-01

Cefmatilen hydrochloride hydrate (S-1090) was administered at 500 and 1000 mg potency/kg once orally to beagle dogs. No deaths occurred. Vomiting, diarrhea or mucous feces occurred on the dosing day, and reddish-brown feces (due to chelated products of S-1090 and its decomposition products with Fe3+ in the diet) were also observed on the dosing and next day. Increases of plasma urea nitrogen and iron were observed on the next day after dosing. No remarkable changes were noted in other examination items. The animals in both groups were considered to be exposed to a similar level of S-1090 based on the toxicokinetic data. The oral lethal dose of S-1090 in dogs was estimated to be more than 1000 mg potency/kg.

Dosimetric evaluation of two treatment planning systems for high dose rate brachytherapy applications

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

Shwetha, Bondel; Ravikumar, Manickam, E-mail: drravikumarm@gmail.com; Supe, Sanjay S.

2012-04-01

Various treatment planning systems are used to design plans for the treatment of cervical cancer using high-dose-rate brachytherapy. The purpose of this study was to make a dosimetric comparison of the 2 treatment planning systems from Varian medical systems, namely ABACUS and BrachyVision. The dose distribution of Ir-192 source generated with a single dwell position was compared using ABACUS (version 3.1) and BrachyVision (version 6.5) planning systems. Ten patients with intracavitary applications were planned on both systems using orthogonal radiographs. Doses were calculated at the prescription points (point A, right and left) and reference points RU, LU, RM, LM, bladder,more » and rectum. For single dwell position, little difference was observed in the doses to points along the perpendicular bisector. The mean difference between ABACUS and BrachyVision for these points was 1.88%. The mean difference in the dose calculated toward the distal end of the cable by ABACUS and BrachyVision was 3.78%, whereas along the proximal end the difference was 19.82%. For the patient case there was approximately 2% difference between ABACUS and BrachyVision planning for dose to the prescription points. The dose difference for the reference points ranged from 0.4-1.5%. For bladder and rectum, the differences were 5.2% and 13.5%, respectively. The dose difference between the rectum points was statistically significant. There is considerable difference between the dose calculations performed by the 2 treatment planning systems. It is seen that these discrepancies are caused by the differences in the calculation methodology adopted by the 2 systems.« less

Post-exposure treatment of non-human primates lethally infected with Ebola virus with EBOTAb, a purified ovine IgG product.

PubMed

Dowall, Stuart D; Jacquot, Frédéric; Landon, John; Rayner, Emma; Hall, Graham; Carbonnelle, Caroline; Raoul, Hervé; Pannetier, Delphine; Cameron, Ian; Coxon, Ruth; Al Abdulla, Ibrahim; Hewson, Roger; Carroll, Miles W

2017-06-22

Despite sporadic outbreaks of Ebola virus (EBOV) over the last 4 decades and the recent public health emergency in West Africa, there are still no approved vaccines or therapeutics for the treatment of acute EBOV disease (EVD). In response to the 2014 outbreak, an ovine immunoglobulin therapy was developed, termed EBOTAb. After promising results in the guinea pig model of EBOV infection, EBOTAb was tested in the cynomolgus macaque non-human primate model of lethal EBOV infection. To ensure stringent therapeutic testing conditions to replicate likely clinical usage, EBOTAb was first delivered 1, 2 or 3 days post-challenge with a lethal dose of EBOV. Results showed a protective effect of EBOTAb given post-exposurally, with survival rates decreasing with increasing time after challenge. Viremia results demonstrated that EBOTAb resulted in a decreased circulation of EBOV in the bloodstream. Additionally, assay of liver enzymes and histology analysis of local tissues identified differences between EBOTAb-treated and untreated groups. The results presented demonstrate that EBOTAb conferred protection against EBOV when given post-exposure and should be explored and developed further as a potential intervention strategy for future outbreaks, which are likely to occur.

Technical report. The application of probability-generating functions to linear-quadratic radiation survival curves.

PubMed

Kendal, W S

2000-04-01

To illustrate how probability-generating functions (PGFs) can be employed to derive a simple probabilistic model for clonogenic survival after exposure to ionizing irradiation. Both repairable and irreparable radiation damage to DNA were assumed to occur by independent (Poisson) processes, at intensities proportional to the irradiation dose. Also, repairable damage was assumed to be either repaired or further (lethally) injured according to a third (Bernoulli) process, with the probability of lethal conversion being directly proportional to dose. Using the algebra of PGFs, these three processes were combined to yield a composite PGF that described the distribution of lethal DNA lesions in irradiated cells. The composite PGF characterized a Poisson distribution with mean, chiD+betaD2, where D was dose and alpha and beta were radiobiological constants. This distribution yielded the conventional linear-quadratic survival equation. To test the composite model, the derived distribution was used to predict the frequencies of multiple chromosomal aberrations in irradiated human lymphocytes. The predictions agreed well with observation. This probabilistic model was consistent with single-hit mechanisms, but it was not consistent with binary misrepair mechanisms. A stochastic model for radiation survival has been constructed from elementary PGFs that exactly yields the linear-quadratic relationship. This approach can be used to investigate other simple probabilistic survival models.

SU-E-T-10: A Clinical Implementation and the Dosimetric Evidence in High Dose Rate Vaginal Multichannel Applicator Brachytherapy

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

Syh, J; Syh, J; Patel, B

2015-06-15

Purpose: The multichannel cylindrical applicator has a distinctive modification of the traditional single channel cylindrical applicator. The novel multichannel applicator has additional peripheral channels that provide more flexibility both in treatment planning process and outcomes. To protect by reducing doses to adjacent organ at risk (OAR) while maintaining target coverage with inverse plan optimization are the goals for such novel Brachytherapy device. Through a series of comparison and analysis of reults in more than forty patients who received HDR Brachytherapy using multichannel vaginal applicator, this procedure has been implemented in our institution. Methods: Multichannel planning was CT image based. Themore » CTV of 5mm vaginal cuff rind with prescribed length was well reconstructed as well as bladder and rectum. At least D95 of CTV coverage is 95% of prescribed dose. Multichannel inverse plan optimization algorithm not only shapes target dose cloud but set dose avoids to OAR’s exclusively. The doses of D2cc, D5cc and D5; volume of V2Gy in OAR’s were selected to compare with single channel results when sole central channel is only possibility. Results: Study demonstrates plan superiorly in OAR’s doe reduction in multi-channel plan. The D2cc of the rectum and bladder were showing a little lower for multichannel vs. single channel. The V2Gy of the rectum was 93.72% vs. 83.79% (p=0.007) for single channel vs. multichannel respectively. Absolute reduced mean dose of D5 by multichannel was 17 cGy (s.d.=6.4) and 44 cGy (s.d.=15.2) in bladder and rectum respectively. Conclusion: The optimization solution in multichannel was to maintain D95 CTV coverage while reducing the dose to OAR’s. Dosimetric advantage in sparing critical organs by using a multichannel applicator in HDR Brachytherapy treatment of the vaginal cuff is so promising and has been implemented clinically.« less

Neutropenia induced in outbred mice by a simplified low-dose cyclophosphamide regimen: characterization and applicability to diverse experimental models of infectious diseases

PubMed Central

Zuluaga, Andres F; Salazar, Beatriz E; Rodriguez, Carlos A; Zapata, Ana X; Agudelo, Maria; Vesga, Omar

2006-01-01

Background For its low cost and ease of handling, the mouse remains the preferred experimental animal for preclinical tests. To avoid the interaction of the animal immune system, in vivo antibiotic pharmacodynamic studies often employ cyclophosphamide (CPM) to induce neutropenia. Although high doses (350–450 mg/kg) are still used and their effects on mouse leukocytes have been described, a lower dose (250 mg/kg) is widely preferred today, but the characteristics and applicability of this approach in outbred mice have not been determined. Methods Fifteen female ICR mice were injected intraperitoneally with 150 and 100 mg/kg of CPM on days 1 and 4, respectively. Blood samples (~160 μL) were drawn from the retro-orbital sinus of each mouse on days 1, 4, 5, 6, 7 and 11. Leukocytes were counted manually and the number of granulocytes was based on microscopic examination of Wright-stained smears. The impact of neutropenia induced by this method was then determined with a variety of pathogens in three different murine models of human infections: pneumonia (Klebsiella pneumoniae, Streptococcus pneumoniae, Staphylococcus aureus), meningoencephalitis (S. pneumoniae), and the thigh model (S. aureus, Escherichia coli, Bacteroides fragilis). Results The basal count of leukocytes was within the normal range for outbred mice. On day 4, there was an 84% reduction in total white blood cells, and by day 5 the leukopenia reached its nadir (370 ± 84 cells/mm3). Profound neutropenia (≤10 neutrophils/mm3) was demonstrated at day 4 and persisted through days 5 and 6. Lymphocytes and monocytes had a 92% and 96% decline between days 1 and 5, respectively. Leukocytes recovered completely by day 11. Mice immunosupressed under this protocol displayed clinical and microbiological patterns of progressive and lethal infectious diseases after inoculation in different organs with diverse human pathogens. Conclusion A CPM total dose of 250 mg/kg is sufficient to induce profound and sustained

Fipronil promotes motor and behavioral changes in honey bees (Apis mellifera) and affects the development of colonies exposed to sublethal doses.

PubMed

Zaluski, Rodrigo; Kadri, Samir Moura; Alonso, Diego Peres; Martins Ribolla, Paulo Eduardo; de Oliveira Orsi, Ricardo

2015-05-01

Bees play a crucial role in pollination and generate honey and other hive products; therefore, their worldwide decline is cause for concern. New broad-spectrum systemic insecticides such as fipronil can harm bees and their use has been discussed as a potential threat to bees' survival. In the present study, the authors evaluate the in vitro toxicity of fipronil and note behavioral and motor activity changes in Africanized adult Apis mellifera that ingest or come into contact with lethal or sublethal doses of fipronil. The effects of sublethal doses on brood viability, population growth, behavior, and the expression of the defensin 1 gene in adult bees were studied in colonies fed with contaminated sugar syrup (8 µg fipronil L(-1) ). Fipronil is highly toxic to bees triggering agitation, seizures, tremors, and paralysis. Bees that are exposed to a lethal or sublethal doses showed reduced motor activity. The number of eggs that hatched, the area occupied by worker eggs, and the number of larvae and pupae that developed were reduced, adult bees showed lethargy, and colonies were abandoned when they were exposed to sublethal doses of fipronil. No change was seen in the bees' expression of defensin 1. The authors conclude that fipronil is highly toxic to honey bees and even sublethal doses may negatively affect the development and maintenance of colonies. © 2015 SETAC.

On the mutagenicity of methadone hydrochloride. Induced dominant lethal mutation and spermatocyte chromosomal aberrations in treated males.

PubMed

Badr, F M; Rabouh, S A; Badr, R S

1979-11-01

The mutagenicity of methadone hydrochloride was tested in male mice using the dominant lethal mutation technique and the spermatocyte test of treated mice. Male mice of C3H inbred strain received one of the following doses, 1, 2, 4 or 6 mg/kg body weight once a day for 3 consecutive days. Another group of mice served as control and received saline instead. Treated males were then mated to virgin females at 3-day intervals for a period of 45 days. Pregnant females were dissected at mid-term and the corpora lutea and intrauterine contents were recorded. The spermatocytes of treated males were examined 45-50 d after treatments with methadone and abnormal pairing configurations were scored. The methadone treatment was found to increase the rate of preimplantation deaths consistently in all post-meiotic stages with all doses used. In addition, the higher doses, 4 and 6 mg, affected spermatogonia stages. Quantitatively, the dose-response relationship cannot be demonstrated though the spectrum of effect increased with higher doses as more spermatogenesis stages became more sensitive to the treatment. In many cases the frequency of live implants showed a positive correlation with preimplantation deaths in contrast with the frequency of early deaths which showed only sporadic variation. The mutation indices based on total embryonic death indicate that methadone hydrochloride affected several stages of germ-cell maturation namely, spermatozoa (M.I. 14-35), late spermatids (M.I. 15-48), early spermatids (M.I. 14-50), late spermatocytes (M.I. 15-43) and spermatogonial stages (M.I. 12-63). Chromosome analysis at diakinesis-metaphase 1 revealed significant increase in the frequency of sex chromosome and autosome univalents with different doses of methadone. The smallest dose applied was quite effective and the data represent direct dose-response relationship. Of the multivalent configuration, the most frequent type was chain quadrivalents. The frequencies of total translocations

The maternally expressed WRKY transcription factor TTG2 controls lethality in interploidy crosses of Arabidopsis.

PubMed

Dilkes, Brian P; Spielman, Melissa; Weizbauer, Renate; Watson, Brian; Burkart-Waco, Diana; Scott, Rod J; Comai, Luca

2008-12-09

The molecular mechanisms underlying lethality of F1 hybrids between diverged parents are one target of speciation research. Crosses between diploid and tetraploid individuals of the same genotype can result in F1 lethality, and this dosage-sensitive incompatibility plays a role in polyploid speciation. We have identified variation in F1 lethality in interploidy crosses of Arabidopsis thaliana and determined the genetic architecture of the maternally expressed variation via QTL mapping. A single large-effect QTL, DR. STRANGELOVE 1 (DSL1), was identified as well as two QTL with epistatic relationships to DSL1. DSL1 affects the rate of postzygotic lethality via expression in the maternal sporophyte. Fine mapping placed DSL1 in an interval encoding the maternal effect transcription factor TTG2. Maternal parents carrying loss-of-function mutations in TTG2 suppressed the F1 lethality caused by paternal excess interploidy crosses. The frequency of cellularization in the endosperm was similarly affected by both natural variation and ttg2 loss-of-function mutants. The simple genetic basis of the natural variation and effects of single-gene mutations suggests that F1 lethality in polyploids could evolve rapidly. Furthermore, the role of the sporophytically active TTG2 gene in interploidy crosses indicates that the developmental programming of the mother regulates the viability of interploidy hybrid offspring.

Dose-current discharge correlation analysis in a Mather type Plasma Focus device for medical applications

NASA Astrophysics Data System (ADS)

Sumini, M.; Mostacci, D.; Tartari, A.; Mazza, A.; Cucchi, G.; Isolan, L.; Buontempo, F.; Zironi, I.; Castellani, G.

2017-11-01

In a Plasma Focus device the plasma collapses into the pinch where it reaches thermonuclear conditions for a few tens of nanoseconds, becoming a multi-radiation source. The nature of the radiation generated depends on the gas filling the chamber and the device working parameters. The self-collimated electron beam generated in the backward direction with respect to the plasma motion is one of the main radiation sources of interest also for medical applications. The electron beam may be guided against a high Z material target to produce an X-ray beam. This technique offers an ultra-high dose rate source of X-rays, able to deliver during the pinch a massive dose (up to 1 Gy per discharge for the PFMA-3 test device), as measured with EBT3 GafchromicⒸfilm tissue equivalent dosimeters. Given the stochastic behavior of the discharge process, a reliable on-line estimate of the dose-delivered is a very challenging task, in some way preventing a systematic application as a potentially interesting therapy device. This work presents an approach to linking the dose registered by the EBT3 GafchromicⒸfilms with the information contained in the signal recorded during the current discharge process. Processing the signal with the Wigner-Ville distribution, a spectrogram was obtained, displaying the information on intensity at various frequency scales, identifying the band of frequencies representative of the pinch events and define some patterns correlated with the dose.

Lethal factor antibodies contribute to lethal toxin neutralization in recipients of anthrax vaccine precipitated.

PubMed

Dumas, Eric K; Garman, Lori; Cuthbertson, Hannah; Charlton, Sue; Hallis, Bassam; Engler, Renata J M; Choudhari, Shyamal; Picking, William D; James, Judith A; Farris, A Darise

2017-06-08

A major difference between two currently licensed anthrax vaccines is presence (United Kingdom Anthrax Vaccine Precipitated, AVP) or absence (United States Anthrax Vaccine Adsorbed, AVA) of quantifiable amounts of the Lethal Toxin (LT) component Lethal Factor (LF). The primary immunogen in both vaccine formulations is Protective Antigen (PA), and LT-neutralizing antibodies directed to PA are an accepted correlate of vaccine efficacy; however, vaccination studies in animal models have demonstrated that LF antibodies can be protective. In this report we compared humoral immune responses in cohorts of AVP (n=39) and AVA recipients (n=78) matched 1:2 for number of vaccinations and time post-vaccination, and evaluated whether the LF response contributes to LT neutralization in human recipients of AVP. PA response rates (≥95%) and PA IgG concentrations were similar in both groups; however, AVP recipients exhibited higher LT neutralization ED 50 values (AVP: 1464.0±214.7, AVA: 544.9±83.2, p<0.0001) and had higher rates of LF IgG positivity (95%) compared to matched AVA vaccinees (1%). Multiple regression analysis revealed that LF IgG makes an independent and additive contribution to the LT neutralization response in the AVP group. Affinity purified LF antibodies from two independent AVP recipients neutralized LT and bound to LF Domain 1, confirming contribution of LF antibodies to LT neutralization. This study documents the benefit of including an LF component to PA-based anthrax vaccines. Copyright © 2017 Elsevier Ltd. All rights reserved.

Embryonic lethality is not sufficient to explain hourglass-like conservation of vertebrate embryos.

PubMed

Uchida, Yui; Uesaka, Masahiro; Yamamoto, Takayoshi; Takeda, Hiroyuki; Irie, Naoki

2018-01-01

Understanding the general trends in developmental changes during animal evolution, which are often associated with morphological diversification, has long been a central issue in evolutionary developmental biology. Recent comparative transcriptomic studies revealed that gene expression profiles of mid-embryonic period tend to be more evolutionarily conserved than those in earlier or later periods. While the hourglass-like divergence of developmental processes has been demonstrated in a variety of animal groups such as vertebrates, arthropods, and nematodes, the exact mechanism leading to this mid-embryonic conservation remains to be clarified. One possibility is that the mid-embryonic period (pharyngula period in vertebrates) is highly prone to embryonic lethality, and the resulting negative selections lead to evolutionary conservation of this phase. Here, we tested this "mid-embryonic lethality hypothesis" by measuring the rate of lethal phenotypes of three different species of vertebrate embryos subjected to two kinds of perturbations: transient perturbations and genetic mutations. By subjecting zebrafish ( Danio rerio ), African clawed frog ( Xenopus laevis ), and chicken ( Gallus gallus ) embryos to transient perturbations, namely heat shock and inhibitor treatments during three developmental periods [early (represented by blastula and gastrula), pharyngula, and late], we found that the early stages showed the highest rate of lethal phenotypes in all three species. This result was corroborated by perturbation with genetic mutations. By tracking the survival rate of wild-type embryos and embryos with genetic mutations induced by UV irradiation in zebrafish and African clawed frogs, we found that the highest decrease in survival rate was at the early stages particularly around gastrulation in both these species. In opposition to the "mid-embryonic lethality hypothesis," our results consistently showed that the stage with the highest lethality was not around the

Derivation of Human Lethal Doses

DTIC Science & Technology

2006-01-19

1956; Blair, 1961; Mason et al., 1965; Clarke , 1969; Cretney, 1976; Gray et al., 1985). Gordon reported blood level of 5 mg/100ml in a victim. The...LD50 ( Clark et al., 1979). This is a primary source for the value. No LD50 for mouse Clinical Management of Poisoning and Drug Overdose 100 mL...Verschueren (2001) lists an oral LD50 range in various mammalian species as 30-112 mg/kg based on Clark et al., (1966 as cited in Verschueren, 2001

Fine Mapping and Transcriptome Analysis Reveal Candidate Genes Associated with Hybrid Lethality in Cabbage (Brassica Oleracea).

PubMed

Xiao, Zhiliang; Hu, Yang; Zhang, Xiaoli; Xue, Yuqian; Fang, Zhiyuan; Yang, Limei; Zhang, Yangyong; Liu, Yumei; Li, Zhansheng; Liu, Xing; Liu, Zezhou; Lv, Honghao; Zhuang, Mu

2017-06-05

Hybrid lethality is a deleterious phenotype that is vital to species evolution. We previously reported hybrid lethality in cabbage ( Brassica oleracea ) and performed preliminary mapping of related genes. In the present study, the fine mapping of hybrid lethal genes revealed that BoHL1 was located on chromosome C1 between BoHLTO124 and BoHLTO130, with an interval of 101 kb. BoHL2 was confirmed to be between insertion-deletion (InDels) markers HL234 and HL235 on C4, with a marker interval of 70 kb. Twenty-eight and nine annotated genes were found within the two intervals of BoHL1 and BoHL2 , respectively. We also applied RNA-Seq to analyze hybrid lethality in cabbage. In the region of BoHL1 , seven differentially expressed genes (DEGs) and five resistance (R)-related genes (two in common, i.e., Bo1g153320 and Bo1g153380 ) were found, whereas in the region of BoHL2 , two DEGs and four R-related genes (two in common, i.e., Bo4g173780 and Bo4g173810 ) were found. Along with studies in which R genes were frequently involved in hybrid lethality in other plants, these interesting R-DEGs may be good candidates associated with hybrid lethality. We also used SNP/InDel analyses and quantitative real-time PCR to confirm the results. This work provides new insight into the mechanisms of hybrid lethality in cabbage.

Developing a virtual reality application for training nuclear power plant operators: setting up a database containing dose rates in the refuelling plant.

PubMed

Ródenas, J; Zarza, I; Burgos, M C; Felipe, A; Sánchez-Mayoral, M L

2004-01-01

Operators in Nuclear Power Plants can receive high doses during refuelling operations. A training programme for simulating refuelling operations will be useful in reducing the doses received by workers as well as minimising operation time. With this goal in mind, a virtual reality application is developed within the framework of the CIPRES project. The application requires doses, both instantaneous and accumulated, to be displayed at all times during operator training. Therefore, it is necessary to set up a database containing dose rates at every point in the refuelling plant. This database is based on radiological protection surveillance data measured in the plant during refuelling operations. Some interpolation routines have been used to estimate doses through the refuelling plant. Different assumptions have been adopted in order to perform the interpolation and obtain consistent data. In this paper, the procedures developed to set up the dose database for the virtual reality application are presented and analysed.

Imaginal Disc Abnormalities in Lethal Mutants of Drosophila

PubMed Central

Shearn, Allen; Rice, Thomas; Garen, Alan; Gehring, Walter

1971-01-01

Late lethal mutants of Drosophila melanogaster, dying after the larval stage of development, were isolated. The homozygous mutant larvae were examined for abnormal imaginal disc morphology, and the discs were injected into normal larval hosts to test their capacities to differentiate into adult structures. In about half of the mutants analyzed, disc abnormalities were found. Included among the abnormalities were missing discs, small discs incapable of differentiating, morphologically normal discs with limited capacities for differentiation, and discs with homeotic transformations. In some mutants all discs were affected, and in others only certain discs. The most extreme abnormal phenotype is a class of “discless” mutants. The viability of these mutant larvae indicates that the discs are essential only for the development of an adult and not of a larva. The late lethals are therefore a major source of mutants for studying the genetic control of disc formation. Images PMID:5002822

Use of pellet guns for crowd control in Kashmir: How lethal is "non-lethal"?

PubMed

David, Siddarth

2017-01-01

The use of pellet guns during the recent unrest in Kashmir as a method of crowd control has been questioned because of several deaths and numerous injuries. Across the world, these rubber pellets have been shown to inflict serious injuries, permanent disability, and death. The volatility of mob violence, inaccuracies in aim of the pellets, over-use of the pellet guns, and the perception of their harmlessness enhances the destructive potential of these so-called non-lethal weapons. There is also the larger ethical question whether any form of pain, however minimal, could be inflicted to control violent crowds.

Sickness behaviour associated with non-lethal infections in wild primates

PubMed Central

Ghai, Ria R.; Fugère, Vincent; Chapman, Colin A.; Goldberg, Tony L.; Davies, T. Jonathan

2015-01-01

Non-lethal parasite infections are common in wildlife, but there is little information on their clinical consequences. Here, we pair infection data from a ubiquitous soil-transmitted helminth, the whipworm (genus Trichuris), with activity data from a habituated group of wild red colobus monkeys (Procolobus rufomitratus tephrosceles) in Kibale National Park, Uganda. We use mixed-effect models to examine the relationship between non-lethal parasitism and red colobus behaviour. Our results indicate that red colobus increased resting and decreased more energetically costly behaviours when shedding whipworm eggs in faeces. Temporal patterns of behaviour also changed, with individuals switching behaviour less frequently when whipworm-positive. Feeding frequency did not differ, but red colobus consumption of bark and two plant species from the genus Albizia, which are used locally in traditional medicines, significantly increased when animals were shedding whipworm eggs. These results suggest self-medicative plant use, although additional work is needed to verify this conclusion. Our results indicate sickness behaviours, which are considered an adaptive response by hosts during infection. Induction of sickness behaviour in turn suggests that these primates are clinically sensitive to non-lethal parasite infections. PMID:26311670

Field evaluations of the VD max approach for substantiation of a 25 kGy sterilization dose and its application to other preselected doses

NASA Astrophysics Data System (ADS)

Kowalski, John B.; Herring, Craig; Baryschpolec, Lisa; Reger, John; Patel, Jay; Feeney, Mary; Tallentire, Alan

2002-08-01

The International and European standards for radiation sterilization require evidence of the effectiveness of a minimum sterilization dose of 25 kGy but do not provide detailed guidance on how this evidence can be generated. An approach, designated VD max, has recently been described and computer evaluated to provide safe and unambiguous substantiation of a 25 kGy sterilization dose. The approach has been further developed into a practical method, which has been subjected to field evaluations at three manufacturing facilities which produce different types of medical devices. The three facilities each used a different overall evaluation strategy: Facility A used VD max for quarterly dose audits; Facility B compared VD max and Method 1 in side-by-side parallel experiments; and Facility C, a new facility at start-up, used VD max for initial substantiation of 25 kGy and subsequent quarterly dose audits. A common element at all three facilities was the use of 10 product units for irradiation in the verification dose experiment. The field evaluations of the VD max method were successful at all three facilities; they included many different types of medical devices/product families with a wide range of average bioburden and sample item portion values used in the verification dose experiments. Overall, around 500 verification dose experiments were performed and no failures were observed. In the side-by-side parallel experiments, the outcomes of the VD max experiments were consistent with the outcomes observed with Method 1. The VD max approach has been extended to sterilization doses >25 and <25 kGy; verification doses have been derived for sterilization doses of 15, 20, 30, and 35 kGy. Widespread application of the VD max method for doses other than 25 kGy must await controlled field evaluations and the development of appropriate specifications/standards.

Uncertainties in Assesment of the Vaginal Dose for Intracavitary Brachytherapy of Cervical Cancer using a Tandem-ring Applicator

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

Berger, Daniel; Dimopoulos, Johannes; Georg, Petra

2007-04-01

Purpose: The vagina has not been widely recognized as organ at risk in brachytherapy for cervical cancer. No widely accepted dose parameters are available. This study analyzes the uncertainties in dose reporting for the vaginal wall using tandem-ring applicators. Methods and Materials: Organ wall contours were delineated on axial magnetic resonance (MR) slices to perform dose-volume histogram (DVH) analysis. Different DVH parameters were used in a feasibility study based on 40 magnetic resonance imaging (MRI)-based treatment plans of different cervical cancer patients. Dose to the most irradiated, 0.1 cm{sup 3}, 1 cm{sup 3}, 2 cm{sup 3}, and at defined pointsmore » on the ring surface and at 5-mm tissue depth were reported. Treatment-planning systems allow different methods of dose point definition. Film dosimetry was used to verify the maximum dose at the surface of the ring applicator in an experimental setup. Results: Dose reporting for the vagina is extremely sensitive to geometrical uncertainties with variations of 25% for 1 mm shifts. Accurate delineation of the vaginal wall is limited by the finite pixel size of MRI and available treatment-planning systems. No significant correlation was found between dose-point and dose-volume parameters. The DVH parameters were often related to noncontiguous volumes and were not able to detect very different situations of spatial dose distributions inside the vaginal wall. Deviations between measured and calculated doses were up to 21%. Conclusions: Reporting either point dose values or DVH parameters for the vaginal wall is based on high inaccuracies because of contouring and geometric positioning. Therefore, the use of prospective dose constraints for individual treatment plans is not to be recommended at present. However, for large patient groups treated within one protocol correlation with vaginal morbidity can be evaluated.« less

Synthetic Lethality Reveals Mechanisms of Mycobacterium tuberculosis Resistance to β-Lactams

PubMed Central

Lun, Shichun; Miranda, David; Kubler, Andre; Guo, Haidan; Maiga, Mariama C.; Winglee, Kathryn; Pelly, Shaaretha

2014-01-01

ABSTRACT Most β-lactam antibiotics are ineffective against Mycobacterium tuberculosis due to the microbe’s innate resistance. The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains has prompted interest to repurpose this class of drugs. To identify the genetic determinants of innate β-lactam resistance, we carried out a synthetic lethality screen on a transposon mutant library for susceptibility to imipenem, a carbapenem β-lactam antibiotic. Mutations in 74 unique genes demonstrated synthetic lethality. The majority of mutations were in genes associated with cell wall biosynthesis. A second quantitative real-time PCR (qPCR)-based synthetic lethality screen of randomly selected mutants confirmed the role of cell wall biosynthesis in β-lactam resistance. The global transcriptional response of the bacterium to β-lactams was investigated, and changes in levels of expression of cell wall biosynthetic genes were identified. Finally, we validated these screens in vivo using the MT1616 transposon mutant, which lacks a functional acyl-transferase gene. Mice infected with the mutant responded to β-lactam treatment with a 100-fold decrease in bacillary lung burden over 4 weeks, while the numbers of organisms in the lungs of mice infected with wild-type bacilli proliferated. These findings reveal a road map of genes required for β-lactam resistance and validate synthetic lethality screening as a promising tool for repurposing existing classes of licensed, safe, well-characterized antimicrobials against tuberculosis. PMID:25227469

"Rickettsia amblyommii" induces cross protection against lethal Rocky Mountain spotted fever in a guinea pig model.

PubMed

Blanton, Lucas S; Mendell, Nicole L; Walker, David H; Bouyer, Donald H

2014-08-01

Rocky Mountain spotted fever (RMSF) is a severe illness caused by Rickettsia rickettsii for which there is no available vaccine. We hypothesize that exposure to the highly prevalent, relatively nonpathogenic "Rickettsia amblyommii" protects against R. rickettsii challenge. To test this hypothesis, guinea pigs were inoculated with "R. amblyommii." After inoculation, the animals showed no signs of illness. When later challenged with lethal doses of R. rickettsii, those previously exposed to "R. amblyommii" remained well, whereas unimmunized controls developed severe illness and died. We conclude that "R. amblyommii" induces an immune response that protects from illness and death in the guinea pig model of RMSF. These results provide a basis for exploring the use of low-virulence rickettsiae as a platform to develop live attenuated vaccine candidates to prevent severe rickettsioses.

SU-E-T-29: A Web Application for GPU-Based Monte Carlo IMRT/VMAT QA with Delivered Dose Verification

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

Folkerts, M; University of California, San Diego, La Jolla, CA; Graves, Y

Purpose: To enable an existing web application for GPU-based Monte Carlo (MC) 3D dosimetry quality assurance (QA) to compute “delivered dose” from linac logfile data. Methods: We added significant features to an IMRT/VMAT QA web application which is based on existing technologies (HTML5, Python, and Django). This tool interfaces with python, c-code libraries, and command line-based GPU applications to perform a MC-based IMRT/VMAT QA. The web app automates many complicated aspects of interfacing clinical DICOM and logfile data with cutting-edge GPU software to run a MC dose calculation. The resultant web app is powerful, easy to use, and is ablemore » to re-compute both plan dose (from DICOM data) and delivered dose (from logfile data). Both dynalog and trajectorylog file formats are supported. Users upload zipped DICOM RP, CT, and RD data and set the expected statistic uncertainty for the MC dose calculation. A 3D gamma index map, 3D dose distribution, gamma histogram, dosimetric statistics, and DVH curves are displayed to the user. Additional the user may upload the delivery logfile data from the linac to compute a 'delivered dose' calculation and corresponding gamma tests. A comprehensive PDF QA report summarizing the results can also be downloaded. Results: We successfully improved a web app for a GPU-based QA tool that consists of logfile parcing, fluence map generation, CT image processing, GPU based MC dose calculation, gamma index calculation, and DVH calculation. The result is an IMRT and VMAT QA tool that conducts an independent dose calculation for a given treatment plan and delivery log file. The system takes both DICOM data and logfile data to compute plan dose and delivered dose respectively. Conclusion: We sucessfully improved a GPU-based MC QA tool to allow for logfile dose calculation. The high efficiency and accessibility will greatly facilitate IMRT and VMAT QA.« less

Interleukin-10 protects neonatal mice from lethal group B streptococcal infection.

PubMed Central

Cusumano, V; Genovese, F; Mancuso, G; Carbone, M; Fera, M T; Teti, G

1996-01-01

We investigated the role of interleukin-10 (IL-10) in a neonatal mouse model of lethal group B streptococci (GBS) sepsis. Plasma IL-10 levels significantly increased at 24 and 48 h after GBS inoculation. Neutralization of IL-10 with specific antibodies had no effect on lethality. Administration of recombinant IL-10 at 20 or 4 h before challenge, but not at later times, resulted in decreased tumor necrosis factor alpha levels and improved survival. IL-10 could be potentially useful for the treatment of GBS sepsis. PMID:8698523

Asthma and risk of lethal prostate cancer in the Health Professionals Follow-Up Study.

PubMed

Platz, Elizabeth A; Drake, Charles G; Wilson, Kathryn M; Sutcliffe, Siobhan; Kenfield, Stacey A; Mucci, Lorelei A; Stampfer, Meir J; Willett, Walter C; Camargo, Carlos A; Giovannucci, Edward

2015-08-15

Inflammation, and more generally, the immune response are thought to influence the development of prostate cancer. To determine the components of the immune response that are potentially contributory, we prospectively evaluated the association of immune-mediated conditions, asthma and hayfever, with lethal prostate cancer risk in the Health Professionals Follow-up Study. We included 47,880 men aged 40-75 years with no prior cancer diagnosis. On the baseline questionnaire in 1986, the men reported diagnoses of asthma and hayfever and year of onset. On the follow-up questionnaires, they reported new asthma and prostate cancer diagnoses. We used Cox proportional hazards regression to estimate relative risks (RRs). In total, 9.2% reported ever having been diagnosed with asthma. In all, 25.3% reported a hayfever diagnosis at baseline. During 995,176 person-years of follow-up by 2012, we confirmed 798 lethal prostate cancer cases (diagnosed with distant metastases, progressed to distant metastasis or died of prostate cancer [N = 625]). Ever having a diagnosis of asthma was inversely associated with risk of lethal (RR = 0.71, 95% confidence interval [CI] = 0.51-1.00) and fatal (RR = 0.64, 95% CI = 0.42-0.96) disease. Hayfever with onset in the distant past was possibly weakly positively associated with risk of lethal (RR = 1.10, 95% CI = 0.92-1.33) and fatal (RR = 1.12, 95% CI = 0.91-1.37) disease. Men who were ever diagnosed with asthma were less likely to develop lethal and fatal prostate cancer. Our findings may lead to testable hypotheses about specific immune profiles in the etiology of lethal prostate cancer. © 2015 UICC.

Neutralizing Antibodies Induced by Gene-Based Hydrodynamic Injection Have a Therapeutic Effect in Lethal Influenza Infection

PubMed Central

Yamazaki, Tatsuya; Nagashima, Maria; Ninomiya, Daisuke; Ainai, Akira; Fujimoto, Akira; Ichimonji, Isao; Takagi, Hidekazu; Morita, Naoko; Murotani, Kenta; Hasegawa, Hideki; Chiba, Joe; Akashi-Takamura, Sachiko

2018-01-01

The influenza virus causes annual epidemics and occasional pandemics and is thus a major public health problem. Development of vaccines and antiviral drugs is essential for controlling influenza virus infection. We previously demonstrated the use of vectored immune-prophylaxis against influenza virus infection. We generated a plasmid encoding neutralizing IgG monoclonal antibodies (mAbs) against A/PR/8/34 influenza virus (IAV) hemagglutinin (HA). We then performed electroporation of the plasmid encoding neutralizing mAbs (EP) in mice muscles and succeeded in inducing the expression of neutralizing antibodies in mouse serum. This therapy has a prophylactic effect against lethal IAV infection in mice. In this study, we established a new method of passive immunotherapy after IAV infection. We performed hydrodynamic injection of the plasmid encoding neutralizing mAbs (HD) involving rapid injection of a large volume of plasmid-DNA solution into mice via the tail vein. HD could induce neutralizing antibodies in the serum and in several mucosal tissues more rapidly than in EP. We also showed that a single HD completely protected the mice even after infection with a lethal dose of IAV. We also established other isotypes of anti-HA antibody (IgA, IgM, IgD, and IgE) and showed that like anti-HA IgG, anti-HA IgA was also effective at combating upper respiratory tract IAV infection. Passive immunotherapy with HD could thus provide a new therapeutic strategy targeting influenza virus infection. PMID:29416543

RELATIVE EFFECTIVENESS OF 14 Mev NEUTRONS AND 200 KVP X-RAYS FOR PRODUCTION OF LETHALITY IN GRASSHOPPER EMBRYOS. A PRELIMINARY STUDY (thesis)

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

Bicker, A.E.

1962-05-01

A test system using the grasshopper embryo with hatching as the criterion for the end-point was proposed to determine the relative effectiveness of 14 Mev neutrons and 200 kvp x rays. Eggs of Chortophaga (14 day) and Encoptolophus (14 day and terminal) were subjected to various doses of both radiations. Values for the medial lethal doses from the data obtained were 650 rads for Chortophaga, 760 rads for Encoptolophus (14 day), and 1800 rads for Encoptolophus (terminal). The shape of the dose-effect curve relative to x- irradiation survival was assumed to be unchanged so that an estimate of the LD/more » sub 50/ could be made. The value obtained was 370 rads. The RBE of 14 Mev neutrons and 200 kvp x rays on Chortophaga (14 day) embryos was 1.76. It was concluded that Chortophaga and Encoptolophus embryos irradiated in the 14 day development stage with hatching as an end-point constitute valid systems for the measurement of the relative effectiveness of the 14 Mev neutrons and 200 kvp x rays. (P.C.H.)« less

The Antimalarial Artemisinin Synergizes with Antibiotics To Protect against Lethal Live Escherichia coli Challenge by Decreasing Proinflammatory Cytokine Release

PubMed Central

Wang, Jun; Zhou, Hong; Zheng, Jiang; Cheng, Juan; Liu, Wei; Ding, Guofu; Wang, Liangxi; Luo, Ping; Lu, Yongling; Cao, Hongwei; Yu, Shuangjiang; Li, Bin; Zhang, Lezhi

2006-01-01

In the present study artemisinin (ART) was found to have potent anti-inflammatory effects in animal models of sepsis induced by CpG-containing oligodeoxy-nucleotides (CpG ODN), lipopolysaccharide (LPS), heat-killed Escherichia coli 35218 or live E. coli. Furthermore, we found that ART protected mice from a lethal challenge by CpG ODN, LPS, or heat-killed E. coli in a dose-dependent manner and that the protection was related to a reduction in serum tumor necrosis factor alpha (TNF-α). More significantly, the administration of ART together with ampicillin or unasyn (a complex of ampicillin and sulbactam) decreased mortality from 100 to 66.7% or 33.3%, respectively, in mice subjected to a lethal live E. coli challenge. Together with the observation that ART alone does not inhibit bacterial growth, this result suggests that ART protection is achieved as a result of its anti-inflammatory activity rather than an antimicrobial effect. In RAW264.7 cells, pretreatment with ART potently inhibited TNF-α and interleukin-6 release induced by CpG ODN, LPS, or heat-killed E. coli in a dose- and time-dependent manner. Experiments utilizing affinity sensor technology revealed no direct binding of ART with CpG ODN or LPS. Flow cytometry further showed that ART did not alter binding of CpG ODN to cell surfaces or the internalization of CpG ODN. In addition, upregulated levels of TLR9 and TLR4 mRNA were not attenuated by ART treatment. ART treatment did, however, block the NF-κB activation induced by CpG ODN, LPS, or heat-killed E. coli. These findings provide compelling evidence that ART may be an important potential drug for sepsis treatment. PMID:16801421

Sodium selenosulfate at an innocuous dose markedly prevents cisplatin-induced gastrointestinal toxicity

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

Li, Jun; Sun, Kang; Ni, Lijuan

Our previous studies in mice revealed that two weeks short-term toxicity of sodium selenosulfate was significantly lower than that of sodium selenite, but selenium repletion efficacy of both compounds was equivalent. In addition, we showed that sodium selenosulfate reduced nephrotoxicity of cisplatin (CDDP) without compromising its anticancer activity, thus leading to a dramatic increase of cancer cure rate from 25% to 75%. Hydration has been used in clinical practice to reduce CDDP-induced nephrotoxicity, but it cannot mitigate CDDP-induced gastrointestinal toxicity. The present work investigated whether sodium selenosulfate is a potential preventive agent for the gastrointestinal toxicity. In tumor-bearing mice, sodiummore » selenosulfate was administered at a dose of 9.5 μmol/kg daily for 11 days, CDDP alone resulted in diarrhea by 88% on day 12, whereas the co-administration of CDDP and sodium selenosulfate dramatically reduced diarrhea to 6% (p < 0.0001). Such a prominent protective effect promoted us to evaluate the safety potential of long-term sodium selenosulfate application. Mice were administered with sodium selenosulfate or sodium selenite for 55 days at the doses of 12.7 and 19 μmol/kg. The low-dose sodium selenite caused growth suppression and hepatotoxicity which were aggravated by the high-dose, leading to 40% mortality rate, but no toxic symptoms were observed in the two sodium selenosulfate groups. Altogether these results clearly show that sodium selenosulfate at an innocuous dose can markedly prevent CDDP-induced gastrointestinal toxicity. -- Highlights: ►Cisplatin resulted in diarrhea in mice by 88%. ►i.p. selenosulfate at 9.5 μmol/kg daily for 11 days reduced diarrhea to 6%. ►i.p. selenosulfate at 19 μmol/kg daily for 55 days was not toxic. ►i.p. selenite at 19 μmol/kg daily for 55 days was lethal. ►Innocuous dose of selenosulfate greatly prevents cisplatin-induced diarrhea.« less

Single-dose replication-defective VSV-based Nipah virus vaccines provide protection from lethal challenge in Syrian hamsters.

PubMed

Lo, Michael K; Bird, Brian H; Chattopadhyay, Anasuya; Drew, Clifton P; Martin, Brock E; Coleman, Joann D; Rose, John K; Nichol, Stuart T; Spiropoulou, Christina F

2014-01-01

Nipah virus (NiV) continues to cause outbreaks of fatal human encephalitis due to spillover from its bat reservoir. We determined that a single dose of replication-defective vesicular stomatitis virus (VSV)-based vaccine vectors expressing either the NiV fusion (F) or attachment (G) glycoproteins protected hamsters from over 1000 times LD50 NiV challenge. This highly effective single-dose protection coupled with an enhanced safety profile makes these candidates ideal for potential use in livestock and humans. Published by Elsevier B.V.

Dose–response tests and semi-field evaluation of lethal and sub-lethal effects of slow release pyriproxyfen granules (Sumilarv®0.5G) for the control of the malaria vectors Anopheles gambiae sensu lato

PubMed Central

2013-01-01

Background Recently research has shown that larviciding can be an effective tool for integrated malaria vector control. Nevertheless, the uptake of this intervention has been hampered by the need to re-apply larvicides frequently. There is a need to explore persistent, environmentally friendly larvicides for malaria vector control to reduce intervention efforts and costs by reducing the frequency of application. In this study, the efficacy of a 0.5% pyriproxyfen granule (Surmilarv®0.5G, Sumitomo Chemicals) was assessed for the control of Anopheles gambiae sensu stricto and Anopheles arabiensis, the major malaria vectors in sub-Saharan Africa. Methods Dose–response and standardized field tests were implemented following standard procedures of the World Health Organization’s Pesticide Evaluation Scheme to determine: (i) the susceptibility of vectors to this formulation; (ii) the residual activity and appropriate retreatment schedule for field application; and, (iii) sub-lethal impacts on the number and viability of eggs laid by adults after exposure to Sumilarv®0.5G during larval development. Results Anopheles gambiae s.s. and An. arabiensis were highly susceptible to Sumilarv®0.5G. Estimated emergence inhibition (EI) values were very low and similar for both species. The minimum dosage that completely inhibited adult emergence was between 0.01-0.03 parts per million (ppm) active ingredient (ai). Compared to the untreated control, an application of 0.018 ppm ai prevented 85% (95% confidence interval (CI) 82%-88%) of adult emergence over six weeks under standardized field conditions. A fivefold increase in dosage of 0.09 ppm ai prevented 97% (95% CI 94%-98%) emergence. Significant sub-lethal effects were observed in the standardized field tests. Female An. gambiae s.s. that were exposed to 0.018 ppm ai as larvae laid 47% less eggs, and females exposed to 0.09 ppm ai laid 74% less eggs than females that were unexposed to the treatment. Furthermore, 77

Prophylactic and therapeutic intranasal administration with an immunomodulator, Hiltonol® (Poly IC:LC), in a lethal SARS-CoV-infected BALB/c mouse model.

PubMed

Kumaki, Yohichi; Salazar, Andres M; Wandersee, Miles K; Barnard, Dale L

2017-03-01

Hiltonol ® , (Poly IC:LC), a potent immunomodulator, is a synthetic, double-stranded polyriboinosinic-polyribocytidylic acid (poly IC) stabilized with Poly-L-lysine and carboxymethyl cellulose (LC). Hiltonol ® was tested for efficacy in a lethal SARS-CoV-infected BALB/c mouse model. Hiltonol ® at 5, 1, 0.5 or 0.25 mg/kg/day by intranasal (i.n.) route resulted in significant survival benefit when administered at selected times 24 h prior to challenge with a lethal dose of mouse-adapted severe acute respiratory syndrome coronavirus (SARS-CoV). The infected BALB/c mice receiving the Hiltonol ® treatments were also significantly effective in protecting mice against weight loss due to infection (p < 0.001). Groups of 20 mice were dosed with Hiltonol ® at 2.5 or 0.75 mg/kg by intranasal instillation 7, 14, and 21 days before virus exposure and a second dose was given 24 h later, prophylactic Hiltonol ® treatments (2.5 mg/kg/day) were completely protective in preventing death, and in causing significant reduction in lung hemorrhage scores, lung weights and lung virus titers. Hiltonol ® was also effective as a therapeutic when give up to 8 h post virus exposure; 100% of the-infected mice were protected against death when Hiltonol ® was administered at 5 mg/kg/day 8 h after infection. Our data suggest that Hiltonol ® treatment of SARS-CoV infection in mice leads to substantial prophylactic and therapeutic effects and could be used for treatment of other virus disease such as those caused by MERS-CoV a related coronavirus. These properties might be therapeutically advantageous if Hiltonol ® is considered for possible clinical use. Published by Elsevier B.V.

Effectiveness of Non-Lethal Capabilities in a Maritime Environment

DTIC Science & Technology

2006-09-01

demonstrates both the space filling properties for quantitative factors of the NOLH and the lack of correlation between the factors. 27 Figure 12 ...11 b. Optical Dazzler ........................................................................ 12 c...Warning Munitions................................................................. 12 2. Lethal Capabilities

Synthetically lethal nanoparticles for treatment of endometrial cancer

NASA Astrophysics Data System (ADS)

Ebeid, Kareem; Meng, Xiangbing; Thiel, Kristina W.; Do, Anh-Vu; Geary, Sean M.; Morris, Angie S.; Pham, Erica L.; Wongrakpanich, Amaraporn; Chhonker, Yashpal S.; Murry, Daryl J.; Leslie, Kimberly K.; Salem, Aliasger K.

2018-01-01

Uterine serous carcinoma, one of the most aggressive types of endometrial cancer, is characterized by poor outcomes and mutations in the tumour suppressor p53. Our objective was to engender synthetic lethality to paclitaxel (PTX), the frontline treatment for endometrial cancer, in tumours with mutant p53 and enhance the therapeutic efficacy using polymeric nanoparticles (NPs). First, we identified the optimal NP formulation through comprehensive analyses of release profiles and cellular-uptake and cell viability studies. Not only were PTX-loaded NPs superior to PTX in solution, but the combination of PTX-loaded NPs with the antiangiogenic molecular inhibitor BIBF 1120 (BIBF) promoted synthetic lethality specifically in cells with the loss-of-function (LOF) p53 mutation. In a xenograft model of endometrial cancer, this combinatorial therapy resulted in a marked inhibition of tumour progression and extended survival. Together, our data provide compelling evidence for future studies of BIBF- and PTX-loaded NPs as a therapeutic opportunity for LOF p53 cancers.

Three-dimensional dose verification of the clinical application of gamma knife stereotactic radiosurgery using polymer gel and MRI.

PubMed

Papagiannis, P; Karaiskos, P; Kozicki, M; Rosiak, J M; Sakelliou, L; Sandilos, P; Seimenis, I; Torrens, M

2005-05-07

This work seeks to verify multi-shot clinical applications of stereotactic radiosurgery with a Leksell Gamma Knife model C unit employing a polymer gel-MRI based experimental procedure, which has already been shown to be capable of verifying the precision and accuracy of dose delivery in single-shot gamma knife applications. The treatment plan studied in the present work resembles a clinical treatment case of pituitary adenoma using four 8 mm and one 14 mm collimator helmet shots to deliver a prescription dose of 15 Gy to the 50% isodose line (30 Gy maximum dose). For the experimental dose verification of the treatment plan, the same criteria as those used in the clinical treatment planning evaluation were employed. These included comparison of measured and GammaPlan calculated data, in terms of percentage isodose contours on axial, coronal and sagittal planes, as well as 3D plan evaluation criteria such as dose-volume histograms for the target volume, target coverage and conformity indices. Measured percentage isodose contours compared favourably with calculated ones despite individual point fluctuations at low dose contours (e.g., 20%) mainly due to the effect of T2 measurement uncertainty on dose resolution. Dose-volume histogram data were also found in a good agreement while the experimental results for the percentage target coverage and conformity index were 94% and 1.17 relative to corresponding GammaPlan calculations of 96% and 1.12, respectively. Overall, polymer gel results verified the planned dose distribution within experimental uncertainties and uncertainty related to the digitization process of selected GammaPlan output data.

Lethal Surveillance: Drones and the Geo-History of Modern War

NASA Astrophysics Data System (ADS)

Kindervater, Katharine Hall

Interdisciplinary both in scope and method, my dissertation, Lethal Surveillance: Drones and the Geo-History of Modern War, examines the history of drone technology from the start of the 20th century to the present in order to understand the significance of the increasing centrality of drones to current American military engagements and security practices more generally. Much of the scholarship on drones and many other contemporary military technologies tends to view the technology as radically new, missing both the historical development of these objects as well as the perspectives and rationalities that are embedded in their use. For this research, I focused on three main periods of drone research and development: the early years of World War I and II in the UK, the Cold War, and the 1990s. In studying this history of the drone, I found that two key trends emerge as significant: the increasing importance of information to warfare under the rubric of intelligence, reconnaissance and surveillance; and a shift toward more dynamic, speedier, and individualized targeting practices. I argue that the widespread use of drones today thus represents the culmination of attempts in war to effectively link these two trends, creating a practice I call lethal surveillance -- with the armed Predator effectively closing the loop between identifying and killing targets. The concept of lethal surveillance, which in my dissertation I place squarely within the histories of modern scientific thinking and Western liberal governance, allows us to see how techniques of Western state power and knowledge production are merging with practices of killing and control in new ways, causing significant changes to both the operations of the state and to practices of war. Framing the drone through the lens of lethal surveillance, therefore, allows us to see the longer histories the drone is embedded in as well as other security practices it is connected to.

Transporting Patients with Lethal Contagious Infections

DTIC Science & Technology

2002-04-01

will be analyzed. If the patient requires a BSL-4 patient care room, he or she must be transported to the US Army Medical Research Institute of...consists of a physician, a registered nurse, and 4 to 6 medics who can manage one patient (Figure 2). The team can provide emer- gency care, such as airway...CLINICAL DECISIONS Section Editor: Colleen Swartz, RN, MSN, CCRN Transporting Patients with Lethal Contagious Infections Q If a trauma patient is

SU-E-T-491: Influence of Applicator Dimensions On Doses to Bladder, Rectum and Sigmoid in HDR Brachytherapy for Cervical Cancer

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

Dumane, V; Rhome, R; Yuan, Y

2015-06-15

Purpose: To study the influence of dimensions of the tandem and ring applicator on bladder D2cc, rectum D2cc and sigmoid D2cc in HDR treatment planning for cervical cancer. Methods: 53 plans from 13 patients treated at our institution with the tandem and ring applicator were retrospectively reviewed. Prescription doses were one of the following: 8 Gy x 3, 7 Gy x 4 and 5.5 Gy x 5. Doses to the D2ccs of the bladder, rectum and the sigmoid were recorded. These doses were normalized to their relative prescriptions doses. Correlations between the normalized bladder D2cc, rectum D2cc and sigmoid D2ccmore » were investigated and linear regression models were developed to study the dependence of these doses on the ring diameter and the applicator angle. Results: Normalized doses to the D2cc of the bladder, rectum and sigmoid showed statistically significant correlation (P < 0.05) to the applicator angle. Significant correlation was also noted for the normalized D2cc of the rectum and the sigmoid with the ring diameter. The normalized bladder D2cc was found to decrease with applicator angle on an average by 22.65% ± 4.43% while the same for the rectum and sigmoid were found to increase on an average by 14.43% ± 1.65% and 14.01% ± 1.42% respectively. Both the rectum and sigmoid D2cc reduced with increasing ring diameter by 12.93% ± 1.95% and 11.27% ± 1.79%. No correlation was observed between the normalized bladder D2cc and the ring diameter. Conclusion: Preliminary regression models developed in this study can potentially aid in the choice of the appropriate applicator angle and ring diameter for tandem and ring implant so as to optimize doses to the bladder, rectum and sigmoid.« less

A new label dosimetry system based on pentacosa-diynoic acid monomer for low dose applications

NASA Astrophysics Data System (ADS)

Abdel-Fattah, A. A.; Abdel-Rehim, F.; Soliman, Y. S.

2012-01-01

The dosimetric characteristics of γ-radiation sensitive labels based on polyvinyl butyral (PVB) and a conjugated diacetylene monomer, 10,12-pentacosa-diynoic acid (PCDA) have been investigated using reflectance colorimeter. Two types of labels (colourless and yellow) based on PCDA monomer were prepared using an Automatic Film Applicator System. Upon γ-ray exposure, the colourless label turns progressively blue, while the yellow colour label turns to green then to dark blue. The colour intensity of the labels is proportional to the radiation absorbed dose. The useful dose range was 15 Gy-2 kGy depending on PCDA monomer concentration. The expanded uncertainty of dose measurement of the colourless label was 6.06 (2 σ).

Ectopic expression of Cripto-1 in transgenic mouse embryos causes hemorrhages, fatal cardiac defects and embryonic lethality

PubMed Central

Lin, Xiaolin; Zhao, Wentao; Jia, Junshuang; Lin, Taoyan; Xiao, Gaofang; Wang, Shengchun; Lin, Xia; Liu, Yu; Chen, Li; Qin, Yujuan; Li, Jing; Zhang, Tingting; Hao, Weichao; Chen, Bangzhu; Xie, Raoying; Cheng, Yushuang; Xu, Kang; Yao, Kaitai; Huang, Wenhua; Xiao, Dong; Sun, Yan

2016-01-01

Targeted disruption of Cripto-1 in mice caused embryonic lethality at E7.5, whereas we unexpectedly found that ectopic Cripto-1 expression in mouse embryos also led to embryonic lethality, which prompted us to characterize the causes and mechanisms underlying embryonic death due to ectopic Cripto-1 expression. RCLG/EIIa-Cre embryos displayed complex phenotypes between embryonic day 14.5 (E14.5) and E17.5, including fatal hemorrhages (E14.5-E15.5), embryo resorption (E14.5-E17.5), pale body surface (E14.5-E16.5) and no abnormal appearance (E14.5-E16.5). Macroscopic and histological examination revealed that ectopic expression of Cripto-1 transgene in RCLG/EIIa-Cre embryos resulted in lethal cardiac defects, as evidenced by cardiac malformations, myocardial thinning, failed assembly of striated myofibrils and lack of heartbeat. In addition, Cripto-1 transgene activation beginning after E8.5 also caused the aforementioned lethal cardiac defects in mouse embryos. Furthermore, ectopic Cripto-1 expression in embryonic hearts reduced the expression of cardiac transcription factors, which is at least partially responsible for the aforementioned lethal cardiac defects. Our results suggest that hemorrhages and cardiac abnormalities are two important lethal factors in Cripto-1 transgenic mice. Taken together, these findings are the first to demonstrate that sustained Cripto-1 transgene expression after E11.5 causes fatal hemorrhages and lethal cardiac defects, leading to embryonic death at E14.5-17.5. PMID:27687577

Testing of candidate non-lethal sampling methods for detection of Renibacterium salmoninarum in juvenile Chinook salmon Oncorhynchus tshawytscha

USGS Publications Warehouse

Elliott, Diane G.; McKibben, Constance L.; Conway, Carla M.; Purcell, Maureen K.; Chase, Dorothy M.; Applegate, Lynn M.

2015-01-01

Non-lethal pathogen testing can be a useful tool for fish disease research and management. Our research objectives were to determine if (1) fin clips, gill snips, surface mucus scrapings, blood draws, or kidney biopsies could be obtained non-lethally from 3 to 15 g Chinook salmon Oncorhynchus tshawytscha, (2) non-lethal samples could accurately discriminate between fish exposed to the bacterial kidney disease agent Renibacterium salmoninarum and non-exposed fish, and (3) non-lethal samples could serve as proxies for lethal kidney samples to assess infection intensity. Blood draws and kidney biopsies caused ≥5% post-sampling mortality (Objective 1) and may be appropriate only for larger fish, but the other sample types were non-lethal. Sampling was performed over 21 wk following R. salmoninarum immersion challenge of fish from 2 stocks (Objectives 2 and 3), and nested PCR (nPCR) and real-time quantitative PCR (qPCR) results from candidate non-lethal samples were compared with kidney tissue analysis by nPCR, qPCR, bacteriological culture, enzyme-linked immunosorbent assay (ELISA), fluorescent antibody test (FAT) and histopathology/immunohistochemistry. R. salmoninarum was detected by PCR in >50% of fin, gill, and mucus samples from challenged fish. Mucus qPCR was the only non-lethal assay exhibiting both diagnostic sensitivity and specificity estimates >90% for distinguishing between R. salmoninarum-exposed and non-exposed fish and was the best candidate for use as an alternative to lethal kidney sample testing. Mucus qPCR R. salmoninarum quantity estimates reflected changes in kidney bacterial load estimates, as evidenced by significant positive correlations with kidney R. salmoninaruminfection intensity scores at all sample times and in both fish stocks, and were not significantly impacted by environmentalR. salmoninarum concentrations.

Development of Eczema Vaccinatum in Atopic Mouse Models and Efficacy of MVA Vaccination against Lethal Poxviral Infection

PubMed Central

Knitlova, Jarmila; Hajkova, Vera; Voska, Ludek; Elsterova, Jana; Obrova, Barbora; Melkova, Zora

2014-01-01

Smallpox vaccine based on live, replicating vaccinia virus (VACV) is associated with several potentially serious and deadly complications. Consequently, a new generation of vaccine based on non-replicating Modified vaccinia virus Ankara (MVA) has been under clinical development. MVA seems to induce good immune responses in blood tests, but it is impossible to test its efficacy in vivo in human. One of the serious complications of the replicating vaccine is eczema vaccinatum (EV) occurring in individuals with atopic dermatitis (AD), thus excluding them from all preventive vaccination schemes. In this study, we first characterized and compared development of eczema vaccinatum in different mouse strains. Nc/Nga, Balb/c and C57Bl/6J mice were epicutaneously sensitized with ovalbumin (OVA) or saline control to induce signs of atopic dermatitis and subsequently trans-dermally (t.d.) immunized with VACV strain Western Reserve (WR). Large primary lesions occurred in both mock- and OVA-sensitized Nc/Nga mice, while they remained small in Balb/c and C57Bl/6J mice. Satellite lesions developed in both mock- and OVA-sensitized Nc/Nga and in OVA-sensitized Balb/c mice with the rate 40–50%. Presence of mastocytes and eosinophils was the highest in Nc/Nga mice. Consequently, we have chosen Nc/Nga mice as a model of AD/EV and tested efficacy of MVA and Dryvax vaccinations against a lethal intra-nasal (i.n.) challenge with WR, the surrogate of smallpox. Inoculation of MVA intra-muscularly (i.m.) or t.d. resulted in no lesions, while inoculation of Dryvax t.d. yielded large primary and many satellite lesions similar to WR. Eighty three and 92% of mice vaccinated with a single dose of MVA i.m. or t.d., respectively, survived a lethal i.n. challenge with WR without any serious illness, while all Dryvax-vaccinated animals survived. This is the first formal prove of protective immunity against a lethal poxvirus challenge induced by vaccination with MVA in an atopic organism. PMID

Activity of ergoferon against lethal influenza A (H3N2) virus infection in mice.

PubMed

Skarnovich, Maria A; Emelyanova, Alexandra G; Petrova, Nataliia V; Borshcheva, Alena A; Gorbunov, Evgeniy A; Mazurkov, Oleg Yu; Skarnovich, Maksim O; Tarasov, Sergey A; Shishkina, Larisa N; Epstein, Oleg I

2017-01-01

The influenza A virus accounts for serious annual viral upper respiratory tract infections. It is constantly able to modify its antigenic structure, thus evading host defence mechanisms. Moreover, currently available anti-influenza agents have a rather limited application, emphasizing the further need for new effective treatments. One of them is ergoferon, a drug containing combined polyclonal antibodies - anti-interferon gamma, anti-CD4 receptor and anti-histamine - in released-active form. The purpose of the study was to assess ergoferon antiviral efficacy in mice challenged with the A/Aichi/2/68 (H3N2) influenza virus. The virus was inoculated intranasally at a 90% lethal dose. Ergoferon was administered at 0.4 ml/day per os in a preventive and therapeutic regimen - daily for 5 days prior to and for 16 days after the challenge. The reference product, Tamiflu (oseltamivir), was used as a positive control treatment - at 20 mg/kg/day for 5 days after the challenge. Mice in the negative control group received distilled water which had been utilized for test sample preparation; untreated control animals received no treatment. Antiviral efficacy was assessed by an increase in survival rate, average life expectancy and virus titre reduction in the challenged mouse lungs. Survival rate and average life expectancy values were increased significantly in groups treated with ergoferon and Tamiflu, as compared with controls. Lung virus titres were reduced in these groups as observed on days 2 and 4 post-inoculation. Ergoferon demonstrated antiviral activity by reducing the severity and duration of the major signs of induced influenza infection.

40 CFR 798.5450 - Rodent dominant lethal assay.

Code of Federal Regulations, 2014 CFR

2014-07-01

... germinal tissue of the test species. Dominant lethals are generally accepted to be the result of... methanesulfonate. (d) Test method—(1) Principle. Generally, male animals are exposed to the test substance and... female in the treated group over the dead implants per female in the control group reflects the post...

40 CFR 798.5450 - Rodent dominant lethal assay.

Code of Federal Regulations, 2011 CFR

2011-07-01

... germinal tissue of the test species. Dominant lethals are generally accepted to be the result of... methanesulfonate. (d) Test method—(1) Principle. Generally, male animals are exposed to the test substance and... female in the treated group over the dead implants per female in the control group reflects the post...

40 CFR 798.5450 - Rodent dominant lethal assay.

Code of Federal Regulations, 2010 CFR

2010-07-01

... germinal tissue of the test species. Dominant lethals are generally accepted to be the result of... methanesulfonate. (d) Test method—(1) Principle. Generally, male animals are exposed to the test substance and... female in the treated group over the dead implants per female in the control group reflects the post...

40 CFR 798.5450 - Rodent dominant lethal assay.

Code of Federal Regulations, 2012 CFR

2012-07-01

... germinal tissue of the test species. Dominant lethals are generally accepted to be the result of... methanesulfonate. (d) Test method—(1) Principle. Generally, male animals are exposed to the test substance and... female in the treated group over the dead implants per female in the control group reflects the post...

40 CFR 798.5450 - Rodent dominant lethal assay.

Code of Federal Regulations, 2013 CFR

2013-07-01

... germinal tissue of the test species. Dominant lethals are generally accepted to be the result of... methanesulfonate. (d) Test method—(1) Principle. Generally, male animals are exposed to the test substance and... female in the treated group over the dead implants per female in the control group reflects the post...

An improved brine shrimp larvae lethality microwell test method.

PubMed

Zhang, Yi; Mu, Jun; Han, Jinyuan; Gu, Xiaojie

2012-01-01

This article described an improved brine shrimp larvae lethality microwell test method. A simply designed connecting vessel with alternative photoperiod was used to culture and collect high yield of active Artemia parthenogenetica nauplii for brine shrimp larvae lethality microwell test. Using this method, pure A. parthenogenetica nauplii suspension was easily cultured and harvested with high density about 100-150 larvae per milliliter and the natural mortality was reduced to near zero by elimination of unnecessary artificial disturbance. And its sensitivity was validated by determination of LC(50)-24 h of different reference toxicants including five antitumor agents, two pesticides, three organic pollutants, and four heavy metals salts, most of which exhibited LC(50)-24 h between 0.07 and 58.43 mg/L except for bleomycin and mitomycin C with LC(50)-24 h over 300 mg/L.

Absolute probability estimates of lethal vessel strikes to North Atlantic right whales in Roseway Basin, Scotian Shelf.

PubMed

van der Hoop, Julie M; Vanderlaan, Angelia S M; Taggart, Christopher T

2012-10-01

Vessel strikes are the primary source of known mortality for the endangered North Atlantic right whale (Eubalaena glacialis). Multi-institutional efforts to reduce mortality associated with vessel strikes include vessel-routing amendments such as the International Maritime Organization voluntary "area to be avoided" (ATBA) in the Roseway Basin right whale feeding habitat on the southwestern Scotian Shelf. Though relative probabilities of lethal vessel strikes have been estimated and published, absolute probabilities remain unknown. We used a modeling approach to determine the regional effect of the ATBA, by estimating reductions in the expected number of lethal vessel strikes. This analysis differs from others in that it explicitly includes a spatiotemporal analysis of real-time transits of vessels through a population of simulated, swimming right whales. Combining automatic identification system (AIS) vessel navigation data and an observationally based whale movement model allowed us to determine the spatial and temporal intersection of vessels and whales, from which various probability estimates of lethal vessel strikes are derived. We estimate one lethal vessel strike every 0.775-2.07 years prior to ATBA implementation, consistent with and more constrained than previous estimates of every 2-16 years. Following implementation, a lethal vessel strike is expected every 41 years. When whale abundance is held constant across years, we estimate that voluntary vessel compliance with the ATBA results in an 82% reduction in the per capita rate of lethal strikes; very similar to a previously published estimate of 82% reduction in the relative risk of a lethal vessel strike. The models we developed can inform decision-making and policy design, based on their ability to provide absolute, population-corrected, time-varying estimates of lethal vessel strikes, and they are easily transported to other regions and situations.

Comparative studies on the lethal, mutagenic, and recombinogenic effects of ultraviolet -A, -B, -C, and visible light with and without 8-methoxypsoralen in Saccharomyces cerevisiae.

PubMed

Mondon, P; Shahin, M M

1992-05-01

Genetic effects of UV-A, UV-B, UV-C, and the combination of 8-methoxypsoralen (8-MOP) with UV-A or visible light were studied in the haploid strain XV185-14C and diploid strain D5 of Saccharomyces cerevisiae. The induction of his+, lys+, and hom+ reverse mutations was measured in strain XV185-14C. In strain D5 we measured the induction of genetically altered colonies, particularly twin spot colonies arising from a mitotic crossing-over. UV-C and UV-B induced point mutations at the three loci in the haploid strain and mitotic crossing-over and other genetic alterations in the diploid strain. UV-C was more mutagenic and recombinogenic than UV-B. UV-A or visible light alone did not induce genotoxic effects at the doses tested. However, UV-A plus 8-MOP produced lethal and mutagenic effects in the haploid strain XV185-14C, although mutagenic activity was less than that of UV-B. Visible light plus 8-MOP also induced genotoxic effects in strain XV185-14C. In the diploid strain D5, UV-A plus 8-MOP induced a higher frequency of genetic alterations than UV-B at comparative doses. Visible light plus 8-MOP was also genetically active in strain D5. The haploid strain was more sensitive to the lethal effects of UV-C, UV-B, UV-A, and impure visible light plus 8-MOP than the diploid strain.

Lethal/sublethal responses of Daphnia magna to acute norfloxacin contamination and changes in phytoplankton-zooplankton interactions induced by this antibiotic

NASA Astrophysics Data System (ADS)

Pan, Ying; Yan, Shi-Wei; Li, Ruo-Zhu; Hu, Yi-Wen; Chang, Xue-Xiu

2017-01-01

Although the well-known antibiotic norfloxacin (NOR) is recognized as an important environmental pollutant, little is known about its impacts on ecological processes, particularly on species interactions. In this paper, we quantified Daphnia magna (Crustacea, Cladocera) responses in mortality rate at lethal NOR concentrations (0, 25, 50, 100, 200, 300 and 400 mg L-1), and in heartbeat rate, swimming behavior and feeding rate (on the green alga Chlorella pyrenoidosa) at sublethal NOR concentrations (0, 25, 50 and 100 mg L-1) to determine the effects of this antibiotic in plankton systems. In 96-h-long lethal experiment, mortality rates of D. magna increased significantly with increasing NOR concentration and exposure time. In sublethal experiments, heartbeat rate decreased, while time ratio of vertical to horizontal swimming (TVH) and the duration of quiescence increased in D. magna individuals exposed to increasing NOR concentrations after 4 and 12 h of exposure. These collectively led to decreases in both average swimming ability and feeding rate, consistent with the positive relationship between average swimming ability and feeding rate. Overall, results indicate that, by affecting zooplankton heartbeat rate and behavior, NOR decreased feeding efficiency of D. magna even at low doses, therefore, it might seriously compromise ecosystem health and function.

Lethal and sub-lethal effects of five pesticides used in rice farming on the earthworm Eisenia fetida.

PubMed

Rico, Andreu; Sabater, Consuelo; Castillo, María-Ángeles

2016-05-01

The toxicity of five pesticides typically used in rice farming (trichlorfon, dimethoate, carbendazim, tebuconazole and prochloraz) was evaluated on different lethal and sub-lethal endpoints of the earthworm Eisenia fetida. The evaluated endpoints included: avoidance behaviour after an exposure period of 2 days; and mortality, weight loss, enzymatic activities (cholinesterase, lactate dehydrogenase and alkaline phosphatase) and histopathological effects after an exposure period of 14 days. Carbendazim was found to be highly toxic to E. fetida (LC50=2mg/kg d.w.), significantly reducing earthworm weight and showing an avoidance response at soil concentrations that are close to those predicted in rice-fields and in surrounding ecosystems. The insecticide dimethoate showed a moderate acute toxicity (LC50=28mg/kg d.w.), whereas the rest of tested pesticides showed low toxicity potential (LC50 values above 100mg/kg d.w.). For these pesticides, however, weight loss was identified as a sensitive endpoint, with NOEC values approximately 2 times or lower than the calculated LC10 values. The investigated effects on the enzymatic activities of E. fetida and the observed histopathological alterations (longitudinal and circular muscle lesions, edematous tissues, endothelial degeneration and necrosis) proved to be sensitive biomarkers to monitor pesticide contamination and are proposed as alternative measures to evaluate pesticide risks on agro-ecosystems. Copyright © 2016 Elsevier Inc. All rights reserved.

Systematic discovery of mutation-specific synthetic lethals by mining pan-cancer human primary tumor data

NASA Astrophysics Data System (ADS)

Sinha, Subarna; Thomas, Daniel; Chan, Steven; Gao, Yang; Brunen, Diede; Torabi, Damoun; Reinisch, Andreas; Hernandez, David; Chan, Andy; Rankin, Erinn B.; Bernards, Rene; Majeti, Ravindra; Dill, David L.

2017-05-01

Two genes are synthetically lethal (SL) when defects in both are lethal to a cell but a single defect is non-lethal. SL partners of cancer mutations are of great interest as pharmacological targets; however, identifying them by cell line-based methods is challenging. Here we develop MiSL (Mining Synthetic Lethals), an algorithm that mines pan-cancer human primary tumour data to identify mutation-specific SL partners for specific cancers. We apply MiSL to 12 different cancers and predict 145,891 SL partners for 3,120 mutations, including known mutation-specific SL partners. Comparisons with functional screens show that MiSL predictions are enriched for SLs in multiple cancers. We extensively validate a SL interaction identified by MiSL between the IDH1 mutation and ACACA in leukaemia using gene targeting and patient-derived xenografts. Furthermore, we apply MiSL to pinpoint genetic biomarkers for drug sensitivity. These results demonstrate that MiSL can accelerate precision oncology by identifying mutation-specific targets and biomarkers.

SU-F-T-433: Evaluation of a New Dose Mimicking Application for Clinical Flexibility and Reliability

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

Hoffman, D; Nair, C Kumaran; Wright, C

2016-06-15

Purpose: Clinical workflow and machine down time occasionally require patients to be temporarily treated on a system other than the initial treatment machine. A new commercial dose mimicking application provides automated cross-platform treatment planning to expedite this clinical flexibility. The aim of this work is to evaluate the feasibility of automatic plan creation and establish a robust clinical workflow for prostate and pelvis patients. Methods: Five prostate and five pelvis patients treated with helical plans were selected for re-planning with the dose mimicking application, covering both simple and complex scenarios. Two-arc VMAT and 7- and 9-field IMRT plans were generatedmore » for each case, with the objective function of achieving similar dose volume histogram from the initial helical plans. Dosimetric comparisons include target volumes and organs at risk (OARs) (rectum, bladder, small bowel, femoral heads, etc.). Dose mimicked plans were evaluated by a radiation oncologist, and patient-specific QAs were performed to validate delivery. Results: Overall plan generation and transfer required around 30 minutes of dosimetrist’s time once the dose-mimicking protocol is setup for each site. The resulting VMAT and 7- and 9-field IMRT plans achieved equivalent PTV coverage and homogeneity (D99/DRx = 97.3%, 97.2%, 97.2% and HI = 6.0, 5.8, and 5.9, respectively), compared to helical plans (97.6% and 4.6). The OAR dose discrepancies were up to 6% in rectum Dmean, but generally lower in bladder, femoral heads, bowel and penile bulb. In the context of 1–5 fractions, the radiation oncologist evaluated the dosimetric changes as not clinically significant. All delivery QAs achieved >90% pass with a 3%/3mm gamma criteria. Conclusion: The automated dose-mimicking workflow offers a strategy to avoid missing treatment fractions due to machine down time with non-clinically significant changes in dosimetry. Future work will further optimize dose mimicking plans and

[Gunshot wounds caused by non-lethal ammunition on the porcine model post-mortem].

PubMed

Jabrocký, Peter; Pivko, Juraj; Vondráková, Mária; Tažký, Boris

2013-10-01

In this article we focus on the effects of so called non-lethal ammunition. We studied possible mechanism of firearm injury formation as a consequence of using firearm on the body, to present a more comprehensive material in wound ballistics. We pointed out possible actions of a projectile causes on human, respectively other animal organisms, as well as to a manner in which an injury is caused by rifles or shotguns using non-lethal ammunition with rubber projectiles. In the experiment, we have focused on macroscopic analysis of the tissue penetrated by a rubber projectile fired from a long firearm and pump-action shotgun while focusing on the anatomical-morphological analysis of entry wounds to determine the effectiveness respectively, the wounding potential of the projectile. The results of the experiment based on the macroscopic analysis of entry wounds, cavities and exit wounds, show that when a rubber projectile penetrates the body it causes loss of the tissue (i.e. the minus effect) and mechanical disruption of the tissue similar to lethal projectile. Based on the measures and ballistic computations we concluded that in specific cases, like for example in a close range hit, a penetration of vital organs can cause serious or even lethal injuries.

Structural basis for the unfolding of anthrax lethal factor by protective antigen oligomers

PubMed Central

Feld, Geoffrey K.; Thoren, Katie L.; Kintzer, Alexander F.; Sterling, Harry J.; Tang, Iok I.; Greenberg, Shoshana G.; Williams, Evan R.; Krantz, Bryan A.

2011-01-01

The protein transporter, anthrax lethal toxin, is comprised of protective antigen (PA), a transmembrane translocase, and lethal factor (LF), a cytotoxic enzyme. Following assembly into holotoxin complexes, PA forms an oligomeric channel that unfolds LF and translocates it into the host cell. We report the crystal structure of the core of a lethal toxin complex to 3.1-Å resolution; the structure contains a PA octamer bound to four LF PA-binding domains (LFN). The first α helix and β strand of each LFN unfold and dock into a deep amphipathic cleft on the surface of the PA octamer, which we call the α clamp. The α clamp possesses nonspecific polypeptide binding activity and is functionally relevant to efficient holotoxin assembly, PA octamer formation, and LF unfolding and translocation. This structure provides insight on the mechanism of translocation-coupled protein unfolding. PMID:21037566

Maternal vaccination with a fimbrial tip adhesin and passive protection of neonatal mice against lethal human enterotoxigenic Escherichia coli challenge.

PubMed

Luiz, Wilson B; Rodrigues, Juliana F; Crabb, Joseph H; Savarino, Stephen J; Ferreira, Luis C S

2015-12-01

Globally, enterotoxigenic Escherichia coli (ETEC) is a leading cause of childhood and travelers' diarrhea, for which an effective vaccine is needed. Prevalent intestinal colonization factors (CFs) such as CFA/I fimbriae and heat-labile enterotoxin (LT) are important virulence factors and protective antigens. We tested the hypothesis that donor strand-complemented CfaE (dscCfaE), a stabilized form of the CFA/I fimbrial tip adhesin, is a protective antigen, using a lethal neonatal mouse ETEC challenge model and passive dam vaccination. For CFA/I-ETEC strain H10407, which has been extensively studied in volunteers, an inoculum of 2 × 10(7) bacteria resulted in 50% lethal doses (LD50) in neonatal DBA/2 mice. Vaccination of female DBA/2 mice with CFA/I fimbriae or dscCfaE, each given with a genetically attenuated LT adjuvant (LTK63) by intranasal or orogastric delivery, induced high antigen-specific serum IgG and fecal IgA titers and detectable milk IgA responses. Neonates born to and suckled by dams antenatally vaccinated with each of these four regimens showed 78 to 93% survival after a 20× LD50 challenge with H10407, compared to 100% mortality in pups from dams vaccinated with sham vaccine or LTK63 only. Crossover experiments showed that high pup survival rates after ETEC challenge were associated with suckling but not birthing from vaccinated dams, suggesting that vaccine-specific milk antibodies are protective. In corroboration, preincubation of the ETEC inoculum with antiadhesin and antifimbrial bovine colostral antibodies conferred a dose-dependent increase in pup survival after challenge. These findings indicate that the dscCfaE fimbrial tip adhesin serves as a protective passive vaccine antigen in this small animal model and merits further evaluation. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Maternal Vaccination with a Fimbrial Tip Adhesin and Passive Protection of Neonatal Mice against Lethal Human Enterotoxigenic Escherichia coli Challenge

PubMed Central

Luiz, Wilson B.; Rodrigues, Juliana F.; Crabb, Joseph H.

2015-01-01

Globally, enterotoxigenic Escherichia coli (ETEC) is a leading cause of childhood and travelers' diarrhea, for which an effective vaccine is needed. Prevalent intestinal colonization factors (CFs) such as CFA/I fimbriae and heat-labile enterotoxin (LT) are important virulence factors and protective antigens. We tested the hypothesis that donor strand-complemented CfaE (dscCfaE), a stabilized form of the CFA/I fimbrial tip adhesin, is a protective antigen, using a lethal neonatal mouse ETEC challenge model and passive dam vaccination. For CFA/I-ETEC strain H10407, which has been extensively studied in volunteers, an inoculum of 2 × 107 bacteria resulted in 50% lethal doses (LD50) in neonatal DBA/2 mice. Vaccination of female DBA/2 mice with CFA/I fimbriae or dscCfaE, each given with a genetically attenuated LT adjuvant (LTK63) by intranasal or orogastric delivery, induced high antigen-specific serum IgG and fecal IgA titers and detectable milk IgA responses. Neonates born to and suckled by dams antenatally vaccinated with each of these four regimens showed 78 to 93% survival after a 20× LD50 challenge with H10407, compared to 100% mortality in pups from dams vaccinated with sham vaccine or LTK63 only. Crossover experiments showed that high pup survival rates after ETEC challenge were associated with suckling but not birthing from vaccinated dams, suggesting that vaccine-specific milk antibodies are protective. In corroboration, preincubation of the ETEC inoculum with antiadhesin and antifimbrial bovine colostral antibodies conferred a dose-dependent increase in pup survival after challenge. These findings indicate that the dscCfaE fimbrial tip adhesin serves as a protective passive vaccine antigen in this small animal model and merits further evaluation. PMID:26371126

The art and science of low-energy applications in medicine: pathology perspectives

NASA Astrophysics Data System (ADS)

Thomsen, Sharon L.

2011-03-01

Applications of low energy non-ionizing irradiation result in non-lethal and lethal effects in cells, tissues and intact individuals. The effects of these applications depend on the physical parameters of the applied energies, the mechanisms of interaction of these energies on the target and the biologic status of the target. Recently, cell death has been found not to be a random accident of situation or age but a range of complicated physiological responses to various extrinsic and intrinsic events some of which are genetically programmed and/ or physiologically regulated. Therefore, cell death has been classified into three general groups: 1) Programmed cell death including apoptosis and necroptosis, cornefication and autophagy; 2) Accidental (traumatic) cell death due to the direct, immediate effects of the lethal event and 3) Necrotic cell death which is, by default, all cell death not associated with programmed or accidental cell death. Lethal low energy non-ionizing application biologic effects involve mechanisms of all three groups as compared to high energy applications that predominantly involve the mechanisms of accidental cell death. Currently, the mechanisms of all these modes of cell death are being vigorously investigated. As research and development of new low energy applications continues, the need to understand the mechanisms of cell death that they produce will be critical to the rational creation of safe, yet effective instruments.

USC-087 protects Syrian hamsters against lethal challenge with human species C adenoviruses.

PubMed

Toth, Karoly; Spencer, Jacqueline F; Ying, Baoling; Tollefson, Ann E; Hartline, Caroll B; Richard, Eric T; Fan, Jiajun; Lyu, Jinglei; Kashemirov, Boris A; Harteg, Cheryl; Reyna, Dawn; Lipka, Elke; Prichard, Mark N; McKenna, Charles E; Wold, William S M

2018-05-01

Human adenoviruses (AdV) cause generally mild infections of the respiratory and GI tracts as well as some other tissues. However, AdV can cause serious infection in severely immunosuppressed individuals, especially pediatric patients undergoing allogeneic hematopoietic stem cell transplantation, where mortality rates are up to 80% with disseminated disease. Despite the seriousness of AdV disease, there are no drugs approved specifically to treat AdV infections. We report here that USC-087, an N-alkyl tyrosinamide phosphonate ester prodrug of HPMPA, the adenine analog of cidofovir, is highly effective against multiple AdV types in cell culture. USC-087 is also effective against AdV-C6 in our immunosuppressed permissive Syrian hamster model. In this model, hamsters are immunosuppressed by treatment with high dose cyclophosphamide. Injection of AdV-C6 (or AdV-C5) intravenously leads to a disseminated infection that resembles the disease seen in humans, including death. We have tested the efficacy of orally-administered USC-087 against the median lethal dose of intravenously administered AdV-C6. USC-087 completely prevented or significantly decreased mortality when administered up to 4 days post challenge. USC-087 also prevented or significantly decreased liver damage caused by AdV-C6 infection, and suppressed virus replication even when administered 4 days post challenge. These results imply that USC-087 is a promising candidate for drug development against HAdV infections. Copyright © 2018 Elsevier B.V. All rights reserved.

Immune Protection against Lethal Fungal-Bacterial Intra-Abdominal Infections.

PubMed

Lilly, Elizabeth A; Ikeh, Melanie; Nash, Evelyn E; Fidel, Paul L; Noverr, Mairi C

2018-01-16

Polymicrobial intra-abdominal infections (IAIs) are clinically prevalent and cause significant morbidity and mortality, especially those involving fungi. Our laboratory developed a mouse model of IAI and demonstrated that intraperitoneal inoculation with Candida albicans or other virulent non- albicans Candida (NAC) species plus Staphylococcus aureus resulted in 70 to 80% mortality in 48 to 72 h due to robust local and systemic inflammation (sepsis). Surprisingly, inoculation with Candida dubliniensis or Candida glabrata with S. aureus resulted in minimal mortality, and rechallenge of these mice with lethal C. albicans / S. aureus (i.e., coninfection) resulted in >90% protection. The purpose of this study was to define requirements for C. dubliniensis / S. aureus -mediated protection and interrogate the mechanism of the protective response. Protection was conferred by C. dubliniensis alone or by killed C. dubliniensis plus live S. aureus S. aureus alone was not protective, and killed S. aureus compromised C. dubliniensis -induced protection. C. dubliniensis / S. aureus also protected against lethal challenge by NAC plus S. aureus and could protect for a long-term duration (60 days between primary challenge and C. albicans/S. aureus rechallenge). Unexpectedly, mice deficient in T and B cells (Rag-1 knockouts [KO]) survived both the initial C. dubliniensis/S. aureus challenge and the C. albicans/S. aureus rechallenge, indicating that adaptive immunity did not play a role. Similarly, mice depleted of macrophages prior to rechallenge were also protected. In contrast, protection was associated with high numbers of Gr-1 hi polymorphonuclear leukocytes (PMNLs) in peritoneal lavage fluid within 4 h of rechallenge, and in vivo depletion of Gr-1 + cells prior to rechallenge abrogated protection. These results suggest that Candida species can induce protection against a lethal C. albicans / S. aureus IAI that is mediated by PMNLs and postulated to be a unique form of

The Major Acute-Phase Protein, Serum Amyloid P Component, in Mice Is Not Involved in Endogenous Resistance against Tumor Necrosis Factor Alpha-Induced Lethal Hepatitis, Shock, and Skin Necrosis

PubMed Central

Van Molle, Wim; Hochepied, Tino; Brouckaert, Peter; Libert, Claude

2000-01-01

The proinflammatory cytokine tumor necrosis factor alpha (TNF-α) induces lethal hepatitis when injected into d-(+)-galactosamine-sensitized mice on the one hand or systemic inflammatory response syndrome (SIRS) in normal mice on the other hand. We studied whether serum amyloid P component (SAP), the major acute-phase protein in mice, plays a protective role in both lethal models. For this purpose, we used SAP0/0 mice generated by gene targeting. We studied the lethal response of SAP0/0 or SAP+/+ mice to both lethal triggers but found no differences in the sensitivity of both types of mice. We also investigated whether SAP is involved in establishing two types of endogenous protection: one using a single injection of interleukin-1β (IL-1β) for desensitization and clearly involving a liver protein, the other by tolerizing mice for 5 days using small doses of human TNF-α. Although after IL-1β or after tolerization the SAP levels in the serum had risen fourfold in the control mice and not in the SAP0/0 mice, the same extents of desensitization and tolerization were achieved. Finally, we observed that the induction of hemorrhagic necrosis in the skin of mice by two consecutive local injections with TNF-α was not altered in SAP0/0 mice. We conclude that the presence or absence of SAP has no influence on the sensitivity of mice to TNF-α-induced hepatitis, SIRS, and hemorrhagic necrosis or on the endogenous protective mechanisms of desensitization or tolerization. PMID:10948120

CDK1 Is a Synthetic Lethal Target for KRAS Mutant Tumours

PubMed Central

Costa-Cabral, Sara; Brough, Rachel; Konde, Asha; Aarts, Marieke; Campbell, James; Marinari, Eliana; Riffell, Jenna; Bardelli, Alberto; Torrance, Christopher; Lord, Christopher J.; Ashworth, Alan

2016-01-01

Activating KRAS mutations are found in approximately 20% of human cancers but no RAS-directed therapies are currently available. Here we describe a novel, robust, KRAS synthetic lethal interaction with the cyclin dependent kinase, CDK1. This was discovered using parallel siRNA screens in KRAS mutant and wild type colorectal isogenic tumour cells and subsequently validated in a genetically diverse panel of 26 colorectal and pancreatic tumour cell models. This established that the KRAS/CDK1 synthetic lethality applies in tumour cells with either amino acid position 12 (p.G12V, pG12D, p.G12S) or amino acid position 13 (p.G13D) KRAS mutations and can also be replicated in vivo in a xenograft model using a small molecule CDK1 inhibitor. Mechanistically, CDK1 inhibition caused a reduction in the S-phase fraction of KRAS mutant cells, an effect also characterised by modulation of Rb, a master control of the G1/S checkpoint. Taken together, these observations suggest that the KRAS/CDK1 interaction is a robust synthetic lethal effect worthy of further investigation. PMID:26881434

76 FR 6054 - Use of Less-Than-Lethal Force: Delegation

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-03

... report any medical problems encountered by subjects being subdued and arrested, and no medical problems.... Therefore, for accuracy in terminology, we replace the term ``non-lethal'' with the more accurate term...

Toxicity and motor changes in Africanized honey bees (Apis mellifera L.) exposed to fipronil and imidacloprid.

PubMed

Bovi, Thaís S; Zaluski, Rodrigo; Orsi, Ricardo O

2018-01-01

This study evaluated the in vitro toxicity and motor activity changes in African-derived adult honey bees (Apis mellifera L.) exposed to lethal or sublethal doses of the insecticides fipronil and imidacloprid. Mortality of bees was assessed to determine the ingestion and contact lethal dose for 24 h using probit analysis. Motor activities in bees exposed to lethal (LD50) and sublethal doses (1/500th of the lethal dose) of both insecticides were evaluated in a behavioral observation box at 1 and 4 h. Ingestion and contact lethal doses of fipronil were 0.2316 ? 0.0626 and 0.0080 ? 0.0021 μg/bee, respectively. Ingestion and contact lethal doses of imidacloprid were 0.1079 ? 0.0375 and 0.0308 ? 0.0218 μg/bee, respectively. Motor function of bees exposed to lethal doses of fipronil and imidacloprid was impaired; exposure to sublethal doses of fipronil but not imidacloprid impaired motor function. The insecticides evaluated in this study were highly toxic to African-derived A. mellifera and caused impaired motor function in these pollinators.

Applications of nonlocal means algorithm in low-dose X-ray CT image processing and reconstruction: a review

PubMed Central

Zhang, Hao; Zeng, Dong; Zhang, Hua; Wang, Jing; Liang, Zhengrong

2017-01-01

Low-dose X-ray computed tomography (LDCT) imaging is highly recommended for use in the clinic because of growing concerns over excessive radiation exposure. However, the CT images reconstructed by the conventional filtered back-projection (FBP) method from low-dose acquisitions may be severely degraded with noise and streak artifacts due to excessive X-ray quantum noise, or with view-aliasing artifacts due to insufficient angular sampling. In 2005, the nonlocal means (NLM) algorithm was introduced as a non-iterative edge-preserving filter to denoise natural images corrupted by additive Gaussian noise, and showed superior performance. It has since been adapted and applied to many other image types and various inverse problems. This paper specifically reviews the applications of the NLM algorithm in LDCT image processing and reconstruction, and explicitly demonstrates its improving effects on the reconstructed CT image quality from low-dose acquisitions. The effectiveness of these applications on LDCT and their relative performance are described in detail. PMID:28303644

Lethal mitochondrial cardiomyopathy in a hypomorphic Med30 mouse mutant is ameliorated by ketogenic diet

PubMed Central

Krebs, Philippe; Fan, Weiwei; Chen, Yen-Hui; Tobita, Kimimasa; Downes, Michael R.; Wood, Malcolm R.; Sun, Lei; Xia, Yu; Ding, Ning; Spaeth, Jason M.; Moresco, Eva Marie Y.; Boyer, Thomas G.; Lo, Cecilia Wen Ya; Yen, Jeffrey; Evans, Ronald M.; Beutler, Bruce

2011-01-01

Deficiencies of subunits of the transcriptional regulatory complex Mediator generally result in embryonic lethality, precluding study of its physiological function. Here we describe a missense mutation in Med30 causing progressive cardiomyopathy in homozygous mice that, although viable during lactation, show precipitous lethality 2–3 wk after weaning. Expression profiling reveals pleiotropic changes in transcription of cardiac genes required for oxidative phosphorylation and mitochondrial integrity. Weaning mice to a ketogenic diet extends viability to 8.5 wk. Thus, we establish a mechanistic connection between Mediator and induction of a metabolic program for oxidative phosphorylation and fatty acid oxidation, in which lethal cardiomyopathy is mitigated by dietary intervention. PMID:22106289

Lethal trap trees and semiochemical repellents as area host protection strategies for spruce beetle (Coleoptera: Curculionidae, Scolytinae) in Utah

Treesearch

Matt Hansen; A. Steven Munson; Darren C. Blackford; David Wakarchuk; Scott Baggett

2016-01-01

We tested lethal trap trees and repellent semiochemicals as area treatments to protect host trees from spruce beetle (Dendroctonus rufipennis Kirby) attacks. Lethal trap tree treatments ("spray treatment") combined a spruce beetle bait with carbaryl treatment of the baited spruce. Repellent treatments ("spray-repellent”) combined a baited lethal...

Mobile-Dose: A Dose-Meter Designed for Use in Automatic Machineries for Dose Manipulation in Nuclear Medicine

NASA Astrophysics Data System (ADS)

de Asmundis, Riccardo; Boiano, Alfonso; Ramaglia, Antonio

2008-06-01

Mobile-Dose has been designed for a very innovative use: the integration in a robotic machinery for automatic preparation of radioactive doses, to be injected to patients in Nuclear Medicine Departments, with real time measurement of the activity under preparation. Mobile-Dose gives a constant measurement of the dose during the filling of vials or syringes, triggering the end of the filling process based on a predefined dose limit. Several applications of Mobile-Dose have been delivered worldwide, from Italian hospitals and clinics to European and Japanese ones. The design of such an instrument and its integration in robotic machineries, was required by an Italian company specialised in radiation protection tools for nuclear applications, in the period 2001-2003. At the time of its design, apparently no commercial instruments with a suitable interfacing capability to the external world existed: we designed it in order to satisfy all the strict requirements coming from the medical aspects (precision within 10%, repeatability, stability, time response) and from the industrial conceiving principles that are mandatory to ensure a good reliability in such a complicated environment. The instrument is suitable to be used in standalone mode too, thanks to its portability and compactness and to the intelligent operator panel programmed for this purpose.

Monitoring Effective Doses Received By Air Crews With A Space Weather Application

NASA Astrophysics Data System (ADS)

Lantos, P.

To fulfil new requirements of the European Community concerning monitoring of effective doses received by air crews, the French Aviation Authority has developed an operational system called Sievert. The SIEVERT system is analysed as an exam- ple of Space Weather application. One of its characteristics is to calculate the dose received on-board each flight on the basis of the specific and detailled flight given by companies. Operational models will be used. As input to the models, the system needs monitoring of galactic cosmic rays and of solar flare particles. The French neu- tron monitors located in Kerguelen Islands (South Indian Ocean) and Terre Adélie (Antarctica) will be used for this purpose. Particular attention will be devoted to evo- lution of the system in conjunction with new measurements available in the frame of a permanent validation process.

Targeting synthetic lethality between the SRC kinase and the EPHB6 receptor may benefit cancer treatment.

PubMed

Paul, James M; Toosi, Behzad; Vizeacoumar, Frederick S; Bhanumathy, Kalpana Kalyanasundaram; Li, Yue; Gerger, Courtney; El Zawily, Amr; Freywald, Tanya; Anderson, Deborah H; Mousseau, Darrell; Kanthan, Rani; Zhang, Zhaolei; Vizeacoumar, Franco J; Freywald, Andrew

2016-08-02

Application of tumor genome sequencing has identified numerous loss-of-function alterations in cancer cells. While these alterations are difficult to target using direct interventions, they may be attacked with the help of the synthetic lethality (SL) approach. In this approach, inhibition of one gene causes lethality only when another gene is also completely or partially inactivated. The EPHB6 receptor tyrosine kinase has been shown to have anti-malignant properties and to be downregulated in multiple cancers, which makes it a very attractive target for SL applications. In our work, we used a genome-wide SL screen combined with expression and interaction network analyses, and identified the SRC kinase as a SL partner of EPHB6 in triple-negative breast cancer (TNBC) cells. Our experiments also reveal that this SL interaction can be targeted by small molecule SRC inhibitors, SU6656 and KX2-391, and can be used to improve elimination of human TNBC tumors in a xenograft model. Our observations are of potential practical importance, since TNBC is an aggressive heterogeneous malignancy with a very high rate of patient mortality due to the lack of targeted therapies, and our work indicates that FDA-approved SRC inhibitors may potentially be used in a personalized manner for treating patients with EPHB6-deficient TNBC. Our findings are also of a general interest, as EPHB6 is downregulated in multiple malignancies and our data serve as a proof of principle that EPHB6 deficiency may be targeted by small molecule inhibitors in the SL approach.

Single-dose Intramuscular-injection Toxicology Test of Water-soluble Carthami-flos and Cervi cornu parvum Pharmacopuncture in a Rat Model.

PubMed

Park, Sunju; Sun, Seung-Ho

2015-09-01

The aim of the study is to investigate both the single-dose intramuscular injection toxicity and the approximate lethal dose of water-soluble Carthami-flos and Cervi cornu parvum pharmacopuncture (WCFC) in male and female Sprague-Dawley (SD) rats. The study was conducted at Biotoxtech Co. according to the Good Laboratory Practice (GLP) regulation and the toxicity test guidelines of the Ministry of Food and Drug Safety (MFDS) after approval of the Institutional Animal Care and Use Committee. Dosages for the control, high dose, middle dose and low dose groups were 0.5 mL/animal of saline and 0.5, 0.25 and 0.125 mL/animal of WCFC, respectively. WCFC was injected into the muscle of the left femoral region by using a disposable syringe (1 mL, 26 gauge). The general symptoms and mortality were observed 30 minutes, 1, 2, 4, and 6 hours after the first injection and then daily for 14 days after the injection. The body weights of the SD rats were measured on the day of the injection (before injection) and on the third, seventh, and fourteenth days after the injection. Serum biochemical and hematologic tests, necropsy examinations, and histopathologic examinations at the injection site were performed after the observation period. No deaths, abnormal clinical symptoms, or significant weight changes were observed in either male or female SD rats in the control or the test (0.125, 0.25, and 0.5 mL/animal) groups during the observation period. No significant differences in hematology and serum biochemistry and no macroscopic abnormalities at necropsy were found. No abnormal reactions at injection sites were noted on the topical tolerance tests. The results of this single-dose toxicity study show that WCFC is safe, its lethal doses in male and female SD rats being estimated to be higher than 0.5 mL/animal.

Radiation-induced genomic instability: radiation quality and dose response

NASA Technical Reports Server (NTRS)

Smith, Leslie E.; Nagar, Shruti; Kim, Grace J.; Morgan, William F.

2003-01-01

Genomic instability is a term used to describe a phenomenon that results in the accumulation of multiple changes required to convert a stable genome of a normal cell to an unstable genome characteristic of a tumor. There has been considerable recent debate concerning the importance of genomic instability in human cancer and its temporal occurrence in the carcinogenic process. Radiation is capable of inducing genomic instability in mammalian cells and instability is thought to be the driving force responsible for radiation carcinogenesis. Genomic instability is characterized by a large collection of diverse endpoints that include large-scale chromosomal rearrangements and aberrations, amplification of genetic material, aneuploidy, micronucleus formation, microsatellite instability, and gene mutation. The capacity of radiation to induce genomic instability depends to a large extent on radiation quality or linear energy transfer (LET) and dose. There appears to be a low dose threshold effect with low LET, beyond which no additional genomic instability is induced. Low doses of both high and low LET radiation are capable of inducing this phenomenon. This report reviews data concerning dose rate effects of high and low LET radiation and their capacity to induce genomic instability assayed by chromosomal aberrations, delayed lethal mutations, micronuclei and apoptosis.

Application of stereo x-ray photogrammetry (SRM) in the determination of absorbed dose values during intracavitary radiation therapy

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

van Kleffens, H.J.; Star, W.M.

1979-04-01

The method of stereo x-ray photogrammetry is described, using a stereo x-ray comparator, as well as some clinical applications. The x-ray equipment consists of two x-ray tubes and a pneumatically driven cassette changer, developed to reduce effects of patient or organ motion between stero radiographs. The accuracy of the set-up is demonstated with measurements on a geometrical model and on a gelatine phantom containing radium needles. The clinical use is reported in determining dose rates to points of the intestinal wall during intracavitary radiotherapy of gynecological cancer. In a number of cases the stereo measurements have resulted in a changemore » in the application time or in the charge or position of the applicator, possibly preventing later complications, as a result of a high dose. Future applications for implant dosimetry (/sup 192/Ir, /sup 125/I) are suggested.« less

A comparative study of proliferative nodules and lethal melanomas in congenital nevi from children.

PubMed

Yélamos, Oriol; Arva, Nicoleta C; Obregon, Roxana; Yazdan, Pedram; Wagner, Annette; Guitart, Joan; Gerami, Pedram

2015-03-01

Differentiating proliferative nodules (PNs) from melanomas arising in congenital nevi (CN) is a considerable challenge for dermatopathologists. Most of the specimens dermatopathologists assess that deal with this differential diagnosis involve proliferations of melanocytes arising in the dermis. In this study, we compare the clinical, histologic, and molecular findings of these 2 conditions. In our database, we found 22 examples of PNs arising in the dermis of CN and 2 cases of lethal melanomas arising from the dermis/epidermis of CN of children. Importantly, we found that among dermal melanocytic proliferations arising from CN in children, PNs are far more common than lethal melanomas. Clinically, multiplicity of lesions favored a diagnosis of PNs, whereas ulceration was infrequent in PNs compared with lethal melanomas. Histologically, PNs showed several distinct patterns including expansile nodules of epithelioid melanocytes with mitotic counts lower than that seen in the melanomas (1.67 vs. 12.5 mitoses/mm), a small round blue cell pattern often highly mitotically active, neurocristic-like, blue nevus-like, a nevoid melanoma-like pattern, or an undifferentiated spindle cell pattern. The lethal melanomas both featured expansile nodules of epithelioid melanocytes with high mitotic counts (range, 5 to 20 mitoses/mm) and an ulcerated overlying epidermis. At the molecular level, the PNs showed mostly whole chromosomal copy number aberrations, which in some cases were accompanied by rare partial chromosomal aberrations, whereas both lethal melanomas showed highly elevated copy number aberrations involving 6p25 without gains of the long arm of chromosome 6.

SU-F-T-35: Optimization of Bladder and Rectal Doses Using a Multi-Lumen Intracavitary Applicator for Gynecological Brachytherapy

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

Laoui, S; Dietrich, S; Sehgal, V

2016-06-15

Purpose: Radiation dose delivery for endometrial cancer using HDR techniques is limited by dose to bladder and rectum. A dosimetric study was performed using Varian Capri vaginal brachytherapy applicator to determine the optimal channel configuration which minimizes dose to bladder and rectum, while providing good target coverage. Methods: A total of 17 patients, 63 plans clinically delivered, and 252 simulated plans using Varian BrachyVision planning system were generated to investigate optimal channel configuration which results in minimum dose to bladder and rectum while providing adequate target coverage. The Capri applicator consists of 13 lumens arranged in two concentric rings, onemore » central lumen and six lumens per ring. Manual dose shaping is invariably required to lower the dose to critical organs. Three-dimensional plans were simulated for 4 channel arrangements, all 13 channels, channel 12 o’clock (close to bladder) and 6 o’clock (close to rectum) deactivated, central channel deactivated, and central channel in addition to 12 o’clock and 6 o’clock deactivated. A relationship between V100, the volume that receives the prescribed dose, and the amount of curie-seconds required to deliver it, was established. Results: Using all 13 channels results in maximum dose to bladder and rectum. Deactivating central channel in addition to 12 o’clock and 6 o’clock resulted in minimizing bladder and rectum doses but compromised target coverage. The relationship between V100, the volume that receives the prescribed dose, and the curie seconds was found to be linear. Conclusion: Deactivating channels 12 o’clock and 6 o’clock was shown to be the optimal configuration leading to minimum dose to bladder and rectum without compromising target coverage. The linear relationship between V100 and the curie- seconds can be used as a verification parameter.« less

Developing Non-Lethal Weapons: The Human Effects Characterization Process

DTIC Science & Technology

2015-06-01

countered more than a dozen, rock-throwing locals. After a Marine fired a 12 - gauge , non-lethal warning munition, the rock throwers fled. Similarly...extended human electromuscular incapacitation (ef- fects similar to those caused by TASER devices used by law enforcement). However, confidence must be

Functional genomics reveals the induction of inflammatory response and metalloproteinase gene expression during lethal Ebola virus infection.

PubMed

Cilloniz, Cristian; Ebihara, Hideki; Ni, Chester; Neumann, Gabriele; Korth, Marcus J; Kelly, Sara M; Kawaoka, Yoshihiro; Feldmann, Heinz; Katze, Michael G

2011-09-01

Ebola virus is the etiologic agent of a lethal hemorrhagic fever in humans and nonhuman primates with mortality rates of up to 90%. Previous studies with Zaire Ebola virus (ZEBOV), mouse-adapted virus (MA-ZEBOV), and mutant viruses (ZEBOV-NP(ma), ZEBOV-VP24(ma), and ZEBOV-NP/VP24(ma)) allowed us to identify the mutations in viral protein 24 (VP24) and nucleoprotein (NP) responsible for acquisition of high virulence in mice. To elucidate specific molecular signatures associated with lethality, we compared global gene expression profiles in spleen samples from mice infected with these viruses and performed an extensive functional analysis. Our analysis showed that the lethal viruses (MA-ZEBOV and ZEBOV-NP/VP24(ma)) elicited a strong expression of genes 72 h after infection. In addition, we found that although the host transcriptional response to ZEBOV-VP24(ma) was nearly the same as that to ZEBOV-NP/VP24(ma), the contribution of a mutation in the NP gene was required for a lethal phenotype. Further analysis indicated that one of the most relevant biological functions differentially regulated by the lethal viruses was the inflammatory response, as was the induction of specific metalloproteinases, which were present in our newly identify functional network that was associated with Ebola virus lethality. Our results suggest that this dysregulated proinflammatory response increased the severity of disease. Consequently, the newly discovered molecular signature could be used as the starting point for the development of new drugs and therapeutics. To our knowledge, this is the first study that clearly defines unique molecular signatures associated with Ebola virus lethality.

Effects of β-glucan polysaccharide revealed by the dominant lethal assay and micronucleus assays, and reproductive performance of male mice exposed to cyclophosphamide

PubMed Central

Oliveira, Rodrigo Juliano; Pesarini, João Renato; Sparça Salles, Maria José; Nakamura Kanno, Tatiane Yumi; dos Santos Lourenço, Ana Carolina; da Silva Leite, Véssia; da Silva, Ariane Fernanda; Matiazi, Hevenilton José; Ribeiro, Lúcia Regina; Mantovani, Mário Sérgio

2014-01-01

β-glucan is a well-known polysaccharide for its chemopreventive effect. This study aimed to evaluate the chemopreventive ability of β-glucan in somatic and germ cells through the dominant lethal and micronucleus assays, and its influence on the reproductive performance of male mice exposed to cyclophosphamide. The results indicate that β-glucan is capable of preventing changes in DNA in both germ cells and somatic ones. Changes in germ cells were evaluated by the dominant lethal assay and showed damage reduction percentages of 46.46% and 43.79% for the doses of 100 and 150 mg/kg. For the somatic changes, evaluated by micronucleus assay in peripheral blood cells in the first week of treatment, damage reduction percentages from 80.63–116.32% were found. In the fifth and sixth weeks, the percentage ranged from 10.20–52.54% and −0.95–62.35%, respectively. Besides the chemopreventive efficiency it appears that the β-glucan, when combined with cyclophosphamide, is able to improve the reproductive performance of males verified by the significant reduction in rates of post-implantation losses and reabsorption in the mating of nulliparous females with males treated with cyclophosphamide. PMID:24688298

Effects of β-glucan polysaccharide revealed by the dominant lethal assay and micronucleus assays, and reproductive performance of male mice exposed to cyclophosphamide.

PubMed

Oliveira, Rodrigo Juliano; Pesarini, João Renato; Sparça Salles, Maria José; Nakamura Kanno, Tatiane Yumi; Dos Santos Lourenço, Ana Carolina; da Silva Leite, Véssia; da Silva, Ariane Fernanda; Matiazi, Hevenilton José; Ribeiro, Lúcia Regina; Mantovani, Mário Sérgio

2014-03-01

β-glucan is a well-known polysaccharide for its chemopreventive effect. This study aimed to evaluate the chemopreventive ability of β-glucan in somatic and germ cells through the dominant lethal and micronucleus assays, and its influence on the reproductive performance of male mice exposed to cyclophosphamide. The results indicate that β-glucan is capable of preventing changes in DNA in both germ cells and somatic ones. Changes in germ cells were evaluated by the dominant lethal assay and showed damage reduction percentages of 46.46% and 43.79% for the doses of 100 and 150 mg/kg. For the somatic changes, evaluated by micronucleus assay in peripheral blood cells in the first week of treatment, damage reduction percentages from 80.63-116.32% were found. In the fifth and sixth weeks, the percentage ranged from 10.20-52.54% and -0.95-62.35%, respectively. Besides the chemopreventive efficiency it appears that the β-glucan, when combined with cyclophosphamide, is able to improve the reproductive performance of males verified by the significant reduction in rates of post-implantation losses and reabsorption in the mating of nulliparous females with males treated with cyclophosphamide.

Adulticidal Susceptibility Evaluation of Aedes albopictus Using New Diagnostic Doses in Penang Island, Malaysia.

PubMed

Rahim, Junaid; Ahmad, Abu H; Ahmad, Hamdan; Ishak, Intan H; Rus, Adanan Che; Maimusa, Hamisu A

2017-09-01

Insecticide-based vector control approaches are facing challenges due to the development of resistance in vector mosquitoes. Therefore, a proper resistance surveillance program using baseline lethal concentrations is crucial for resistance management strategies. Currently, the World Health Organization's (WHO) diagnostic doses established for Aedes aegypti and Anopheles species are being used to study the resistance status of Aedes albopictus. In this study, we established the diagnostic doses for permethrin, deltamethrin, and malathion using a known susceptible reference strain. Five field-collected populations were screened against these doses, following the WHO protocol. This study established the diagnostic dose of malathion at 2.4%, permethrin at 0.95%, and deltamethrin at 0.28%, which differ from the WHO doses for Aedes aegypti and Anopheles spp. Among the insecticides tested on the 5 wild populations, only deltamethrin showed high effectiveness. Different susceptibility and resistance patterns were observed with permethrin, malathion, and dichloro-diphenyl-trichloroethane (DDT) at 4%. This study may assist the health authorities to improve future chemical-based vector control operations in dengue-endemic areas.

Monte Carlo dose calculations for high-dose-rate brachytherapy using GPU-accelerated processing.

PubMed

Tian, Z; Zhang, M; Hrycushko, B; Albuquerque, K; Jiang, S B; Jia, X

2016-01-01

Current clinical brachytherapy dose calculations are typically based on the Association of American Physicists in Medicine Task Group report 43 (TG-43) guidelines, which approximate patient geometry as an infinitely large water phantom. This ignores patient and applicator geometries and heterogeneities, causing dosimetric errors. Although Monte Carlo (MC) dose calculation is commonly recognized as the most accurate method, its associated long computational time is a major bottleneck for routine clinical applications. This article presents our recent developments of a fast MC dose calculation package for high-dose-rate (HDR) brachytherapy, gBMC, built on a graphics processing unit (GPU) platform. gBMC-simulated photon transport in voxelized geometry with physics in (192)Ir HDR brachytherapy energy range considered. A phase-space file was used as a source model. GPU-based parallel computation was used to simultaneously transport multiple photons, one on a GPU thread. We validated gBMC by comparing the dose calculation results in water with that computed TG-43. We also studied heterogeneous phantom cases and a patient case and compared gBMC results with Acuros BV results. Radial dose function in water calculated by gBMC showed <0.6% relative difference from that of the TG-43 data. Difference in anisotropy function was <1%. In two heterogeneous slab phantoms and one shielded cylinder applicator case, average dose discrepancy between gBMC and Acuros BV was <0.87%. For a tandem and ovoid patient case, good agreement between gBMC and Acruos BV results was observed in both isodose lines and dose-volume histograms. In terms of the efficiency, it took ∼47.5 seconds for gBMC to reach 0.15% statistical uncertainty within the 5% isodose line for the patient case. The accuracy and efficiency of a new GPU-based MC dose calculation package, gBMC, for HDR brachytherapy make it attractive for clinical applications. Copyright © 2016 American Brachytherapy Society. Published by

Low dose systemic or intralesional meglumine antimoniate treatment for American tegumentary leishmaniasis results in low lethality, low incidence of relapse, and low late mucosal involvement in a referral centre in Rio de Janeiro, Brazil (2001-2013).

PubMed

Brahim, Lucia Regina; Valete-Rosalino, Cláudia Maria; Antônio, Liliane de Fátima; Pimentel, Maria Inês Fernandes; Lyra, Marcelo Rosandiski; Paes, Luiz Eduardo de Carvalho; Costa, Ananda Dutra da; Vieira, Iracema Forni; Dias, Cristina Maria Giordano; Duque, Maria Cristina de Oliveira; Marzochi, Mauro Celio de Almeida; Schubach, Armando de Oliveira

2017-12-01

American tegumentary leishmaniasis (ATL) is a non-lethal parasitic disease that presents with cutaneous (CL) and mucosal (ML) clinical forms. ATL treatment aims at healing the lesions and preventing the development of the late mucosal form. Systemic meglumine antimoniate (MA) therapy with 10-20 mg Sb5+/kg/day is the first choice of treatment. However, alternative therapies using 5 mg Sb5+/kg/day or intralesional (IL) MA are the usual regimens at the National Institute of Infectious Diseases (NIID), Rio de Janeiro, Brazil. To evaluate lethality and the incidence of relapse and development of late ML in CL patients treated at NIID from 2001 until 2013. Data were recovered from records of all ATL patients diagnosed during that period. Out of 777 patients, 753 were treated with MA (96.9%). Of those, 89.1% received alternative therapy of 9.9% IL and 79.2% systemic 5 mg Sb5+/kg/day. Some patients required 1-3 additional courses of treatment, thus making a total of 997 courses; 85.2% of them were subjected to alternative therapies. Lethality was 0.1%, relapse incidence 5.8%, and late ML incidence 0.25%. As a final outcome for the 777 patients, 95.9% were cured, 0.1% died and 4.0% were not able to follow-up. Alternative MA schedules resulted in low lethality without increase of relapse or late ML incidence.

Interferon gamma-dependent intestinal pathology contributes to the lethality in bacterial superantigen-induced toxic shock syndrome.

PubMed

Tilahun, Ashenafi Y; Holz, Marah; Wu, Tsung-Teh; David, Chella S; Rajagopalan, Govindarajan

2011-02-03

Toxic shock syndrome (TSS) caused by the superantigen exotoxins of Staphylococcus aureus and Streptococcus pyogenes is characterized by robust T cell activation, profound elevation in systemic levels of multiple cytokines, including interferon-γ (IFN-γ), followed by multiple organ dysfunction and often death. As IFN-γ possesses pro- as well as anti-inflammatory properties, we delineated its role in the pathogenesis of TSS. Antibody-mediated in vivo neutralization of IFN-γ or targeted disruption of IFN-γ gene conferred significant protection from lethal TSS in HLA-DR3 transgenic mice. Following systemic high dose SEB challenge, whereas the HLA-DR3.IFN-γ(+/+) mice became sick and succumbed to TSS, HLA-DR3.IFN-γ(-/-) mice appeared healthy and were significantly protected from SEB-induced lethality. SEB-induced systemic cytokine storm was significantly blunted in HLA-DR3.IFN-γ(-/-) transgenic mice. Serum concentrations of several cytokines (IL-4, IL-10, IL-12p40 and IL-17) and chemokines (KC, rantes, eotaxin and MCP-1) were significantly lower in HLA-DR3.IFN-γ(-/-) transgenic mice. However, SEB-induced T cell expansion in the spleens was unaffected and expansion of SEB-reactive TCR Vβ8(+) CD4(+) and CD8(+) T cells was even more pronounced in HLA-DR3.IFN-γ(-/-) transgenic mice when compared to HLA-DR3.IFN-γ(+/+) mice. A systematic histopathological examination of several vital organs revealed that both HLA-DR3.IFN-γ(+/+) and HLA-DR3.IFN-γ(-/-) transgenic mice displayed comparable severe inflammatory changes in lungs, and liver during TSS. Remarkably, whereas the small intestines from HLA-DR3.IFN-γ(+/+) transgenic mice displayed significant pathological changes during TSS, the architecture of small intestines in HLA-DR3.IFN-γ(-/-) transgenic mice was preserved. In concordance with these histopathological changes, the gut permeability to macromolecules was dramatically increased in HLA-DR3.IFN-γ(+/+) but not HLA-DR3.IFN-γ(-/-) mice during TSS. Overall

Interferon Gamma-Dependent Intestinal Pathology Contributes to the Lethality in Bacterial Superantigen-Induced Toxic Shock Syndrome

PubMed Central

Tilahun, Ashenafi Y.; Holz, Marah; Wu, Tsung-Teh; David, Chella S.; Rajagopalan, Govindarajan

2011-01-01

Toxic shock syndrome (TSS) caused by the superantigen exotoxins of Staphylococcus aureus and Streptococcus pyogenes is characterized by robust T cell activation, profound elevation in systemic levels of multiple cytokines, including interferon-γ (IFN-γ), followed by multiple organ dysfunction and often death. As IFN-γ possesses pro- as well as anti-inflammatory properties, we delineated its role in the pathogenesis of TSS. Antibody-mediated in vivo neutralization of IFN-γ or targeted disruption of IFN-γ gene conferred significant protection from lethal TSS in HLA-DR3 transgenic mice. Following systemic high dose SEB challenge, whereas the HLA-DR3.IFN-γ+/+ mice became sick and succumbed to TSS, HLA-DR3.IFN-γ−/− mice appeared healthy and were significantly protected from SEB-induced lethality. SEB-induced systemic cytokine storm was significantly blunted in HLA-DR3.IFN-γ−/− transgenic mice. Serum concentrations of several cytokines (IL-4, IL-10, IL-12p40 and IL-17) and chemokines (KC, rantes, eotaxin and MCP-1) were significantly lower in HLA-DR3.IFN-γ−/− transgenic mice. However, SEB-induced T cell expansion in the spleens was unaffected and expansion of SEB-reactive TCR Vβ8+ CD4+ and CD8+ T cells was even more pronounced in HLA-DR3.IFN-γ−/− transgenic mice when compared to HLA-DR3.IFN-γ+/+ mice. A systematic histopathological examination of several vital organs revealed that both HLA-DR3.IFN-γ+/+ and HLA-DR3.IFN-γ−/− transgenic mice displayed comparable severe inflammatory changes in lungs, and liver during TSS. Remarkably, whereas the small intestines from HLA-DR3.IFN-γ+/+ transgenic mice displayed significant pathological changes during TSS, the architecture of small intestines in HLA-DR3.IFN-γ−/− transgenic mice was preserved. In concordance with these histopathological changes, the gut permeability to macromolecules was dramatically increased in HLA-DR3.IFN-γ+/+ but not HLA-DR3.IFN-γ−/− mice during TSS. Overall, IFN

The acute lethal dose 50 (LD50) of caffeine in albino rats.

PubMed

Adamson, Richard H

2016-10-01

An acute LD50 is a statistically derived amount of a substance that can be expected to cause death in 50% of the animals when given by a specified route as a single dose and the animals observed for a specified time period. Although conducting routine acute toxicity testing in rodents has been criticized, it can serve useful functions and also have practical implications. Material safety data sheets (MSDS) will reflect the acute toxicity of a substance and may require workers to wear protective gear, if appropriate, based on the LD50. There is no information in the scientific published literature which calculates a mean LD50 and standard deviation for caffeine administered orally to rats, using studies performed under good laboratory practice (GLP) or equivalent. This report does that and should be useful to manufacturers, packagers, transporters and regulators of this material. Using data from studies that are reproducible and reliable, the most accurate estimate of the acute LD50 of caffeine administered orally in male albino rats is hereby reported to be 367/mg/kg. Copyright © 2016 Elsevier Inc. All rights reserved.

Efficacy of Favipiravir Alone and in Combination With Ribavirin in a Lethal, Immunocompetent Mouse Model of Lassa Fever.

PubMed

Oestereich, Lisa; Rieger, Toni; Lüdtke, Anja; Ruibal, Paula; Wurr, Stephanie; Pallasch, Elisa; Bockholt, Sabrina; Krasemann, Susanne; Muñoz-Fontela, César; Günther, Stephan

2016-03-15

We studied the therapeutic potential of favipiravir (T-705) for Lassa fever, both alone and in combination with ribavirin. Favipiravir suppressed Lassa virus replication in cell culture by 5 log10 units. In a novel lethal mouse model, it lowered the viremia level and the virus load in organs and normalized levels of cell-damage markers. Treatment with 300 mg/kg per day, commenced 4 days after infection, when the viremia level had reached 4 log10 virus particles/mL, rescued 100% of Lassa virus-infected mice. We found a synergistic interaction between favipiravir and ribavirin in vitro and an increased survival rate and extended survival time when combining suboptimal doses in vivo. © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America.

Lethal coalitionary aggression and long-term alliance formation among Yanomamö men.

PubMed

Macfarlan, Shane J; Walker, Robert S; Flinn, Mark V; Chagnon, Napoleon A

2014-11-25

Some cross-cultural evidence suggests lethal coalitionary aggression in humans is the product of residence and descent rules that promote fraternal interest groups, i.e., power groups of coresident males bonded by kinship. As such, human lethal coalitions are hypothesized to be homologous to chimpanzee (Pan troglodytes) border patrols. However, humans demonstrate a unique metagroup social structure in which strategic alliances allow individuals to form coalitions transcending local community boundaries. We test predictions derived from the fraternal interest group and strategic alliance models using lethal coalition data from a lowland South American population, the Yanomamö. Yanomamö men who kill an enemy acquire a special status, termed unokai. We examine the social characteristics of co-unokais or men who jointly kill others. Analyses indicate co-unokais generally are (i) from the same population but from different villages and patrilines, (ii) close age mates, and (iii) maternal half-first cousins. Furthermore, the incident rate for co-unokai killings increases if men are similar in age, from the same population, and from different natal communities. Co-unokais who have killed more times in the past and who are more genetically related to each other have a higher probability of coresidence in adulthood. Last, a relationship exists between lethal coalition formation and marriage exchange. In this population, internal warfare unites multiple communities, and co-unokais strategically form new residential groups and marriage alliances. These results support the strategic alliance model of coalitionary aggression, demonstrate the complexities of human alliance formation, and illuminate key differences in social structure distinguishing humans from other primates.

Lethal coalitionary aggression and long-term alliance formation among Yanomamö men

PubMed Central

Macfarlan, Shane J.; Walker, Robert S.; Flinn, Mark V.; Chagnon, Napoleon A.

2014-01-01

Some cross-cultural evidence suggests lethal coalitionary aggression in humans is the product of residence and descent rules that promote fraternal interest groups, i.e., power groups of coresident males bonded by kinship. As such, human lethal coalitions are hypothesized to be homologous to chimpanzee (Pan troglodytes) border patrols. However, humans demonstrate a unique metagroup social structure in which strategic alliances allow individuals to form coalitions transcending local community boundaries. We test predictions derived from the fraternal interest group and strategic alliance models using lethal coalition data from a lowland South American population, the Yanomamö. Yanomamö men who kill an enemy acquire a special status, termed unokai. We examine the social characteristics of co-unokais or men who jointly kill others. Analyses indicate co-unokais generally are (i) from the same population but from different villages and patrilines, (ii) close age mates, and (iii) maternal half-first cousins. Furthermore, the incident rate for co-unokai killings increases if men are similar in age, from the same population, and from different natal communities. Co-unokais who have killed more times in the past and who are more genetically related to each other have a higher probability of coresidence in adulthood. Last, a relationship exists between lethal coalition formation and marriage exchange. In this population, internal warfare unites multiple communities, and co-unokais strategically form new residential groups and marriage alliances. These results support the strategic alliance model of coalitionary aggression, demonstrate the complexities of human alliance formation, and illuminate key differences in social structure distinguishing humans from other primates. PMID:25349394

NOTE: Clinical application of a OneDose™ MOSFET for skin dose measurements during internal mammary chain irradiation with high dose rate brachytherapy in carcinoma of the breast

NASA Astrophysics Data System (ADS)

Kinhikar, Rajesh A.; Sharma, Pramod K.; Tambe, Chandrashekhar M.; Mahantshetty, Umesh M.; Sarin, Rajiv; Deshpande, Deepak D.; Shrivastava, Shyam K.

2006-07-01

In our earlier study, we experimentally evaluated the characteristics of a newly designed metal oxide semiconductor field effect transistor (MOSFET) OneDose™ in-vivo dosimetry system for Ir-192 (380 keV) energy and the results were compared with thermoluminescent dosimeters (TLDs). We have now extended the same study to the clinical application of this MOSFET as an in-vivo dosimetry system. The MOSFET was used during high dose rate brachytherapy (HDRBT) of internal mammary chain (IMC) irradiation for a carcinoma of the breast. The aim of this study was to measure the skin dose during IMC irradiation with a MOSFET and a TLD and compare it with the calculated dose with a treatment planning system (TPS). The skin dose was measured for ten patients. All the patients' treatment was planned on a PLATO treatment planning system. TLD measurements were performed to compare the accuracy of the measured results from the MOSFET. The mean doses measured with the MOSFET and the TLD were identical (0.5392 Gy, 15.85% of the prescribed dose). The mean dose was overestimated by the TPS and was 0.5923 Gy (17.42% of the prescribed dose). The TPS overestimated the skin dose by 9% as verified by the MOSFET and TLD. The MOSFET provides adequate in-vivo dosimetry for HDRBT. Immediate readout after irradiation, small size, permanent storage of dose and ease of use make the MOSFET a viable alternative for TLDs.

Tissue responses to low protracted doses of high let radiations or photons: Early and late damage relevant to radio-protective countermeasures

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

Ainsworth, E.J.; Afzal, S.M.J.; Crouse, D.A.

1988-01-01

Early and late murine tissue responses to single or fractionated low doses of heavy charged particles, fission-spectrum neutrons or gamma rays are considered. Damage to the hematopoietic system is emphasized, but results on acute lethality, host response to challenge with transplanted leukemia cells and life-shortening are presented. Low dose rates per fraction were used in some neutron experiments. Split-dose lethality studies (LD 50/30) with fission neutrons indicated greater accumulation of injury during a 9 fraction course (over 17 days) than was the case for ..gamma..-radiation. When total doses of 96 or 247 cGy of neutrons or ..gamma.. rays were givenmore » as a single dose or in 9 fractions, a significant sparing effect on femur CFU-S depression was observed for both radiation qualities during the first 11 days, but there was not an earlier return to normal with dose fractionation. During the 9 fraction sequence, a significant sparing effect of low dose rate on CFU-S depression was observed in both neutron and ..gamma..-irradiated mice. CFU-S content at the end of the fractionation sequence did not correlate with measured LD 50/30. Sustained depression of femur and spleen CFU-S and a significant thrombocytopenia were observed when a total neutron dose of 240 cGy was given in 72 fractions over 24 weeks at low dose rates. The temporal aspects of CFU-S repopulation were different after a single versus fractionated neutron doses. The sustained reduction in the size of the CFU-S population was accompanied by an increase in the fraction in DNA synthesis. The proliferation characteristics and effects of age were different for radial CFU-S population closely associated with bone, compared with the axial population that can be readily aspirated from the femur. In aged irradiated animals, the CFU-S proliferation/redistribution response to typhoid vaccine showed both an age and radiation effect. 63 refs., 6 figs., 7 tabs.« less

A New Orally Active, Aminothiol Radioprotector-Free of Nausea and Hypotension Side Effects at Its Highest Radioprotective Doses

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

Soref, Cheryl M.; Hacker, Timothy A.; Fahl, William E., E-mail: fahl@oncology.wisc.edu

Purpose: A new aminothiol, PrC-210, was tested for orally conferred radioprotection (rats, mice; 9.0 Gy whole-body, which was otherwise lethal to 100% of the animals) and presence of the debilitating side effects (nausea/vomiting, hypotension/fainting) that restrict use of the current aminothiol, amifostine (Ethyol, WR-2721). Methods and Materials: PrC-210 in water was administered to rats and mice at times before irradiation, and percent-survival was recorded for 60 days. Subcutaneous (SC) amifostine (positive control) or SC PrC-210 was administered to ferrets (Mustela putorius furo) and retching/emesis responses were recorded. Intraperitoneal amifostine (positive control) or PrC-210 was administered to arterial cannulated rats tomore » score drug-induced hypotension. Results: Oral PrC-210 conferred 100% survival in rat and mouse models against an otherwise 100% lethal whole-body radiation dose (9.0 Gy). Oral PrC-210, administered by gavage 30-90 min before irradiation, conferred a broad window of radioprotection. The comparison of PrC-210 and amifostine side effects was striking because there was no retching or emesis in 10 ferrets treated with PrC-210 and no induced hypotension in arterial cannulated rats treated with PrC-210. The tested PrC-210 doses were the ferret and rat equivalent doses of the 0.5 maximum tolerated dose (MTD) PrC-210 dose in mice. The human equivalent of this mouse 0.5 MTD PrC-210 dose would likely be the highest PrC-210 dose used in humans. By comparison, the mouse 0.5 MTD amifostine dose, 400 {mu}g/g body weight (equivalent to the human amifostine dose of 910 mg/m{sup 2}), when tested at equivalent ferret and rat doses in the above models produced 100% retching/vomiting in ferrets and 100% incidence of significant, progressive hypotension in rats. Conclusions: The PrC-210 aminothiol, with no detectable nausea/vomiting or hypotension side effects in these preclinical models, is a logical candidate for human drug development to use in

Early treatment with intravenous lipid emulsion in a potentially lethal hydroxychloroquine intoxication.

PubMed

Ten Broeke, R; Mestrom, E; Woo, L; Kreeftenberg, H

2016-06-01

This case report describes the possible benefit of intravenous lipid emulsion in two patients surviving a severe intoxication with hydroxychloroquine in a dose that was previously considered to be lethal. The first case involves a 25-year-old female who ingested 17.5 grams of hydroxychloroquine, approximately one hour before presentation. An ECG showed QRS widening and the lab results showed hypokalaemia. She became unconscious, and developed hypotension and eventually apnoea. After intubation, supportive care consisted of norepinephrine and supplementation of potassium. Moreover, sodium bicarbonate and intravenous lipid emulsion were started to prevent cardiac toxicity. After these interventions, haemodynamic stability was established within a few hours. Although cardiomyopathy was confirmed, the patient recovered after two weeks. The second case concerns a 25-year-old male who took 5 grams of hydroxychloroquine. At presentation, two hours after intake, he showed QTc prolongation and hypokalaemia. The patient was treated with the usual supportive care and, although presentation to hospital was later, with intravenous lipid emulsion. Also this patient recovered. In conclusion, these cases show the benefit of supplemental intravenous lipid emulsion to prevent cardiac toxicity after a severe intoxication with hydroxychloroquine.

The consistency of Fletcher-Suit applicator geometry and of the rectal probe’s position in high dose rate brachytherapy treatment fraction of cervix carcinoma

PubMed Central

2009-01-01

Purpose The dose values computed with the treatment planning system and the in vivo dose measurements with semiconductor detectors in rectum during the high dose rate brachytherapy treatment fraction of the cervix carcinoma are occasionally significantly different. We’ve investigated the consistency of the Fletcher-Suit applicator geometry and the in vivo rectal probe’s position stability during the high dose rate brachytherapy treatment fraction. Material and methods The patient lied in a lithotomic position during a biplane reconstruction images, throughout the treatment planning and dose administration. We obtained post-treatment reconstruction images and prepared a post-treatment plan. The amount of 14 treatment fractions of 10 patients were considered in the study. Two methods were applied: evaluation of the difference of reconstructed pre-treatment and post-treatment applicator points and rectal probe’s detectors being relevant to the co-ordinate system fixed to the applicator, and estimation of applicators and rectal probe’s reallocation with respect to the pelvic bones with registration of pre- and post-treatment reconstruction images. Results We’ve experienced good consistency in the Fletcher-Suit applicator geometry in all treatment fractions. 70% of them presented small variation in the rectal probe’s position, while the rest showed significant shift in the applicator or rectal probe’s position with regard to the pelvic bones. PMID:27807458

Myxoma virus M130R is a novel virulence factor required for lethal myxomatosis in rabbits.

PubMed

Barrett, John W; Werden, Steven J; Wang, Fuan; McKillop, William M; Jimenez, June; Villeneuve, Danielle; McFadden, Grant; Dekaban, Gregory A

2009-09-01

Myxoma virus (MV) is a highly lethal, rabbit-specific poxvirus that induces a disease called myxomatosis in European rabbits. In an effort to understand the function of predicted immunomodulatory genes we have deleted various viral genes from MV and tested the ability of these knockout viruses to induce lethal myxomatosis. MV encodes a unique 15 kD cytoplasmic protein (M130R) that is expressed late (12h post infection) during infection. M130R is a non-essential gene for MV replication in rabbit, monkey or human cell lines. Construction of a targeted gene knockout virus (vMyx130KO) and infection of susceptible rabbits demonstrate that the M130R knockout virus is attenuated and that loss of M130R expression allows the rabbit host immune system to effectively respond to and control the lethal effects of MV. M130R expression is a bona fide poxviral virulence factor necessary for full and lethal development of myxomatosis.

Induction of high tolerance to artemisinin by sub-lethal administration: A new in vitro model of P. falciparum.

PubMed

De Lucia, Serena; Tsamesidis, Ioannis; Pau, Maria Carmina; Kesely, Kristina R; Pantaleo, Antonella; Turrini, Francesco

2018-01-01

Artemisinin resistance is a major threat to malaria control efforts. Resistance is characterized by an increase in the Plasmodium falciparum parasite clearance half-life following treatment with artemisinin-based combination therapies (ACTs) and an increase in the percentage of surviving parasites. The remarkably short blood half-life of artemisinin derivatives may contribute to drug-resistance, possibly through factors including sub-lethal plasma concentrations and inadequate exposure. Here we selected for a new strain of artemisinin resistant parasites, termed the artemisinin resistant strain 1 (ARS1), by treating P. falciparum Palo Alto (PA) cultures with sub-lethal concentrations of dihydroartemisinin (DHA). The resistance phenotype was maintained for over 1 year through monthly maintenance treatments with low doses of 2.5 nM DHA. There was a moderate increase in the DHA IC50 in ARS1 when compared with parental strain PA after 72 h of drug exposure (from 0.68 nM to 2 nM DHA). In addition, ARS1 survived treatment physiologically relevant DHA concentrations (700 nM) observed in patients. Furthermore, we confirmed a lack of cross-resistance against a panel of antimalarials commonly used as partner drugs in ACTs. Finally, ARS1 did not contain Pfk13 propeller domain mutations associated with ART resistance in the Greater Mekong Region. With a stable growth rate, ARS1 represents a valuable tool for the development of new antimalarial compounds and studies to further elucidate the mechanisms of ART resistance.