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Sample records for lethal doses application

  1. Derivation of Human Lethal Doses

    DTIC Science & Technology

    2006-01-19

    extrapolate to human lethal doses. In this effort, Ekwall et al. (1998) collected data on human lethal doses in acute poisonings from handbooks on...emergency medicine, pharmacology, forensic medicine, and industrial chemical toxicology, in addition to a poison information center. The authors presented...lethal doses would be dose-response data in people. Estimates of doses from case reports of fatal poisonings provide information on what doses can be

  2. The median lethal dose and its estimation.

    PubMed

    Finney, D J

    1985-02-01

    An important paper by Zbinden and Fluri-Roversi (1981) has shown the many weaknesses in any policy or regulatory system that regards an estimated LD50 in an animal species as an adequate guide to toxicity in man. The present paper draws attention to some statistical aspects of LD50 estimation that are too often neglected or misunderstood when this quantity is wanted. It is solely concerned with practice when a LD50 must be estimated, and deliberately does not approach the broader issues of whether the LD50 should be estimated. A first need is clear distinction between the true but unknown form of dependence of mortality on dose and the estimate of it (or of a particular property such as the LD50) that is obtainable from an experiment. Some assumptions are necessary before any estimation is possible. The graphical and semi-graphical methods that once were popular because of their simplicity and speed are today only reasonable as a last resort, when data are wholly inadequate and all that can be found is a very rough preliminary indication. Many "simple" arithmetical methods have been shown to be inherently bad, in that equally simple alternatives are usually more precise and less subject to bias. The Spearman-Kärber method remains as a useful possibility, demanding little knowledge of the form of the response curves but often needing other unverifiable assumptions. For most purposes, maximum likelihood estimation of a parametric formulation of the response curve is the best choice, not only because of theoretical merits but also because it can now be performed on a microcomputer in a very few seconds.

  3. Chicken embryo lethality assay for determining the lethal dose and virulence of Enterococcus faecalis.

    PubMed

    Blanco, Ana E; Barz, Martin; Icken, Wiebke; Cavero, David; Sharifi, A Reza; Voss, Matthias; Preisinger, Rudolf; Buxadé, Carlos

    2017-10-01

    Enterococcus faecalis is the major pathogen found in field cases of amyloid arthropathy in chickens. Given the need for a better understanding of the virulence mechanisms of the causative strains, the embryo lethality assay (ELA) is proposed in the present study as a model to evaluate the virulence of E. faecalis strains, specifically the pathogenic avian strain K923/96, which was previously related with amyloid arthropathy. Hence, 0.2 ml of five doses of the cited strain (from 2.5 to 2500 colony-forming units (CFU) per ml) were inoculated into the allantoic cavity of 10-day-old embryos. The embryo mortality rate (EMR) was determined by daily candling of the eggs over a period of seven days and based on this information the median lethal dose (LD50) was calculated. The ELA was repeated four times on a sample of 3443 eggs. The infectious dose showed a significant effect on the EMR. The EMR with the doses of 2.5, 5, 25, 250 and 2500 CFU/ml was 43%, 45%, 63%, 90% and 93%, respectively. The estimated dose at LD50 was 6.6 CFU/ml. As expected, the higher the infectious dose, the greater the EMR and the lower the embryo survival time. The highest EMR was recorded after three and four days post-inoculation in all doses. In conclusion, these results can be used as a basis for further researches on the E. faecalis virulence. In order to corroborate its model capacity to predict the virulence of this bacterium, more ELAs with different E. faecalis strains are required.

  4. Ethylene oxide dose and dose-rate effects in the mouse dominant-lethal test

    SciTech Connect

    Generoso, W.M.; Cain, K.T.; Hughes, L.A.; Sega, G.A.; Braden, P.W.; Gosslee, D.G.; Shelby, M.D.

    1986-01-01

    In the dose-response study, male mice were exposed by inhalation to ethylene oxide (EtO) for 4 consecutive days. Mice were exposed for 6 hr per day to 300 ppm, 400 ppm, or 500 ppm EtO for a daily total of 1800, 2400, or 3000 ppm X hr (total exposures of 7200, 9600 and 12,000 ppm X hr), respectively. In the dose-rate study, mice were given a total exposure of 1800 ppm X hr per day, also for 4 consecutive days, delivered either at 300 ppm in 6 hr, 600 ppm in 3 hr, or 1200 ppm in 1.5 hr. Quantitation of dominant-lethal responses was made on matings involving sperm exposed as late spermatids and early spermatozoa, the most sensitive stages to EtO. In the dose-response study, a dose-related increase in dominant-lethal mutations was observed, the dose-response curve proved to be nonlinear. In the dose-rate study, increasing the exposure concentrations resulted in increased dominant-lethal responses.

  5. Comparative study of peritoneal macrophage functions in mice receiving lethal and non-lethal doses of LPS.

    PubMed

    Víctor, V M; De la Fuente, M

    2000-01-01

    In previous studies, we have observed changes in several functions of peritoneal macrophages from female BALB/c mice with lethal endotoxic shock caused by intraperitoneal injection of Escherichia coli O55:B5 lipopolysaccharide (LPS; 100 mg/kg), which were associated with a high production of superoxide anion and tumor necrosis factor alpha (TNF-alpha). In the present work, both a lethal dose (250 mg/kg) and a non-lethal dose (100 mg/kg) of LPS were used in female Swiss mice. In peritoneal macrophages, the following functions were studied at 2, 4, 12 and 24 h after LPS injection: adherence to substrate, chemotaxis, ingestion of particles, and superoxide anion and TNF-alpha production. In both groups, the results showed a stimulation of adherence, ingestion and superoxide production as well as a decrease of chemotaxis, whereas TNF-alpha could not be detected in either of the two groups. These effects were more evident with the 250 mg/kg dose, especially as regards superoxide anion production, which was higher in the animals treated with a lethal dose of LPS.

  6. Non-Lethal Weaponry: From Tactical to Strategic Applications

    DTIC Science & Technology

    1999-01-01

    at lower levels. The end result is best de- scribed by the current commander in chief of U.S. Central Command, General Anthony Zinni: “Non- lethal ...San Diego Union Tribune, November 1, 1997. 3 Nick Lewer and Steven Schofield, Non- lethal Weapons: A Fatal Attraction? (Atlantic Highlands, N.J.: Zed...Non- lethal weapons are evolving. To datethey have been seen as applicable onthe tactical level in military operationsother than war. The demand for

  7. Characterization of infectious dose and lethal dose of two strains of infectious hematopoietic necrosis virus (IHNV).

    PubMed

    McKenney, Douglas G; Kurath, Gael; Wargo, Andrew R

    2016-03-02

    The ability to infect a host is a key trait of a virus, and differences in infectivity could put one virus at an evolutionary advantage over another. In this study we have quantified the infectivity of two strains of infectious hematopoietic necrosis virus (IHNV) that are known to differ in fitness and virulence. By exposing juvenile rainbow trout (Oncorhynchus mykiss) hosts to a wide range of virus doses, we were able to calculate the infectious dose in terms of ID50 values for the two genotypes. Lethal dose experiments were also conducted to confirm the virulence difference between the two virus genotypes, using a range of virus doses and holding fish either in isolation or in batch so as to calculate LD50 values. We found that infectivity is positively correlated with virulence, with the more virulent genotype having higher infectivity. Additionally, infectivity increases more steeply over a short range of doses compared to virulence, which has a shallower increase. We also examined the data using models of virion interaction and found no evidence to suggest that virions have either an antagonistic or a synergistic effect on each other, supporting the independent action hypothesis in the process of IHNV infection of rainbow trout.

  8. Characterization of infectious dose and lethal dose of two strains of infectious hematopoietic necrosis virus (IHNV)

    USGS Publications Warehouse

    McKenney, Douglas; Kurath, Gael; Wargo, Andrew

    2016-01-01

    The ability to infect a host is a key trait of a virus, and differences in infectivity could put one virus at an evolutionary advantage over another. In this study we have quantified the infectivity of two strains of infectious hematopoietic necrosis virus (IHNV) that are known to differ in fitness and virulence. By exposing juvenile rainbow trout (Oncorhynchus mykiss) hosts to a wide range of virus doses, we were able to calculate the infectious dose in terms of ID50 values for the two genotypes. Lethal dose experiments were also conducted to confirm the virulence difference between the two virus genotypes, using a range of virus doses and holding fish either in isolation or in batch so as to calculate LD50values. We found that infectivity is positively correlated with virulence, with the more virulent genotype having higher infectivity. Additionally, infectivity increases more steeply over a short range of doses compared to virulence, which has a shallower increase. We also examined the data using models of virion interaction and found no evidence to suggest that virions have either an antagonistic or a synergistic effect on each other, supporting the independent action hypothesis in the process of IHNV infection of rainbow trout.

  9. Subchronic chloroform priming protects mice from a subsequently administered lethal dose of chloroform

    SciTech Connect

    Philip, Binu K.; Anand, Sathanandam S.; Palkar, Prajakta S.; Mumtaz, Moiz M.; Latendresse, John R.; Mehendale, Harihara M. . E-mail: mehendale@ulm.edu

    2006-10-01

    Protection offered by pre-exposure priming with a small dose of a toxicant against the toxic and lethal effects of a subsequently administered high dose of the same toxicant is autoprotection. Although autoprotection has been extensively studied with diverse toxicants in acute exposure regimen, not much is known about autoprotection after priming with repeated exposure. The objective of this study was to investigate this concept following repeated exposure to a common water contaminant, chloroform. Swiss Webster (SW) mice, exposed continuously to either vehicle (5% Emulphor, unprimed) or chloroform (150 mg/kg/day po, primed) for 30 days, were challenged with a normally lethal dose of chloroform (750 mg chloroform/kg po) 24 h after the last exposure. As expected, 90% of the unprimed mice died between 48 and 96 h after administration of the lethal dose in contrast to 100% survival of mice primed with chloroform. Time course studies indicated lower hepato- and nephrotoxicity in primed mice as compared to unprimed mice. Hepatic CYP2E1, glutathione levels (GSH), and covalent binding of {sup 14}C-chloroform-derived radiolabel did not differ between livers of unprimed and primed mice after lethal dose exposure, indicating that protection in liver is neither due to decreased bioactivation nor increased detoxification. Kidney GSH and glutathione reductase activity were upregulated, with a concomitant reduction in oxidized glutathione in the primed mice following lethal dose challenge, leading to decreased renal covalent binding of {sup 14}C-chloroform-derived radiolabel, in the absence of any change in CYP2E1 levels. Buthionine sulfoximine (BSO) intervention led to 70% mortality in primed mice challenged with lethal dose. These data suggest that higher detoxification may play a role in the lower initiation of kidney injury observed in primed mice. Exposure of primed mice to a lethal dose of chloroform led to 40% lower chloroform levels (AUC{sub 15-360min}) in the systemic

  10. Mechanism of Lethal Interaction of Hazardous Chemicals at Subtoxic Doses

    DTIC Science & Technology

    1991-09-20

    doses of chemicals are employed are not very represen- tative.of low level, environmental exposure.* Prior exposure to nontoxic levels of the pesticide...representative of low level, environmental exposure. Prior exposure to nontoxic levels of the pesticide KeponeO (chlordecone, CD) results in a 67-fold...mediated cytotoxicity. Toxicol. Appl. Pharmacol., 9: 323-333,1989. 6. Rao, S. B., Young, R. A. and Mehendale, H. M. Polyamines and related enzymes

  11. Myocardial adrenergic responsiveness after lethal and nonlethal doses of endotoxin

    SciTech Connect

    Shepherd, R.E.; Lang, C.H.; McDonough, K.H.

    1987-02-01

    A dose-dependent impairment of intrinsic myocardial performance has been observed following in vivo administration of endotoxin. The present study reports a dose-dependent increase in plasma catecholamines following endotoxin (ET) that may impair ..beta..-adrenergic responsiveness. Hearts were removed from pentobarbital-anesthetized rats 4 h after a bolus injection of saline or ET and were studied as isolated cell preparations following collagenase digestion. Responsiveness of isoproterenol-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) accumulation in myocytes prepared from hearts of animals injected with 10 and 100 ..mu..g ET was decreased when compared with control rats and was significantly blunted in myocytes prepared from animals receiving 1000 ..mu..g ET. Similar sensitivities of the cAMP system existed, as judged by similar half-maximum effective concentration values. cAMP accumulation in the presence of 1 ..mu..M forskolin was depressed in myocytes from the 1000-..mu..g ET animals; ..beta..-adrenergic receptor density was decreased 25% in myocytes from high-dose ET animals when compared with control animals. This was accompanied by a nonsignificant reduction in the affinity of binding sites for (+/-)(/sup 3/H)CGP 12177. The blunted myocyte hormonal responsiveness following ET challenge appears to be related to the decreased activity of the adenylate cyclase that may be attributed to alterations in both receptor density and in the adenylate cyclase itself.

  12. Determination of the median lethal dose of botulinum serotype E in channel catfish fingerlings

    USDA-ARS?s Scientific Manuscript database

    The median lethal dose of botulinum serotype E in 5.3-g channel catfish Ictalurus punctatus fingerlings was determined. Five tanks (five fish/tank) were assigned to each of the following treatment groups: 70, 50, 35, 25, or 15 pg of purified botulinum serotype E. Fish were injected intracoelomically...

  13. Continuous exposure to non-lethal doses of sodium iodate induces retinal pigment epithelial cell dysfunction

    PubMed Central

    Zhang, Xiao-Yu; Ng, Tsz Kin; Brelén, Mårten Erik; Wu, Di; Wang, Jian Xiong; Chan, Kwok Ping; Yung, Jasmine Sum Yee; Cao, Di; Wang, Yumeng; Zhang, Shaodan; Chan, Sun On; Pang, Chi Pui

    2016-01-01

    Age-related macular degeneration (AMD), characterized by progressive degeneration of retinal pigment epithelium (RPE), is the major cause of irreversible blindness and visual impairment in elderly population. We previously established a RPE degeneration model using an acute high dose sodium iodate to induce oxidative stress. Here we report findings on a prolonged treatment of low doses of sodium iodate on human RPE cells (ARPE-19). RPE cells were treated continuously with low doses (2–10 mM) of sodium iodate for 5 days. Low doses (2–5 mM) of sodium iodate did not reduce RPE cell viability, which is contrasting to cell apoptosis in 10 mM treatment. These low doses are sufficient to retard RPE cell migration and reduced expression of cell junction protein ZO-1. Phagocytotic activity of RPE cells was attenuated by sodium iodate dose-dependently. Sodium iodate also increased expression of FGF-2, but suppressed expression of IL-8, PDGF, TIMP-2 and VEGF. Furthermore, HTRA1 and epithelial-to-mesenchymal transition marker proteins were downregulated, whereas PERK and LC3B-II proteins were upregulated after sodium iodate treatment. These results suggested that prolonged exposure to non-lethal doses of oxidative stress induces RPE cell dysfunctions that resemble conditions in AMD. This model can be used for future drug/treatment investigation on AMD. PMID:27849035

  14. Cellular glutathione peroxidase protects mice against lethal oxidative stress induced by various doses of diquat.

    PubMed

    Fu, Y; Cheng, W H; Ross, D A; Lei, X g

    1999-11-01

    This study was to determine if cellular glutathione peroxidase (GPX1) protects against acute oxidative stress induced by diquat. Lethality and hepatic biochemical indicators in GPX1 knockout mice [GPX1(-/-)] were compared with those of wild-type mice (WT) after an intraperitoneal injection of diquat at 6, 12, 24, or 48 mg/kg of body weight. Although the WT survived all the doses, the GPX1(-/-) survived only 6 mg diquat/kg and were killed by 12, 24, and 48 mg diquat/kg at 52, 4.4 and 3.9 hr, respectively. Compared with those of surviving mice that were sacrificed on Day 7, the dead GPX1(-/-) had diquat dose-dependent increases (P < 0.05) in plasma alanine aminotransferase (ALT) activities. The GPX1(-/-) also had higher (P < 0.05) liver carbonyl contents than those of the WT, but the differences were irrespective of diquat doses. Whereas hepatic total GPX and phospholipid hydroperoxide glutathione peroxidase activities or hepatic GPX1 protein was not significantly affected by the diquat treatment, liver thioredoxin reductase and catalase activities were lower (P < 0.05) in the GPX1(-/-) injected with 12 mg diquat/kg than those of other groups. In conclusion, normal GPX1 expression is necessary to protect mice against the lethality, hepatic protein oxidation, and elevation of plasma ALT activity induced by 12-48 mg diquat/kg.

  15. Non-Lethal Weaponry: Applications to AC-130 Gunships

    DTIC Science & Technology

    2002-04-01

    Nick, and Steven Schofield. Non- Lethal Weapons—A Fatal Attraction? Military strategies and Technologies for the 21st Century Conflict. (London, UK: Zes...December 1995. 7 Summaries mainly compiled from five sources: Nick Lewer and Steven Schofield, Non- Lethal Weapons—A Fatal Attraction? Military Strategies...Notes 1 Summaries primarily compiled from these seven sources: Nick Lewer and Steven Schofield, Non- Lethal Weapons—A Fatal Attraction? Military

  16. Chloroquine Improves Survival and Hematopoietic Recovery After Lethal Low-Dose-Rate Radiation

    SciTech Connect

    Lim Yiting; Hedayati, Mohammad; Merchant, Akil A.; Zhang Yonggang; Yu, Hsiang-Hsuan M.; Kastan, Michael B.; Matsui, William; DeWeese, Theodore L.

    2012-11-01

    Purpose: We have previously shown that the antimalarial agent chloroquine can abrogate the lethal cellular effects of low-dose-rate (LDR) radiation in vitro, most likely by activating the ataxia-telangiectasia mutated (ATM) protein. Here, we demonstrate that chloroquine treatment also protects against lethal doses of LDR radiation in vivo. Methods and Materials: C57BL/6 mice were irradiated with a total of 12.8 Gy delivered at 9.4 cGy/hour. ATM null mice from the same background were used to determine the influence of ATM. Chloroquine was administered by two intraperitoneal injections of 59.4 {mu}g per 17 g of body weight, 24 hours and 4 hours before irradiation. Bone marrow cells isolated from tibia, fibula, and vertebral bones were transplanted into lethally irradiated CD45 congenic recipient mice by retroorbital injection. Chimerism was assessed by flow cytometry. In vitro methylcellulose colony-forming assay of whole bone marrow cells and fluorescence activated cell sorting analysis of lineage depleted cells were used to assess the effect of chloroquine on progenitor cells. Results: Mice pretreated with chloroquine before radiation exhibited a significantly higher survival rate than did mice treated with radiation alone (80% vs. 31%, p = 0.0026). Chloroquine administration before radiation did not affect the survival of ATM null mice (p = 0.86). Chloroquine also had a significant effect on the early engraftment of bone marrow cells from the irradiated donor mice 6 weeks after transplantation (4.2% vs. 0.4%, p = 0.015). Conclusion: Chloroquine administration before radiation had a significant effect on the survival of normal but not ATM null mice, strongly suggesting that the in vivo effect, like the in vitro effect, is also ATM dependent. Chloroquine improved the early engraftment of bone marrow cells from LDR-irradiated mice, presumably by protecting the progenitor cells from radiation injury. Chloroquine thus could serve as a very useful drug for protection

  17. Chloroquine improves survival and hematopoietic recovery following lethal low dose- rate radiation

    PubMed Central

    Lim, Yiting; Hedayati, Mohammad; Merchant, Akil A.; Zhang, Yonggang; Yu, Hsiang-Hsuan M; Kastan, Michael B.; Matsui, William; DeWeese, Theodore L.

    2012-01-01

    Purpose We have previously shown that the anti-malarial agent chloroquine can abrogate the lethal cellular effects of low dose-rate (LDR) radiation in vitro, most likely by activating the ataxia-telangiectasia mutated (ATM) protein. Here, we demonstrate that chloroquine treatment also protects against lethal doses of LDR radiation in vivo. Methods and Materials C57BL/6 mice were irradiated with total of 12.8 Gy delivered at 9.4 cGy/hr. ATM null mice from the same background were used to determine the influence of ATM. Chloroquine was administered by two intraperitoneal injections of 59.4 μg per 17 g of body weight, 24 hrs and 4 hrs before irradiation. Bone marrow cells isolated from tibia, fibula and vertebral bones were transplanted into lethally irradiated CD45 congenic recipient mice by retro orbital injection. Chimerism was assessed by flow cytometry. In vitro methyl cellulose colony forming assay of whole bone marrow cells as well as FACS analysis of lineage depleted cells was used to assess the effect of chloroquine on progenitor cells. Results Mice pretreated with chloroquine prior to radiation exhibited a significantly higher survival rate compared to mice treated with radiation alone (80 vs.31 percent, p=0.0026). Chloroquine administration prior to radiation did not impact the survival of ATM null mice (p=0.86). Chloroquine also had a significant effect on the early engraftment of bone marrow cells from the irradiated donor mice 6 weeks after the transplantation (4.2 percent vs. 0.4 percent, p=0.015). Conclusion Chloroquine administration prior to radiation had a significant effect on the survival of normal but not ATM null mice strongly suggesting that the in vivo effect like the in vitro effect is also ATM dependent. Chloroquine improved the early engraftment of bone marrow cells from LDR irradiated mice, presumably by protecting the progenitor cells from radiation injury. Chloroquine thus could serve as a very useful drug for protection against the

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

    SciTech Connect

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

    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. 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.

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

    PubMed

    Palkar, Prajakta S; Philip, Binu K; Reddy, Ramesh N; Mehendale, Harihara M

    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. 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.

  20. Pre-treatment with low-dose endotoxin prolongs survival from experimental lethal endotoxic shock: Benefit for lethal peritonitis by Escherichia coli.

    PubMed

    Kopanakis, Konstantinos; Tzepi, Ira-Maria; Pistiki, Aikaterini; Carrer, Dionyssia-Pinelopi; Netea, Mihai G; Georgitsi, Marianna; Lymperi, Maria; Droggiti, Dionyssia-Irini; Liakakos, Theodoros; Machairas, Anastasios; Giamarellos-Bourboulis, Evangelos J

    2013-06-01

    Although LPS tolerance is well-characterized, it remains unknown if it is achieved even with single doses of lipopolysaccharide (LPS) and if it offers protection against lethal bacterial infections. To this end, C57B6 mice were assigned to groups A (sham); B (saline i.p followed after 24h by i.p 30mg/kg LPS); and C (3mg/kg LPS i.p followed after 24h by i.p 30mg/kg LPS). Survival was monitored and animals were sacrificed early after lethal challenge for measurement of tumour necrosis factor-alpha (TNFα) in serum; isolation of splenocytes and cytokine stimulation; and flow-cytometry for apoptosis and TREM-1. Experiments were repeated with mice infected i.p by Escherichia coli after challenging with saline or LPS. Mortality of group B was 72.2% compared with 38.9% of group C (p: 0.020). Serum TNFα of group C was lower than group B. Expression of TREM-1 of group C on monocytes/neutrophils was greater than group B. Release of TNFα, of IFNγ and of IL-17 from splenocytes of group C was lower than group B and the opposite happened for IL-10 showing evidence of cellular reprogramming. In parallel, apoptosis of circulating lymphocytes and of splenocytes of group C was greater compared with group B. Pre-treatment of mice challenged by E. coli with low dose LPS led to 0% mortality compared with 90% of saline pre-treated mice; in these mice, splenocytes improved over-time their capacity for release of IFNγ. It is concluded that single low doses of LPS lead to early reprogramming of the innate immune response and prolong survival after lethal E. coli challenge.

  1. 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.

  2. Effects of sub-lethal doses of glyphosate on honeybee navigation.

    PubMed

    Sol Balbuena, María; Tison, Léa; Hahn, Marie-Luise; Greggers, Uwe; Menzel, Randolf; Farina, Walter M

    2015-07-10

    Glyphosate (GLY) is a herbicide that is widely used in agriculture for weed control. Although reports about the impact of GLY in snails, crustaceans and amphibians exist, few studies have investigated its sub-lethal effects in non-target organisms such as the honeybee Apis mellifera, the main pollen vector in commercial crops. Here, we tested whether exposure to three sub-lethal concentrations of GLY (2.5, 5 and 10 mg/L corresponding to 0.125, 0.250 and 0.500 µg/animal) affects the homeward flight path of honeybees in an open field. We performed an experiment in which forager honeybees were trained to an artificial feeder, and then captured, fed with sugar solution containing GLY traces and released from a novel site (the release site, RS) either once or twice. Their homeward trajectories were tracked using harmonic radar technology. We found that honeybees that had been fed with solution containing 10 mg/L GLY spent more time performing homeward flights than control bees or bees treated with lower GLY concentrations. They also performed more indirect homing flights. Moreover, the proportion of direct homeward flights performed after a second release at the RS increased in control bees but not in treated bees. These results suggest that, in honeybees, exposure to GLY doses commonly found in agricultural settings impairs the cognitive capacities needed to retrieve and integrate spatial information for a successful return to the hive. Therefore, honeybee navigation is affected by ingesting traces of the most widely used herbicide worldwide, with potential long-term negative consequences for colony foraging success.

  3. Aquatain® Mosquito Formulation (AMF) for the control of immature Anopheles gambiae sensu stricto and Anopheles arabiensis: dose-responses, persistence and sub-lethal effects.

    PubMed

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

    2014-09-16

    Persistent monomolecular surface films could benefit larval source management for malaria control by reducing programme costs and managing insecticide resistance. This study evaluated the efficacy of the silicone-based surface film, Aquatain® Mosquito Formulation (AMF), for the control of the Afrotropical malaria vectors, Anopheles gambiae sensu stricto and Anopheles arabiensis in laboratory dose-response assays and standardized field tests. Tests were carried out following guidelines made by the World Health Organization Pesticide Evaluation Scheme (WHOPES). Sub-lethal effects of AMF were evaluated by measuring egg-laying and hatching of eggs laid by female An. gambiae s.s. that emerged from habitats treated with a dose that resulted in 50% larval mortality in laboratory tests. Both vector species were highly susceptible to AMF. The estimated lethal doses to cause complete larval mortality in dose-response tests in the laboratory were 1.23 (95% confidence interval (CI) 0.99-1.59) ml/m2 for An. gambiae s.s. and 1.35 (95% CI 1.09-1.75) ml/m2 for An. arabiensis. Standardized field tests showed that a single dose of AMF at 1 ml/m2 inhibited emergence by 85% (95% CI 82-88%) for six weeks. Females exposed as larvae to a sub-lethal dose of AMF were 2.2 times less likely (Odds ratio (OR) 0.45, 95% CI 0.26-0.78) to lay eggs compared to those from untreated ponds. However, exposure to sub-lethal doses neither affected the number of eggs laid by females nor the proportion hatching. AMF provided high levels of larval control for a minimum of six weeks, with sub-lethal doses reducing the ability of female mosquitoes to lay eggs. The application of AMF provides a promising novel strategy for larval control interventions against malaria vectors in Africa. Further field studies in different eco-epidemiological settings are justified to determine the persistence of AMF film for mosquito vector control and its potential for inclusion in integrated vector management programmes.

  4. Establishment of a mouse model of 70% lethal dose by total-body irradiation

    PubMed Central

    Ryu, Seung-Hyun; Park, Jong-Hyung; Jeong, Eui-Suk; Choi, Soo-Young; Ham, Seung-Hoon; Park, Jin-Il; Jeon, Hee-Yeon; Kim, Jun-Young; Yoo, Ran-Ji; Lee, Yong-Jin; Woo, Sang-Keun

    2016-01-01

    Whereas increasing concerns about radiation exposure to nuclear disasters or side effects of anticancer radiotherapy, relatively little research for radiation damages or remedy has been done. The purpose of this study was to establish level of LD70/30 (a lethal dose for 70% of mice within 30 days) by total-body γ irradiation (TBI) in a mouse model. For this purpose, at first, 8-week-old male ICR and C57BL/6N mice from A and B companies were received high dose (10, 11, 12 Gy) TBI. After irradiation, the body weight and survival rate were monitored for 30 days consecutively. In next experiment, 5-week-old male ICR and C57BL/6N mice from B company were received same dose irradiation. Results showed that survival rate and body weight change rate in inbred C57BL/6N mice were similar between A and B company. In ICR mice, however, survival rate and body weight change rate were completely different among the companies. Significant difference of survival rate both ICR and C57BL6N mice was not observed in between 5-week-old and 8-week-old groups receiving 10 or 12 Gy TBI. Our results indicate that the strain and age of mice, and even purchasing company (especially outbred), should be matched over experimental groups in TBI experiment. Based on our results, 8-week-old male ICR mice from B company subjected to 12 Gy of TBI showed LD70/30 and suitable as a mouse model for further development of new drug using the ideal total-body irradiation model. PMID:27382380

  5. Establishment of a mouse model of 70% lethal dose by total-body irradiation.

    PubMed

    Ryu, Seung-Hyun; Park, Jong-Hyung; Jeong, Eui-Suk; Choi, Soo-Young; Ham, Seung-Hoon; Park, Jin-Il; Jeon, Hee-Yeon; Kim, Jun-Young; Yoo, Ran-Ji; Lee, Yong-Jin; Woo, Sang-Keun; Choi, Yang-Kyu

    2016-06-01

    Whereas increasing concerns about radiation exposure to nuclear disasters or side effects of anticancer radiotherapy, relatively little research for radiation damages or remedy has been done. The purpose of this study was to establish level of LD70/30 (a lethal dose for 70% of mice within 30 days) by total-body γ irradiation (TBI) in a mouse model. For this purpose, at first, 8-week-old male ICR and C57BL/6N mice from A and B companies were received high dose (10, 11, 12 Gy) TBI. After irradiation, the body weight and survival rate were monitored for 30 days consecutively. In next experiment, 5-week-old male ICR and C57BL/6N mice from B company were received same dose irradiation. Results showed that survival rate and body weight change rate in inbred C57BL/6N mice were similar between A and B company. In ICR mice, however, survival rate and body weight change rate were completely different among the companies. Significant difference of survival rate both ICR and C57BL6N mice was not observed in between 5-week-old and 8-week-old groups receiving 10 or 12 Gy TBI. Our results indicate that the strain and age of mice, and even purchasing company (especially outbred), should be matched over experimental groups in TBI experiment. Based on our results, 8-week-old male ICR mice from B company subjected to 12 Gy of TBI showed LD70/30 and suitable as a mouse model for further development of new drug using the ideal total-body irradiation model.

  6. Diet restriction enhances compensatory liver tissue repair and survival following administration of lethal dose of thioacetamide.

    PubMed

    Ramaiah, S K; Soni, M G; Bucci, T J; Mehendale, H M

    1998-05-01

    Diet restriction is known to prevent a plethora of age-associated diseases including cancer. However, the effects of diet restriction on noncancer end points are not known. The objective of this study was to investigate whether diet restriction protects against hepatotoxicity of thioacetamide (TA), and if so, to investigate the underlying mechanism. Male Sprague-Dawley rats (250-275 g) were maintained on 65% of their ad libitum (AL) food consumption for a period of 3 weeks and then treated with a single low dose of 50 mg TA/kg i.p.. Plasma enzymes (ALT and SDH), hepatic glycogen levels, and 3H-thymidine incorporation into hepatocellular nuclear DNA were measured during a time course (0-120 h) after TA administration. Liver sections were examined for histopathology, and cell-cycle progression was assessed by proliferating cell nuclear antigen (PCNA) immunohistochemistry. In AL rats hepatic necrosis was evident at 12 h, peaked at 36 h, persisted up to 72 h, and was resolved by 96 h. In the diet-restricted (DR) group hepatic necrosis was observed at 12 h, peaked at 24 h, persisted till 72 h, and was resolved by 96 h. Maximal injury indicated by enzyme elevation occurred in DR rats and was approximately sixfold greater than that observed in the AL group. Histopathological examination of the liver sections revealed liver injury concordant with plasma enzyme elevations. There was a higher and sustained S-phase synthesis in the DR rats compared to AL group. S-phase stimulation was evident at 36 h, peaked at 48 h, and persisted until 96 h in the DR rats, whereas in the AL rats peak S-phase stimulation occurred at 36 h and subsided by 72 h. PCNA studies revealed a corresponding stimulation of cell-cycle progression indicating highly stimulated compensatory tissue repair. The 14-day lethality experiments (600 mg TA/kg i.p.) indicated 70% survival in the DR rats compared to 10% survival in the AL group. Although diet restriction increases hepatotoxic injury of TA, it protects

  7. A Case Study: What Doses of Amanita phalloides and Amatoxins Are Lethal to Humans?

    PubMed

    Yilmaz, Ismail; Ermis, Fatih; Akata, Ilgaz; Kaya, Ertugrul

    2015-12-01

    There are few data estimating the human lethal dose of amatoxins or of the toxin level present in ingested raw poisonous mushrooms. Here, we present a patient who intentionally ingested several wild collected mushrooms to assess whether they were poisonous. Nearly 1 day after ingestion, during which the patient had nausea and vomiting, he presented at the emergency department. His transaminase levels started to increase starting from hour 48 and peaking at hour 72 (alanine aminotransferase 2496 IU/L; aspartate aminotransferase 1777 IU/L). A toxin analysis was carried out on the mushrooms that the patient said he had ingested. With reversed-phase high-performance liquid chromatography analysis, an uptake of approximately 21.3 mg amatoxin from nearly 50 g mushroom was calculated; it consisted of 11.9 mg alpha amanitin, 8.4 mg beta amanitin, and 1 mg gamma amanitin. In the urine sample taken on day 4, 2.7 ng/mL alpha amanitin and 1.25 ng/mL beta amanitin were found, and there was no gamma amanitin. Our findings suggest that the patient ingested approximately 0.32 mg/kg amatoxin, and fortunately recovered after serious hepatotoxicity developed.

  8. Median lethal dose, antimalarial activity, phytochemical screening and radical scavenging of methanolic Languas galanga rhizome extract.

    PubMed

    Al-Adhroey, Abdulelah H; Nor, Zurainee M; Al-Mekhlafi, Hesham M; Mahmud, Rohela

    2010-11-16

    The methanolic extract of Languas galanga rhizomes was investigated for antimalarial activity against Plasmodium berghei (NK65) infections in mice. The median lethal dose was determined to ascertain the safety of the extract in ICR mice of both sexes. The antimalarial activities during early and established infections, as well as the prophylactic activity were evaluated. Phytochemical screening and radical scavenging activity of the extract were also investigated to elucidate the possible mechanism of the antimalarial properties. The acute oral toxicity (LD₅₀) of Languas galanga extract in mice was established to be 4.998 mg/kg. The extract of Languas galanga rhizomes demonstrated significant antiplasmodial activity in all the three models of the antimalarial evaluations. Phytochemical screening revealed the presence of some vital antiplasmodial constituents such as terpenoids and flavonoids. The extract also exhibited a moderate capacity to scavenge the free radicals. The rhizome extract of Languas galanga thus possesses antimalarial activity, which explains the rational usage of this plant in traditional Malaysian medicine.

  9. [Survival after poisoning due to intake of ten-times lethal dose of acetone].

    PubMed

    Zettinig, G; Watzinger, N; Eber, B; Henning, G; Klein, W

    1997-11-28

    A 42-year-old man was found unconscious, having swallowed 800 ml of an unknown liquid with suicidal intent. On admission, when his breath smelled strongly of acetone, he was intubated and ventilated, and several gastric lavages were performed. The serum acetone concentration was 2000 mg/l, that in urine 2300 mg/l. The residue of the liquid in the bottle from which he had drunk was pure acetone. Acetone poisoning having been established he was carefully hyperventilated, haemofiltration was performed over 16 hours and forced diuresis with high fluid intake was undertaken. His condition quickly improved and he was extubated after 14 hours. There was no subsequent evidence of organ damage. Repeated measurements of acetone in blood and urine indicated its elimination with a half-life of 11 hours. Literature search revealed that this was the second highest concentration of acetone in blood and urine followed by survival. This case demonstrates that, after acute acetone poisoning with an amount ten times the lethal dose, intensive care and rapid elimination of acetone can achieve sequelae-free survival.

  10. 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

  11. Materials Applications for Non-Lethal: Aqueous Foams

    SciTech Connect

    GOOLSBY,TOMMY D.; SCOTT,STEVEN H.

    1999-09-15

    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 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 (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

  12. Combatting synthetic designer opioids: active vaccination ablates lethal doses of fentanyl class drugs

    PubMed Central

    Bremer, Paul T.; Kimishima, Atsushi; Schlosburg, Joel E.; Zhou, Bin; Collins, Karen C.; Janda, Kim D.

    2016-01-01

    Fentanyl is an addictive prescription opioid that is over 80 times more potent than morphine. The synthetic nature of fentanyl has enabled the creation of dangerous ‘designer drug’ analogues that escape toxicology screening, yet display comparable potency to the parent drug. Alarmingly, a large number of fatalities have been linked to overdose of fentanyl derivatives. Herein, we report an effective immunotherapy for reducing the psychoactive effects of fentanyl class drugs. A single conjugate vaccine was created that elicited high levels of antibodies with cross-reactivity for a wide panel of fentanyl analogues. Moreover, vaccinated mice gained significant protection from lethal fentanyl doses. Lastly, a surface plasmon resonance (SPR)-based technique was established enabling drug specificity profiling of antibodies derived directly from serum. Our newly developed fentanyl vaccine and analytical methods may assist in the battle against synthetic opioid abuse. Fentanyl is an effective synthetic opioid that is used legally as a schedule II prescription pain reliever. However, fentanyl presents a significant abuse liability due to the euphoric feeling it induces via activation of μ-opioid receptors (MOR) in the brain; the same pharmacological target as the illegal schedule I opioid, heroin.[1] Excessive activation of MOR results in respiratory depression which can be fatal.[2] Fentanyl exceeds the potency of heroin by >10-fold, and morphine by >80-fold posing a significant risk of overdose when it is consumed from unregulated sources.[3] Furthermore, the ease of fentanyl synthesis enables illegal production and the creation of designer drug analogues.[4] The fact that the pharmacology of these analogues has yet to be properly characterized makes them particularly dangerous, especially when certain modifications, even methyl additions, can increase potency, notably at the 3-position (Figure 1).[5] PMID:26879590

  13. Physiological response of alligator gar juveniles (Atractosteus spatula) exposed to sub-lethal doses of pollutants.

    PubMed

    González, Carlos Aguilera; Cruz, Julio; Alfaro, Roberto Mendoza

    2015-08-01

    Alligator gar populations have declined because of overfishing, habitat loss and pollution. Over time, the exposure to different pollutants have affected these fishes as a consequence of their high trophic level, bottom-dwelling habits and long life span. In order to evaluate the physiological effects of pollutants on alligator gar, juveniles (6, 12 and 24 months) were exposed to sub-lethal doses of diazinon, β-naphthoflavone (BNF) and 17 β-estradiol (E2) by intraperitoneal injection. After 2 days of exposure, liver samples were taken to determine the activities of acetylcholinesterase, butyrylcholinesterase and carboxylesterase; alkaline and acid phosphatases (ALP and ACP); ethoxyresorufin o-deethylase (EROD); glutathione s-transferase (GST); superoxide dismutase (SOD), and vitellogenin (VTG) concentration. Two additional bioassays consisting on the exposure of compounds through water or food were performed and after 4 and 28 days, respectively, biomarkers were determined. All esterases were inhibited in organisms exposed to diazinon as well as in 6-months gar exposed to E2 and BNF. In contrast, ALP activity increased in gar exposed to diazinon and E2, while ACP activity did not show any variations. No EROD activity was registered after exposure to the different pollutants, despite being one of the most sensitive and common detoxification biomarkers used for fishes. GST activity reduction was detected when gar were exposed to E2 and BNF, while SOD activity increased after exposure to diazinon and E2. Finally, VTG levels were higher in animals exposed to E2 compared to other treatments. Overall, these results suggest that alligator gar juveniles have a low biotransformation metabolism and show that they are especially sensitive to those pollutants affecting the nervous system.

  14. [Sensitivity of Jatropha curcas seeds to (60)Co-gamma radiation and their medial lethal doses in radiation breeding].

    PubMed

    Wang, Zhao-Yu; Lin, Jing-Ming; Luo, Li; Xu, Zeng-Fu

    2009-03-01

    To study the sensitivity of Jatropha curcas seeds from three different locations to (60)Co-gamma radiation and to determine the medial lethal doses (LD50) of (60)Co-gamma radiation for these seeds. Six different radiation doses (0, 100, 150, 200, 250 and 300 Gy) were used. Based on the germination rate 50%, LD50 doses of (60)Co-gamma radiation for the seeds were calculated using linear regression equation. LD50 doses of (60)Co-gamma radiation for these seeds were 178 Gy (seeds from Guangdong), 132 Gy (seeds from Hainan) and 198 Gy (seeds from India) respectively. Increasing radiation doses caused more significant changes in leaf shape of the M1 seedlings. The results provides an important experimental basis for the radiation breeding of the important herbal and energy plant J. curcas.

  15. Sub-Lethal Dose of Shiga Toxin 2 from Enterohemorrhagic Escherichia coli Affects Balance and Cerebellar Cytoarchitecture

    PubMed Central

    Pinto, Alipio; Cangelosi, Adriana; Geoghegan, Patricia A.; Tironi-Farinati, Carla; Brener, Gabriela J.; Goldstein, Jorge

    2016-01-01

    Shiga toxin producing Escherichia coli may damage the central nervous system before or concomitantly to manifested hemolytic–uremic syndrome symptoms. The cerebellum is frequently damaged during this syndrome, however, the deleterious effects of Shiga toxin 2 has never been integrally reported by ultrastructural, physiological and behavioral means. The aim of this study was to determine the cerebellar compromise after intravenous administration of a sub-lethal dose of Shiga toxin 2 by measuring the cerebellar blood–brain barrier permeability, behavioral task of cerebellar functionality (inclined plane test), and ultrastructural analysis (transmission electron microscope). Intravenous administration of vehicle (control group), sub-lethal dose of 0.5 and 1 ηg of Stx2 per mouse were tested for behavioral and ultrastructural studies. A set of three independent experiments were performed for each study (n = 6). Blood–brain barrier resulted damaged and consequently its permeability was significantly increased. Lower scores obtained in the inclined plane task denoted poor cerebellar functionality in comparison to their controls. The most significant lower score was obtained after 5 days of 1 ηg of toxin administration. Transmission electron microscope micrographs from the Stx2-treated groups showed neurons with a progressive neurodegenerative condition in a dose dependent manner. As sub-lethal intravenous Shiga toxin 2 altered the blood brain barrier permeability in the cerebellum the toxin penetrated the cerebellar parenchyma and produced cell damaged with significant functional implications in the test balance. PMID:26904009

  16. Sub-Lethal Dose of Shiga Toxin 2 from Enterohemorrhagic Escherichia coli Affects Balance and Cerebellar Cytoarchitecture.

    PubMed

    D'Alessio, Luciana; Pinto, Alipio; Cangelosi, Adriana; Geoghegan, Patricia A; Tironi-Farinati, Carla; Brener, Gabriela J; Goldstein, Jorge

    2016-01-01

    Shiga toxin producing Escherichia coli may damage the central nervous system before or concomitantly to manifested hemolytic-uremic syndrome symptoms. The cerebellum is frequently damaged during this syndrome, however, the deleterious effects of Shiga toxin 2 has never been integrally reported by ultrastructural, physiological and behavioral means. The aim of this study was to determine the cerebellar compromise after intravenous administration of a sub-lethal dose of Shiga toxin 2 by measuring the cerebellar blood-brain barrier permeability, behavioral task of cerebellar functionality (inclined plane test), and ultrastructural analysis (transmission electron microscope). Intravenous administration of vehicle (control group), sub-lethal dose of 0.5 and 1 ηg of Stx2 per mouse were tested for behavioral and ultrastructural studies. A set of three independent experiments were performed for each study (n = 6). Blood-brain barrier resulted damaged and consequently its permeability was significantly increased. Lower scores obtained in the inclined plane task denoted poor cerebellar functionality in comparison to their controls. The most significant lower score was obtained after 5 days of 1 ηg of toxin administration. Transmission electron microscope micrographs from the Stx2-treated groups showed neurons with a progressive neurodegenerative condition in a dose dependent manner. As sub-lethal intravenous Shiga toxin 2 altered the blood brain barrier permeability in the cerebellum the toxin penetrated the cerebellar parenchyma and produced cell damaged with significant functional implications in the test balance.

  17. Effect of delayed anthrax vaccine dose on Bacillus anthracis protective antigen IgG response and lethal toxin neutralization activity.

    PubMed

    Pittman, Phillip R; Fisher, Diana; Quinn, Xiaofei; Schmader, Trevor; Barrera-Oro, Julio G

    2013-10-17

    We describe the Bacillus anthracis protective antigen IgG antibody response and the B. anthracis lethal toxin neutralization activity to a delayed dose of anthrax vaccine adsorbed (AVA, BioThrax(®)) using validated assays. 373 individuals received 1, 2, or 3 priming doses, 18-24 months afterward, they received a delayed dose of AVA. Overall, 23.6% of subjects showed detectable anti-PA IgG before the boost, compared to 99.2% (P<0.0001) 28 days after the boost. Geometric mean anti-PA IgG concentration (GMC) was 1.66 μg/mL before and 887.82 μg/mL after the boost (P<0.0001). The proportion of individuals with four-fold increase in GMC following the boost ranged from 93.8% to 100%. Robust anti-PA IgG levels and B. anthracis lethal toxin neutralization activity are induced when an AVA dose is delayed as long as two years. These data support continuing with the vaccination schedule when a dose is delayed as long as two years rather than restarting the series. Published by Elsevier Ltd.

  18. Prediction of lethal/effective concentration/dose in the presence of multiple auxiliary covariates and components of variance

    USGS Publications Warehouse

    Gutreuter, S.; Boogaard, M.A.

    2007-01-01

    Predictors of the percentile lethal/effective concentration/dose are commonly used measures of efficacy and toxicity. Typically such quantal-response predictors (e.g., the exposure required to kill 50% of some population) are estimated from simple bioassays wherein organisms are exposed to a gradient of several concentrations of a single agent. The toxicity of an agent may be influenced by auxiliary covariates, however, and more complicated experimental designs may introduce multiple variance components. Prediction methods lag examples of those cases. A conventional two-stage approach consists of multiple bivariate predictions of, say, medial lethal concentration followed by regression of those predictions on the auxiliary covariates. We propose a more effective and parsimonious class of generalized nonlinear mixed-effects models for prediction of lethal/effective dose/concentration from auxiliary covariates. We demonstrate examples using data from a study regarding the effects of pH and additions of variable quantities 2???,5???-dichloro-4???- nitrosalicylanilide (niclosamide) on the toxicity of 3-trifluoromethyl-4- nitrophenol to larval sea lamprey (Petromyzon marinus). The new models yielded unbiased predictions and root-mean-squared errors (RMSEs) of prediction for the exposure required to kill 50 and 99.9% of some population that were 29 to 82% smaller, respectively, than those from the conventional two-stage procedure. The model class is flexible and easily implemented using commonly available software. ?? 2007 SETAC.

  19. 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

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

    PubMed

    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

    2015-10-01

    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.

  1. Extension of time until cardiac arrest after injection of a lethal dose of pentobarbital in the hibernating Syrian hamster.

    PubMed

    Miyazawa, Seiji; Shiina, Takahiko; Takewaki, Tadashi; Shimizu, Yasutake

    2009-03-01

    The aim of the present study was to examine whether entry of peripherally injected drugs into the central nervous system is reduced during hibernation. When a lethal dose of pentobarbital was injected intraperitoneally, the time until cardiac arrest was significantly longer in hibernating hamsters than in active controls. The time difference was not a consequence of low body temperature or diminished circulation, because mimicking these parameters in artificial hypothermia did not prolong the time. In contrast, there was no difference in the time until cardiac arrest after intracerebroventricular injection of the anesthetic. These results indicate that entry of peripherally injected anesthetics into the central nervous system may be suppressed during hibernation.

  2. A cytomegalovirus-based vaccine provides long-lasting protection against lethal Ebola virus challenge after a single dose.

    PubMed

    Tsuda, Yoshimi; Parkins, Christopher J; Caposio, Patrizia; Feldmann, Friederike; Botto, Sara; Ball, Susan; Messaoudi, Ilhem; Cicin-Sain, Luka; Feldmann, Heinz; Jarvis, Michael A

    2015-05-05

    Ebola virus (Zaire ebolavirus; EBOV) is a highly lethal hemorrhagic disease virus that most recently was responsible for two independent 2014 outbreaks in multiple countries in Western Africa, and the Democratic Republic of the Congo, respectively. Herein, we show that a cytomegalovirus (CMV)-based vaccine provides durable protective immunity from Ebola virus following a single vaccine dose. This study has implications for human vaccination against ebolaviruses, as well as for development of a 'disseminating' vaccine to target these viruses in wild African great apes. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Effect of chronic non-lethal doses of non-metals and metals on hepatic metallothionein in Channa punctatus (Bloch).

    PubMed

    Dalal, R; Bhattacharya, S

    1991-07-01

    Compared to non-metal toxicants (ammonia, 1.56 ppm; and phenol, 10 ppm), the metals (CdCl2, 30 ppm; HgCl2, 16.7 ppb; and ZnCl2, 6 ppm) significantly induced hepatic metallothionein (MT) concentrations in C. punctatus, exposed independently to non-lethal doses of these toxicants for 28 days. It is suggested that hepatic MT serves as a metal-sequestering protein and is involved in the detoxication of metals only and ensures protection from toxic chemicals in ambience.

  4. Prediction of Protein-Peptide Interactions: Application of the XPairIT to Anthrax Lethal Factor and Substrates

    DTIC Science & Technology

    2013-09-01

    Prediction of Protein-Peptide Interactions: Application of the XPairIt API to Anthrax Lethal Factor and Substrates by Margaret M. Hurley and...Peptide Interactions: Application of the XPairIt API to Anthrax Lethal Factor and Substrates Margaret M. Hurley and Michael S. Sellers Weapons and...Prediction of Protein-Peptide Interactions: Application of the XPairIt API to Anthrax Lethal Factor and Substrates 5a. CONTRACT NUMBER ORAUW911QX-04-C

  5. Determination of the Median Lethal Dose and Electrophoretic Pattern of Hottentotta saulcyi (Scorpiones, Buthidae) Scorpion Venom

    PubMed Central

    Yağmur, Ersen Aydın; Özkan, Özcan; Karaer, K Zafer

    2015-01-01

    Background: In this study, we investigated the lethal potency, electrophoretic protein pattern and in vivo effects of Hottentotta saulcyi scorpion venom in mice. Methods: Scorpions were collected at night, by using a UV lamp from Mardin Province, Turkey. Venom was obtained from mature H. saulcyi scorpions by electrical stimulation of the telson. The lethality of the venom was determined by i.v. injections using Swiss mice. In vivo effects of the venom were assessed by using the intraperitoneal route (ip) injections into mice (20±1g) and monitored for 24 h. The protein profiles of the scorpion venom were analyzed by NuPAGE® Novex® 4–12 % gradient Bis-Tris gel followed by Coomassie blue staining. Results: The lethal assay of the venom was 0.73 mg/kg in mice. We determined the electrophoretic protein pattern of this scorpion venom to be 4, 6, 9, 31, 35, 40, 46 and 69 kDa by SDS-PAGE. Analysis of electrophoresis indicated that H. saulcyi scorpion intoxicated mice exhibited autonomic nervous system symptoms (tachypnea, restlessness, hyperexcitability, convulsions, salivation, lacrimation, weakness). Conclusions: Hottentotta saulcyi scorpion venom includes short-chain neurotoxins and long-chain neurotoxins according to the electrophoretic protein patterns. The stings of H. saulcyi scorpion must be considered of risk for humans in the southeastern region, Turkey. PMID:26623435

  6. 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

  7. 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

  8. Treatment Following Intoxication With Lethal Dose of Paraquat: A Case Report and Review of Literature

    PubMed Central

    Davarpanah, Mohammad Ali; Hosseinzadeh, Farideh; Mohammadi, S. Saeed

    2015-01-01

    Introduction: Paraquat is a widely used nitrogen-based herbicide which is lethal and causes multi-organ failure by accumulation in cells, which subsequently leads to death. Case Presentation: The present case report introduced a 25-year-old male with nausea, vomiting, and severe substernal burning sensation after incidentally ingestion of a large amount of paraquat. The treatment of the patient with antioxidants (N-acetylcysteine and vitamin E) and hemodialysis started immediately after arriving to the hospital. Conclusions: Immediate and adequate use of antioxidants and hemodialysis has an undeniable and important role in survival of patients after ingestion of a large amount of paraquat. PMID:26568853

  9. Effects of melatonin in rats in the initial third stage of pregnancy exposed to sub-lethal doses of herbicides.

    PubMed

    Almeida, Lécio Leone de; Teixeira, Álvaro Aguiar Coelho; Soares, Anísio Francisco; Cunha, Franklin Magliano da; Silva, Valdemiro Amaro da; Vieira Filho, Leucio Duarte; Wanderley-Teixeira, Valéria

    2017-04-01

    Exposure to the herbicides Paraquat (PQ) and Roundup(®) may cause cell lesions due to an increase in oxidative stress levels in different biological systems, even in the reproductive system. Evaluate the possible changes in reproductive parameters and hepatic, as well as its prevention by simultaneous application of melatonin. Thirty-five female rats at the age of 3 months were divided into seven groups: three groups exposed to sub-lethal doses of the herbicides PQ (50mg/kg) and Roundup(®) (500mg/kg) (n=5, G2, G3 and G4); three groups exposed to herbicides and simultaneous treatment with 10mg/kg of Melatonin (n=5, G5, G6 and G7) and control group (n=5, G1) from the first to the seventh day of pregnancy. On the seventh day of pregnancy, the rats were anesthetized and euthanized, followed by laparotomy to remove their reproductive tissues and liver. Body and ovary weights were taken and the number of implantation sites, corpora lutea, preimplantation losses, implantation rates were counted and histopathology of the implantation sites, morphometry of the surface and glandular epithelia of endometrium and hepatic oxidative stress were undertaken. The present study shows the decrease in body and ovary weight, decrease in the number of implantation sites, implantation rate, in the total number of corpora lutea and increase of preimplantation percentages were observed when compared to the G1: Fig. 1 and Table 1, (p>0.001 ANOVA/Tukey). The histopathological analysis of the implantation sites showed a disorder of the cytotrophoblast and cell degeneration within the blastocyst cavity in Fig. 4. Morphometry revealed a reduction in surface and glandular epithelia and in the diameter of the endometrial glands (Table 2; p>0.05 ANOVA/Tukey), whereas in liver, serum levels of thiobarbituric acid reactive substances (TBARS) were found to be significantly elevated (Fig. 2; p>0.001; p>0.05 ANOVA/Tukey), and serum level of reduced glutathione (GSH) was significantly lower (Fig. 3; p

  10. 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.

  11. [Effect of lethal doses of plants of the Agavaceae family on the cardiac activity and oviposition of Biophalaria havanensis (Mollusca: Planobidae)].

    PubMed

    Díaz Garcés, R; Ferrer López, J R

    1996-01-01

    Work was carried out with lethal doses of 3 agavaceas, Agave legrelliana, Agave fourcroydes and Agave franzosinii, and it was determined the influences of LD50 and LD90 of agavaceas on the cardiac activity reduction. As a result, it was found that A. fourcryodes has the aqueous extract influencing the most on the reduction of heart rate. LD90 of agavaceas also affects the embrionary development of eggs having between 1 and 7 days of oviposition. The greatest affectation was found among the first. A. fourcroydes and A. legrelliana, respectively, influence the most on the reduction of the amount of eggs. The number of eggs ovipositted by mollucs surviving the application of LD90 from A. franzosinii is lower, as well as the number of hatched eggs.

  12. Clinical parameters, postmortem analysis and estimation of lethal dose in victims of a massive intoxication with diethylene glycol.

    PubMed

    Ferrari, Luis A; Giannuzzi, Leda

    2005-10-04

    could be observed. The lethal dose for human beings estimated in this work ranged from 0.014 to 0.170 mg DEG/kg body weight. This is a lower lethal dose than reported in a separate incident in Haiti. These results may contribute to the understanding of DEG's metabolic pathway and provides data from lethal doses in humans.

  13. Mechanism of lethal interaction of hazardous chemicals at subtoxic doses. Final report, 1 Nov 87-31 Aug 91

    SciTech Connect

    Mehendale, H.M.

    1991-09-20

    The possibility of unusual toxicity due to interaction of toxic chemicals upon environmental or occupational exposures to two or more chemicals, particularly when exposures involve levels ordinarily considered harmless individually is an important toxicological concern. Progress in this area of environmental toxicology has suffered for want of a model where the two interactants are individually nontoxic. Models, where toxic doses of chemicals are employed are not very representative of low level, environmental exposure. Prior exposure to nontoxic levels of the pesticide Kepone (chlordecone, CD) results in a 67-fold amplification of CCI4 lethality in experimental animals. This propensity for chlordecone to potentiate hepatotoxicity of halomethanes such as CCI4, CHCI3 and BrCCI3 has been the subject of this intense inquiry to unravel the underlying mechanism. The biological effects of this interaction include extensive hepatotoxicity characterized by histological alterations, hepatic dysfunction, and perturbation of related biochemical parameters.

  14. 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.

  15. 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

  16. Temporal changes in tissue repair permit survival of diet-restricted rats from an acute lethal dose of thioacetamide.

    PubMed

    Ramaiah, S K; Bucci, T J; Warbritton, A; Soni, M G; Mehendale, H M

    1998-10-01

    Although, diet restriction (DR) has been shown to substantially increase longevity while reducing or delaying the onset of age-related diseases, little is known about the mechanisms underlying the beneficial effects of DR on acute toxic outcomes. An earlier study (S. K. Ramaiah et al., 1998, Toxicol. Appl. Pharmacol. 150, 12-21) revealed that a 35% DR compared to ad libitum (AL) feeding leads to a substantial increase in liver injury of thioacetamide (TA) at a low dose (50 mg/kg, i.p.). Higher liver injury was accompanied by enhanced survival. A prompt and enhanced tissue repair response in DR rats at the low dose (sixfold higher liver injury) occurred, whereas at equitoxic doses (50 mg/kg in DR and 600 mg/kg in AL rats) tissue repair in AL rats was substantially diminished and delayed. The extent of liver injury did not appear to be closely related to the extent of stimulated tissue repair response. The purpose of the present study was to investigate the time course (0-120 h) of liver injury and liver tissue repair at the high dose (600 mg TA/kg, i.p., lethal in AL rats) in AL and DR rats. Male Sprague-Dawley rats (225-275 g) were 35% diet restricted compared to their AL cohorts for 21 days and on day 22 they received a single dose of TA (600 mg/kg, i.p.). Liver injury was assessed by plasma ALT and by histopathological examination of liver sections. Tissue repair was assessed by [3H]thymidine incorporation into hepatonuclear DNA and proliferating cell nuclear antigen (PCNA) immunohistochemistry during 0-120 h after TA injection. In AL-fed rats hepatic necrosis was evident at 12 h, peaked at 60 h, and persisted thereafter until mortality (3 to 6 days). Peak liver injury was approximately twofold higher in DR rats compared to that seen in AL rats. Hepatic necrosis was evident at 36 h, peaked at 48 h, persisted until 96 h, and returned to normal by 120 h. Light microscopy of liver sections revealed progression of hepatic injury in AL rats whereas injury regressed

  17. 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.

  18. Controlled bioassay systems for determination of lethal infective doses of tissue homogenates containing Taura syndrome or white spot syndrome virus.

    PubMed

    Prior, Sarah; Browdy, Craig L; Shepard, Eleanor F; Laramore, Rolland; Parnell, Pamela G

    2003-03-31

    In vivo bioassay is the predominant method for evaluating the infectivity of materials potentially harboring viable shrimp pathogens and determining the relative susceptibility of shrimp species to viral infections. A controlled bioassay system for white spot syndrome virus (WSSV) and Taura syndrome virus (TSV) was developed utilizing 260 ml tissue culture flasks modified with an air exchange vent. Individual shrimp (1.00 +/- 0.25 g) were placed in separate flasks containing artificial seawater (100 to 150 ml) and held in an incubator at 27 degrees C. After a 48 h acclimation period, shrimp were either injected intramuscularly with viral inoculum or exposed to virus-laden water. Water was exchanged and shrimp were fed a commercial food pellet daily except 24 h post-infection (p.i.). Bioassays were performed with serial dilutions of stock viral preparations and shrimp mortality was recorded for 7 d p.i. Mortality rates of test animals permitted the estimation of the lethal infective doses, LD50 and LD90. The LD50 of the TSV injection preparation was estimated at viral dilutions of 1:7.692 x 10(7) (Trial 1) and 1:6.667 x 10(7) (Trial 2). The LD50s of 2 different WSSV injection preparations were estimated at 1:4.444 x 10(6) and 1:4.505 x 10(6). The LD50 for the TSV waterborne challenge was 1:9916 (Trial 1) and 1:15 710 (Trial 2) at 20 degrees C and 1:1272 at 27 degrees C. A second waterborne TSV inoculum challenge at 27 degrees C produced an LD50 of 1:2857. WSSV doses used in the waterborne challenge only reached 39% mortality, which did not allow for the estimation of effective lethal doses. Bioassay by injection proved to be a more reliable method of estimating viral infectivity compared to waterborne method. The dose-response curves developed can serve as a basis for controlled comparisons of relative levels of viral infectivity of specific tissue preparations and for controlled comparisons of relative susceptibility of shrimp species or stocks to viral pathogens.

  19. 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.

  20. Lower dose of hypertonic saline dextran reduces the risk of lethal rebleeding in uncontrolled hemorrhage.

    PubMed

    Riddez, Louis; Drobin, Dan; Sjöstrand, Fredrik; Svensén, Christer; Hahn, Robert G

    2002-05-01

    To challenge whether the recommended dose of 4 mL/kg of 7.5% sodium chloride in 6% Dextran (HSD) is optimal for fluid resuscitation in uncontrolled hemorrhage, 30 anesthetized pigs were randomized to receive a 5-min intravenous infusion of either 1, 2, or 4 mL/kg of HSD beginning 10 min after inducing a 5-mm laceration in the infrarenal aorta. In addition to conventional hemodynamic monitoring, the blood loss was calculated as the difference in blood flow rates between flow probes placed proximal and distal to the injury. The results show that the bleeding stopped between 3 and 4 min after the injury and amounted to 338+/-92 mL (mean +/- SEM), which corresponds to 28.5%+/-6.6% of the estimated blood volume. After treatment with HSD was started, six rebleeding events occurred in the 1-mL group, 11 in the 2-mL group, and 16 in the 4-mL group. The amount of blood lost due to rebleeding increased significantly with the dose of HSD and was also associated with a fatal outcome. The total blood loss was 408 mL in the survivors and 630 mL in the nonsurvivors (median, P < 0.007). The mortality in the three groups was 20%, 50%, and 50%, respectively. In conclusion, infusing 4 mL/kg of HSD after uncontrolled aortic hemorrhage promoted rebleeding and increased the mortality, while a dose of 1 mL/kg appeared to be more suitable.

  1. Low-Dose-Rate Irradiation for 1 Hour Induces Protection Against Lethal Radiation Doses but Does Not Affect Life Span of DBA/2 Mice

    PubMed Central

    Altaner, Čestmír; Altanerova, Veronika; Ebbesen, Peter; Pettersen, Erik O.

    2016-01-01

    Prior findings showed that serum from DBA/2 mice that had been given whole-body irradiation for 1 hour at a low dose rate (LDR) of 30 cGy/h induced protection against radiation in reporter cells by a mechanism depending on transforming growth factor β3 and inducible nitric oxide synthase activity. In the present study, the effect of the 1 hour of LDR irradiation on the response of the preirradiated mice to a subsequent lethal dose and on the life span is examined. These DBA/2 mice were prime irradiated for 1 hour at 30 cGy/h. Two experiments with 9 and 9.5 Gy challenge doses given 6 weeks after priming showed increased survival in primed mice compared to unprimed mice followed up to 225 and 81 days after challenge irradiation, respectively. There was no overall significant difference in life span between primed and unprimed mice when no challenge irradiation was given. The males seemed to have a slight increase in lifespan after priming while the opposite was seen for the females. PMID:27867323

  2. 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.

  3. Increased Radioresistance to Lethal Doses of Gamma Rays in Mice and Rats after Exposure to Microwave Radiation Emitted by a GSM Mobile Phone Simulator

    PubMed Central

    Mortazavi, SMJ; Mosleh-Shirazi, MA; Tavassoli, AR; Taheri, M; Mehdizadeh, AR; Namazi, SAS; Jamali, A; Ghalandari, R; Bonyadi, S; Haghani, M; Shafie, M

    2013-01-01

    The aim of this study was to investigate the effect of pre-irradiation with microwaves on the induction of radioadaptive response. In the 1st phase of the study, 110 male mice were divided into 8 groups. The animals in these groups were exposed/sham-exposed to microwave, low dose rate gamma or both for 5 days. On day six, the animals were exposed to a lethal dose (LD). In the 2nd phase, 30 male rats were divided into 2 groups of 15 animals. The 1st group received microwave exposure. The 2nd group (controls) received the same LD but there was no treatment before the LD. On day 5, all animals were whole-body irradiated with the LD. Statistically significant differences between the survival rate of the mice only exposed to lethal dose of gamma radiation before irradiation with a lethal dose of gamma radiation with those of the animals pre-exposed to either microwave (p=0.02), low dose rate gamma (p=0.001) or both of these physical adapting doses (p=0.003) were observed. Likewise, a statistically significant difference between survival rates of the rats in control and test groups was observed. Altogether, these experiments showed that exposure to microwave radiation may induce a significant survival adaptive response. PMID:23930107

  4. Recombinant Isfahan Virus and Vesicular Stomatitis Virus Vaccine Vectors Provide Durable, Multivalent, Single-Dose Protection against Lethal Alphavirus Challenge

    PubMed Central

    Matassov, Demetrius; Seymour, Robert L.; Latham, Theresa; Gorchakov, Rodion V.; Nowak, Rebecca M.; Leal, Grace; Hamm, Stefan; Eldridge, John H.; Tesh, Robert B.; Clarke, David K.

    2017-01-01

    ABSTRACT The demonstrated clinical efficacy of a recombinant vesicular stomatitis virus (rVSV) vaccine vector has stimulated the investigation of additional serologically distinct Vesiculovirus vectors as therapeutic and/or prophylactic vaccine vectors to combat emerging viral diseases. Among these viral threats are the encephalitic alphaviruses Venezuelan equine encephalitis virus (VEEV) and Eastern equine encephalitis virus (EEEV), which have demonstrated potential for natural disease outbreaks, yet no licensed vaccines are available in the event of an epidemic. Here we report the rescue of recombinant Isfahan virus (rISFV) from genomic cDNA as a potential new vaccine vector platform. The rISFV genome was modified to attenuate virulence and express the VEEV and EEEV E2/E1 surface glycoproteins as vaccine antigens. A single dose of the rISFV vaccine vectors elicited neutralizing antibody responses and protected mice from lethal VEEV and EEEV challenges at 1 month postvaccination as well as lethal VEEV challenge at 8 months postvaccination. A mixture of rISFV vectors expressing the VEEV and EEEV E2/E1 glycoproteins also provided durable, single-dose protection from lethal VEEV and EEEV challenges, demonstrating the potential for a multivalent vaccine formulation. These findings were paralleled in studies with an attenuated form of rVSV expressing the VEEV E2/E1 glycoproteins. Both the rVSV and rISFV vectors were attenuated by using an approach that has demonstrated safety in human trials of an rVSV/HIV-1 vaccine. Vaccines based on either of these vaccine vector platforms may present a safe and effective approach to prevent alphavirus-induced disease in humans. IMPORTANCE This work introduces rISFV as a novel vaccine vector platform that is serologically distinct and phylogenetically distant from VSV. The rISFV vector has been attenuated by an approach used for an rVSV vector that has demonstrated safety in clinical studies. The vaccine potential of the rISFV vector

  5. Photosensitized damage inflicted on plasma membranes of live cells by an extracellular generator of singlet oxygen--a linear dependence of a lethal dose on light intensity.

    PubMed

    Zarębski, Mirosław; Kordon, Magdalena; Dobrucki, Jurek W

    2014-01-01

    We describe a study of the influence of a dose rate, i.e. light intensity or photon flux, on the efficiency of induction of a loss of integrity of plasma membranes of live cells in culture. The influence of a photon flux on the size of the light dose, which was capable of causing lethal effects, was measured in an experimental system where singlet oxygen was generated exclusively outside of live cells by ruthenium(II) phenantroline complex. Instantaneous, sensitive detection of a loss of integrity of a plasma membrane was achieved by fluorescence confocal imaging of the entry of this complex into a cell interior. We demonstrate that the size of the lethal dose of light is directly proportional to the intensity of the exciting light. Thus, the probability of a photon of the exciting light inflicting photosensitized damage on plasma membranes diminishes with increasing density of the incident photons.

  6. A U-shaped dose-response relationship between x radiation and sex-linked recessive lethal mutation in male germ cells of Drosophila.

    PubMed

    Koana, Takao; Tsujimura, Hidenobu

    2010-07-01

    We reported previously that low-dose X irradiation of DNA repair-proficient immature sperm of wild-type Drosophila melanogaster at a low dose rate (50 mGy/min) resulted in a mutation frequency that was lower than that in the sham-irradiated group. Therefore, a U-shaped dose-response relationship was suggested. Here we show that the dose-response curve is actually U-shaped by carrying out a large-scale sex-linked recessive lethal assay using Drosophila. No reduction of the mutation frequency was observed in a strain mutant for the nucleotide excision repair gene mei-9a (Drosophila homologue of human XPF). Introduction of a chromosome fragment containing mei-9+ into the mei-9a mutant strain restored the reduction of the mutation frequency in the low-dose-irradiated group. These results showed that DNA repair was responsible for the U-shaped dose-response relationship in Drosophila.

  7. Degeneration and Regeneration of Murine Skeletal Neuromuscular Junctions after Intramuscular Injection with a Sublethal Dose of Clostridium sordellii Lethal Toxin

    PubMed Central

    Barbier, Julien; Popoff, Michel R.; Molgó, Jordi

    2004-01-01

    Clostridium sordellii lethal toxin (LT), a 250-kDa protein which is the bacteria's major virulence factor, belongs to a family of large clostridial cytotoxins which glucosylate small GTP-binding proteins. Here, we report the results of our ex vivo analysis of the structure and function of skeletal neuromuscular tissue obtained from mice at various times after intramuscular injection of a sublethal dose of LT (0.25 ng/g of body wt). The toxin caused, within 24 h, pronounced localized edema, inflammation, myofibril disassembly, and degeneration of skeletal muscle fibers in the injected area, and it glucosylated the muscle tissue's small GTPases. Regeneration of the damaged fibers was evident 6 to 9 days postinjury and was completed by 60 days. The expression of dystrophin, laminin, and fast and neonatal myosin in regenerating fibers, detected by immunofluorescence microscopy, confirmed that LT does not impair the high regenerative capacity of murine skeletal muscle fibers. Functional studies revealed that LT affects muscle contractility and neuromuscular transmission. However, partial recovery of nerve-evoked muscle twitches and tetanic contractions was observed by day 15 postinjection, and extensive remodeling of the neuromuscular junction's nerve terminals and clusters of muscle acetylcholine receptors was still evident 30 days postinjection. In conclusion, to the best of our knowledge, this is the first report to characterize the degeneration and regeneration of skeletal neuromuscular tissue after in vivo exposure to a large clostridial cytotoxin. In addition, our data may provide an explanation for the severe neuromuscular alterations accompanying wound infections caused by C. sordellii. PMID:15155613

  8. 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

  9. Degeneration and regeneration of murine skeletal neuromuscular junctions after intramuscular injection with a sublethal dose of Clostridium sordellii lethal toxin.

    PubMed

    Barbier, Julien; Popoff, Michel R; Molgó, Jordi

    2004-06-01

    Clostridium sordellii lethal toxin (LT), a 250-kDa protein which is the bacteria's major virulence factor, belongs to a family of large clostridial cytotoxins which glucosylate small GTP-binding proteins. Here, we report the results of our ex vivo analysis of the structure and function of skeletal neuromuscular tissue obtained from mice at various times after intramuscular injection of a sublethal dose of LT (0.25 ng/g of body wt). The toxin caused, within 24 h, pronounced localized edema, inflammation, myofibril disassembly, and degeneration of skeletal muscle fibers in the injected area, and it glucosylated the muscle tissue's small GTPases. Regeneration of the damaged fibers was evident 6 to 9 days postinjury and was completed by 60 days. The expression of dystrophin, laminin, and fast and neonatal myosin in regenerating fibers, detected by immunofluorescence microscopy, confirmed that LT does not impair the high regenerative capacity of murine skeletal muscle fibers. Functional studies revealed that LT affects muscle contractility and neuromuscular transmission. However, partial recovery of nerve-evoked muscle twitches and tetanic contractions was observed by day 15 postinjection, and extensive remodeling of the neuromuscular junction's nerve terminals and clusters of muscle acetylcholine receptors was still evident 30 days postinjection. In conclusion, to the best of our knowledge, this is the first report to characterize the degeneration and regeneration of skeletal neuromuscular tissue after in vivo exposure to a large clostridial cytotoxin. In addition, our data may provide an explanation for the severe neuromuscular alterations accompanying wound infections caused by C. sordellii.

  10. Effect of sub-lethal doses of vancomycin and oxacillin on biofilm formation by vancomycin intermediate resistant Staphylococcus aureus.

    PubMed

    Mirani, Zulfiqar Ali; Jamil, Nusrat

    2011-04-01

    Biofilms are means of protection to bacteria against antibiotics and antibodies. Catheters and others tube devices used by patients are prone to accumulation of thick layers of biofilms as hiding place for etiologic agents, resulting in substantial morbidity and mortality. Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of hospital-acquired infections. Vancomycin remains the only treatment of choice for MRSA infections. In the present study a vancomycin resistant S. aureus (VRSA) (Labeled as CP2) was isolated from the blood of a post-operative cardiac patient. It harbors a plasmid which carry vanA gene and exhibited low-level vancomycin resistance (MIC 16 μg/ml), high level of oxacillin/methicillin resistance (MIC 500 μg/ml) and was sensitive to teicoplanin. CP2 also found to carry icaA gene on its chromosome. This strain exhibited resistance to triton-X100 induced autolysis under sub-inhibitory concentration of vancomycin and produced some extracellular matrix material that surrounding the cells. These characteristic features have warranted us to study the biofilm formation by CP2 on biomedical indwellings in presence of vancomycin and oxacillin. Our findings suggest that sub-lethal dose of vancomycin induced the biofilm formation by CP2 on nylon and silicon indwellings whereas oxacillin facilitated the biofilm formation on glass surfaces exclusively. This implicates that not only the antibiotics but also the indwelling material influences biofilm formation. Therefore, these implants serve as potential surfaces for bacterial adhesion that lead to biofilm formation, thus provide hiding places for pathogens from the actions of antimicrobials.

  11. Low-dose irradiation prior to bone marrow transplantation results in ATM activation and increased lethality in Atm-deficient mice.

    PubMed

    Pietzner, J; Merscher, B M; Baer, P C; Duecker, R P; Eickmeier, O; Fußbroich, D; Bader, P; Del Turco, D; Henschler, R; Zielen, S; Schubert, R

    2016-04-01

    Ataxia telangiectasia is a genetic instability syndrome characterized by neurodegeneration, immunodeficiency, severe bronchial complications, hypersensitivity to radiotherapy and an elevated risk of malignancies. Repopulation with ATM-competent bone marrow-derived cells (BMDCs) significantly prolonged the lifespan and improved the phenotype of Atm-deficient mice. The aim of the present study was to promote BMDC engraftment after bone marrow transplantation using low-dose irradiation (IR) as a co-conditioning strategy. Atm-deficient mice were transplanted with green fluorescent protein-expressing, ATM-positive BMDCs using a clinically relevant non-myeloablative host-conditioning regimen together with TBI (0.2-2.0 Gy). IR significantly improved the engraftment of BMDCs into the bone marrow, blood, spleen and lung in a dose-dependent manner, but not into the cerebellum. However, with increasing doses, IR lethality increased even after low-dose IR. Analysis of the bronchoalveolar lavage fluid and lung histochemistry revealed a significant enhancement in the number of inflammatory cells and oxidative damage. A delay in the resolution of γ-H2AX-expression points to an insufficient double-strand break repair capacity following IR with 0.5 Gy in Atm-deficient splenocytes. Our results demonstrate that even low-dose IR results in ATM activation. In the absence of ATM, low-dose IR leads to increased inflammation, oxidative stress and lethality in the Atm-deficient mouse model.

  12. 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.

  13. 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.

  14. The effects of sub-chronic administration of sub-lethal doses of amitraz/xylene on selected reproductive parameters of male Wistar rats.

    PubMed

    Omoja, V U; Anika, S M; Asuzu, I U

    2016-01-01

    This study investigated the effects of sub-chronic administration of sub-lethal doses of amitraz on some testicular parameters of Albino rats. Twenty-four adult male Albino rats (100 ± 10 g) randomly assigned into four groups were used for the study. Groups A, B and C received 10.0, 2.0 and 0.4 mg/kg amitraz in 10 ml/kg water while group D received equivalent volume of water orally and daily for 84 days. Serum testosterone levels (TESL) were assessed on days 0, 28, 56 and 84. Epididymal sperm reserve (ESR), testicular sperm reserve (TSR), testicular weight index (TWI) and testicular histology were evaluated at the end of the experiment. Results revealed dose-dependent reduction (P<0.05) in the mean TESL, ESR and TSR in the amitraz-treated groups as the dose of the amitraz increased. Histological study revealed testicular degeneration characterized by depopulation of seminiferous tubules and depletion of the spermatogenic cells in rats in group A. It was concluded that sub-chronic administration of sub-lethal doses of amitraz could lead to reduced sperm quantity.

  15. The effects of sub-chronic administration of sub-lethal doses of amitraz/xylene on selected reproductive parameters of male Wistar rats

    PubMed Central

    Omoja, V. U.; Anika, S. M.; Asuzu, I. U.

    2016-01-01

    This study investigated the effects of sub-chronic administration of sub-lethal doses of amitraz on some testicular parameters of Albino rats. Twenty-four adult male Albino rats (100 ± 10 g) randomly assigned into four groups were used for the study. Groups A, B and C received 10.0, 2.0 and 0.4 mg/kg amitraz in 10 ml/kg water while group D received equivalent volume of water orally and daily for 84 days. Serum testosterone levels (TESL) were assessed on days 0, 28, 56 and 84. Epididymal sperm reserve (ESR), testicular sperm reserve (TSR), testicular weight index (TWI) and testicular histology were evaluated at the end of the experiment. Results revealed dose-dependent reduction (P<0.05) in the mean TESL, ESR and TSR in the amitraz-treated groups as the dose of the amitraz increased. Histological study revealed testicular degeneration characterized by depopulation of seminiferous tubules and depletion of the spermatogenic cells in rats in group A. It was concluded that sub-chronic administration of sub-lethal doses of amitraz could lead to reduced sperm quantity. PMID:28224014

  16. 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

  17. 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 (LD50) and the No Observed Adverse Effect Level (NOAEL) in mice by using an accurate well-characterized TTX standard.

  18. Chimeric Anti-Staphylococcal Enterotoxin B Antibodies and Lovastatin Act Synergistically to Provide In Vivo Protection against Lethal Doses of SEB

    PubMed Central

    Tilahun, Mulualem E.; Kwan, Alan; Natarajan, Kannan; Quinn, Megan; Tilahun, Ashenafi Y.; Xie, Chen; Margulies, David H.; Osborne, Barbara A.; Goldsby, Richard A.; Rajagopalan, Govindarajan

    2011-01-01

    Staphylococcal enterotoxin B (SEB) is one of a family of toxins secreted by Staphylococcus aureus that act as superantigens, activating a large fraction of the T-cell population and inducing production of high levels of inflammatory cytokines that can cause toxic shock syndrome (TSS) and death. Extracellular engagement of the TCR of T-cells and class II MHC of antigen presenting cells by SEB triggers the activation of many intracellular signaling processes. We engineered chimeric antibodies to block the extracellular engagement of cellular receptors by SEB and used a statin to inhibit intracellular signaling. Chimeric human-mouse antibodies directed against different neutralizing epitopes of SEB synergistically inhibited its activation of human T-cells in vitro. In the in vivo model of lethal toxic shock syndrome (TSS) in HLA-DR3 transgenic mice, two of these antibodies conferred significant partial protection when administered individually, but offered complete protection in a synergistic manner when given together. Similarly, in vivo, lovastatin alone conferred only partial protection from TSS similar to single anti-SEB antibodies. However, used in combination with one chimeric neutralizing anti-SEB antibody, lovastatin provided complete protection against lethal TSS in HLA-DR3 transgenic mice. These experiments demonstrate that in vivo protection against lethal doses of SEB can be achieved by a statin of proven clinical safety and chimeric human-mouse antibodies, agents now widely used and known to be of low immunogenicity in human hosts. PMID:22102880

  19. 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

  20. A study of the shape of dose-response curves for acute lethality at low response: a megadaphnia study'

    SciTech Connect

    Sebaugh, J.L.; Wilson, J.D.; Tucker, M.W.; Adams, W.J. )

    1991-12-01

    Dose-response curves were developed for the immobilization response in Daphnia magna to four toxicants. The purpose of this work was to study the effect of the form of the model and the number of concentration levels used on the estimates of typical low-dose effective concentrations (1%, 5%, 10%). The generalized four-parameter logistic model was used as the reference. When using 12 concentration levels, one of the logistic family two- or three-parameter models was shown reliably to represent each of these various sets of dose-response data, and to provide adequate estimates of EC01 and EC05, as well as EC10 and EC50. For two of the toxicants, an asymmetric model was required. When reducing the number of concentrations to five, the EC10 and EC50 were well estimated by the probit model, with acceptable results at the EC05 level.

  1. Toxicological Study No. 75-51-YJ81-93, 4-Amino-2-Nitrotoluene (4A2NT) Oral Approximate Lethal Dose 14-day Range Finding 90-Day Subchronic Feeding Studies in Rats, August 1991-November 1993

    DTIC Science & Technology

    1994-07-01

    NOVEMBER 1993 1. PURPOSE. The oral approximate lethal dose study was conducted todetennine an approximate dosage range at which to begin the 14-day...5000 mg/Kg. The 14-day range fmding study suggested a probable compound related effect in the薘~m (high dose ) exposure groups of both sexes and a...possible compound related effect mIlle 1000 ppm (middle dose ) exposure groups of both sexes. An NOAEL was not established for the 90-day subchronic

  2. Dendrimer-RNA nanoparticles generate protective immunity against lethal Ebola, H1N1 influenza, and Toxoplasma gondii challenges with a single dose

    PubMed Central

    Chahal, Jasdave S.; Khan, Omar F.; Cooper, Christopher L.; McPartlan, Justine S.; Tsosie, Jonathan K.; Tilley, Lucas D.; Sidik, Saima M.; Langer, Robert; Bavari, Sina; Ploegh, Hidde L.; Anderson, Daniel G.

    2016-01-01

    Vaccines have had broad medical impact, but existing vaccine technologies and production methods are limited in their ability to respond rapidly to evolving and emerging pathogens, or sudden outbreaks. Here, we develop a rapid-response, fully synthetic, single-dose, adjuvant-free dendrimer nanoparticle vaccine platform wherein antigens are encoded by encapsulated mRNA replicons. To our knowledge, this system is the first capable of generating protective immunity against a broad spectrum of lethal pathogen challenges, including H1N1 influenza, Toxoplasma gondii, and Ebola virus. The vaccine can be formed with multiple antigen-expressing replicons, and is capable of eliciting both CD8+ T-cell and antibody responses. The ability to generate viable, contaminant-free vaccines within days, to single or multiple antigens, may have broad utility for a range of diseases. PMID:27382155

  3. HDAC inhibitors enhance the lethality of low dose salinomycin in parental and stem-like GBM cells.

    PubMed

    Booth, Laurence; Roberts, Jane L; Conley, Adam; Cruickshanks, Nichola; Ridder, Thomas; Grant, Steven; Poklepovic, Andrew; Dent, Paul

    2014-03-01

    The present studies determined whether the antibiotic salinomycin interacted with HDAC inhibitors to kill primary human GBM cells. Regardless of PTEN, ERBB1, or p53 mutational status salinomycin interacted with HDAC inhibitors in a synergistic fashion to kill GBM cells. Inhibition of CD95/Caspase 8 or of CD95/RIP-1/AIF signaling suppressed killing by the drug combination. Salinomycin increased the levels of autophagosomes that correlated with increased p62 and LC3II levels; valproate co-treatment correlated with reduced LC3II and p62 expression, and increased caspase 3 cleavage. Molecular inhibition of autophagosome formation was protective against drug exposure. The drug combination enhanced eIF2α phosphorylation and decreased expression of MCL-1 and phosphorylation of mTOR and p70 S6K. Activation of p70 S6K or mTOR promoted cell survival in the face of combined drug exposure. Overexpression of BCL-XL or c-FLIP-s was protective. Collectively our data demonstrate that the lethality of low nanomolar concentrations of salinomycin are enhanced by HDAC inhibitors in GBM cells and that increased death receptor signaling together with reduced mitochondrial function are causal in the combinatorial drug necro-apoptotic killing effect.

  4. An acute exposure to a sub-lethal dose of soman triggers anxiety-related behavior in guinea pigs: interactions with acute restraint.

    PubMed

    Mamczarz, Jacek; Pereira, Edna F R; Aracava, Yasco; Adler, Michael; Albuquerque, Edson X

    2010-01-01

    In this study, we tested the hypothesis that a single exposure of guinea pigs to sub-lethal doses of soman triggers anxiety-related behavior that is modifiable by acute stress. Prepubertal male guinea pigs were subjected to one of the following treatments: (i) saline (0.5 ml/kg, sc), (ii) soman (0.6x or 0.8xLD50, sc), (iii) saline followed 30 min later by 2-h restraint, or (iv) soman followed 30 min later by 2-h restraint. Behavior of the animals was examined 2 and 3 months later in a large open field and in the elevated plus maze. Animals that had been exposed to restraint stress alone or soman alone showed decreased exploratory activity when tested in the open field with bare floor at light intensity of 20-30 lx. Total distance traveled and distance traveled in the center of the field were shorter for animals that were exposed to either restraint stress or soman than for saline-injected animals. In addition, animals challenged with soman or restraint stress remained immobile for a longer time in the open field than did saline-injected guinea pigs. Performance in the elevated plus maze test revealed that exposure of guinea pigs to soman or restraint stress decreased their number of entries and the time spent in the open arms of the maze (measures of anxiety) and reduced their overall locomotor activity. Soman exposure and restraint stress cancelled out each other's effect on locomotion, while only attenuating one another's effect on anxiety-related behavior. It is concluded that a single exposure to sub-lethal doses of soman triggers long-lasting anxiogenesis and decreased locomotor activity and that acute restraint stress modifies the magnitude of these effects. 2009 Elsevier Inc. All rights reserved.

  5. Pretreatment of mice with lipopolysaccharide (LPS) or IL-1β exerts dose-dependent opposite effects on Shiga toxin-2 lethality

    PubMed Central

    Palermo, M; Alves-Rosa, F; Rubel, C; Fernández, G C; Fernández-Alonso, G; Alberto, F; Rivas, M; Isturiz, M

    2000-01-01

    Haemolytic uraemic syndrome (HUS) has been closely associated with infection with a group of Shiga toxin-producing enterohaemorrhagic Eschericchia coli in young children. Shiga toxins (Stx) have been implicated as pathogenic agents of HUS by binding to the surface receptor of endothelial cells. LPS is a central product of the Gram-negative bacteria and several reports have documented that both LPS and Stx are important for disease development. In this study the reciprocal interactions between LPS and Stx2 are analysed in a mouse model. The results demonstrated that LPS was able to reduce or enhance Stx2 toxicity, depending on the dose and the timing of the injection. The involvement of the main early cytokines induced by LPS, tumour necrosis factor alpha (TNF-α) and IL-1β, in those LPS opposite effects on Stx2 toxicity was evaluated. Stx2 toxicity was enhanced by in vivo injection of murine TNF-α and low doses of murine IL-1β. However, at higher doses of IL-1β which induced corticosteroid increase in serum, Stx2 lethality was decreased. Considering that dexamethasone and IL-1β reproduce the LPS protective effects, it is suggested that endogenous corticosteroids secondary to the inflammatory response induced by LPS, mediate the protection against Stx2. It can be concluded that the fine equilibrium between proinflammatory and anti-inflammatory activities strongly influences Stx2 toxicity. PMID:10606967

  6. Acute parietal and chief cell changes induced by a lethal dose of lipopolysaccharide in mouse stomach before thrombus formation.

    PubMed

    Ito, K; Ishida, K; Shishido, T; Tabata, H; Miura, H; Okamiya, H; Hanada, T

    2000-01-01

    The common lipopolysaccharide (LPS)-induced gastric lesions, such as erosions or ulcers, have been investigated in depth. Little is known, however, about the acute gastric lesions following a high dose of LPS. In a time-course study, ICR female mice were given a high subcutaneous dose of LPS (50 mg/kg). Mice were sacrificed at 4, 6, 12, and 24 hours after dosing and were assessed histopathologically for acute gastric lesions. The major gastric changes were seen in the fundic region and included vacuolar degeneration of parietal cells and apoptosis of chief cells. The vacuole in parietal cells was apparent as early as 4 hours postinjection (PI), and apoptosis of chief cells was apparent at 12 hours PI. Thrombus formation, in contrast, was not seen until 24 hours PI. No erosion, ulcer, or hemorrhage was seen in any gastric region in any of the treated animals at 24 hours PI. These results indicate that a subcutaneous high dose of LPS in mice causes vacuolar degeneration of parietal cells and apoptosis of chief cells before thrombus formation or subsequent ulcerative lesions.

  7. Development and Application of a Lifestyle Score for Prevention of Lethal Prostate Cancer.

    PubMed

    Kenfield, Stacey A; Batista, Julie L; Jahn, Jaquelyn L; Downer, Mary Kathryn; Van Blarigan, Erin L; Sesso, Howard D; Giovannucci, Edward L; Stampfer, Meir J; Chan, June M

    2016-03-01

    Several lifestyle factors have been associated with risk of lethal prostate cancer, but little is known about their combined effect. Our objective was to develop and apply a lifestyle score for prevention of lethal prostate cancer. We developed a lifestyle score among 42 701 men in the Health Professionals Follow-up Study (HPFS) followed from 1986 to 2010 and applied it among 20 324 men in the Physicians' Health Study (PHS) followed from 1982 to 2010. One point was given for each of: not currently smoking or quit 10 or more years ago, body mass index under 30 kg/m(2), high vigorous physical activity, high intake of tomatoes and fatty fish, and low intake of processed meat. Diet-only scores (range = 0-3) and total scores (range = 0-6) were calculated. We used multivariable Cox proportional hazards regression to estimate the risk of lethal prostate cancer, adjusting for potential risk factors of lethal prostate cancer. All statistical tests were two-sided. We observed 576 lethal prostate cancer events in HPFS and 337 in PHS. Men with 5-6 vs 0-1 points had a 68% decreased risk of lethal prostate cancer (hazard ratio [HR] = 0.32, 95% confidence interval [CI] = 0.19 to 0.52) in HPFS and a non-statistically significant 38% decreased risk (HR = 0.62, 95% CI = 0.30 to 1.26) in PHS. For dietary factors only, men with 3 vs 0 points had a 46% decreased risk (HR = 0.54, 95% CI = 0.30 to 0.96) in the HPFS and a non-statistically significant 30% decreased risk (HR = 0.70, 95% CI = 0.40 to 1.23) in PHS. Adhering to a healthy lifestyle, defined by not smoking, normal body weight, high physical activity, and a healthy diet, may lower risk of lethal prostate cancer. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  8. [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.

  9. Genetic determinant of Bacillus pumilus lipase lethality and its application as positive selection cloning vector in Escherichia coli.

    PubMed

    Mabizela-Mokoena, Nobalanda Betty; Limani, Shonisani Wendy; Ncube, Ignatious; Piater, Lizelle Ann; Litthauer, Derek; Nthangeni, Mulalo Bethuel

    2017-09-01

    Positive selection vectors carry genes that upon expression produce proteins that cause host cell deaths. Insertion of foreign DNA fragments within the ORF of the gene disrupts the lethal effect of the expressed protein. This study described the cloning of Family I.4 Bacillus pumilus lipase gene whose expressed protein is toxic and lethal to Escherichia coli JM109 (DE3) cells. The determinant of toxicity was identified through Error-prone PCR to be the nature of amino acid residue resident at position 28 of the mature lipase protein. The presence of Thr/Ser28 within the mature lipases of B. pumilus and B. licheniformis resulted in lethality to E. coli cells. However, the Thr28Ala or Thr28Gly mutations relieved the lethal phenotype of mature Family I.4 Bacillus lipases. The toxic effect of the expressed mature B. pumilus lipase protein was exploited in the development of a positive selection cloning vector. The B. pumilus lipase gene was synthesised to contain 13 unique silent restriction sites within the ORF, and placed under the regulation of T7 promoter of the pET expression system. Insertional inactivation of the gene's toxic protein was achieved by cloning DNA fragments of different sizes within the designed multiple cloning sites. The toxic effect of the lipase protein was disrupted indicating the potential of the gene for application in suicidal positive selection cloning vectors. The results revealed that protein expression and engineering studies aimed at optimal production of mature Family I.4 Bacillus lipases in E. coli should take into consideration the nature of amino acid 28 resident. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Non-Lethal Weapons: A Technology Gap or Lack or Available Systems, Training, and Proper Application

    DTIC Science & Technology

    2016-06-10

    ensure that non-lethal weapons are being employed to increase the likelihood of mission success. Creative and innovative mindsets that see the value in...increase the likelihood of mission success. Creative and innovative mindsets that see the value in this technology will be necessary to adapt to every...likelihood of mission success. Creative and innovative mindsets that see the value in this technology will be necessary to adapt to every changing

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

    PubMed Central

    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. PMID:26376487

  12. 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.

  13. Modification of the brain proteome of Africanized honeybees (Apis mellifera) exposed to a sub-lethal doses of the insecticide fipronil.

    PubMed

    Roat, T C; dos Santos-Pinto, J R A; Dos Santos, L D; Santos, K S; Malaspina, O; Palma, M S

    2014-11-01

    Fipronil is a phenylpyrazole insecticide that is widely used in Brazilian agriculture for pest control. Although honeybees are not targets of fipronil, studies indicate that this pesticide can be harmful to honeybees. To assess the effects of fipronil in the brain of Africanized Apis mellifera workers, this study focused on the toxico-proteome profiling of the brain of newly emerged and aged honeybee workers that were exposed to a sub-lethal dose (10 pg fipronil per day. i.e. (1)/100 of LD50/bee/day during 5 days) of the insecticide. Proteomic analysis identified 25 proteins that were differentially up-regulated or down-regulated when the fipronil-exposed and non-exposed groups were compared. These proteins are potentially related to pathogen susceptibility, neuronal chemical stress, neuronal protein misfolding, and occurrence of apoptosis, ischemia, visual impairment, damaged synapse formation, brain degeneration, memory and learning impairment. The exposure of honeybees to a very low dose of fipronil, even for a short period of time (5 days), was sufficient to cause a series of important neuroproteomic changes in the brains of honeybees.

  14. Loss of Jak2 selectively suppresses DC-mediated innate immune response and protects mice from lethal dose of LPS-induced septic shock.

    PubMed

    Zhong, Jixin; Yang, Ping; Muta, Kenjiro; Dong, Robert; Marrero, Mario; Gong, Feili; Wang, Cong-Yi

    2010-03-09

    Given the importance of Jak2 in cell signaling, a critical role for Jak2 in immune cells especially dendritic cells (DCs) has long been proposed. The exact function for Jak2 in DCs, however, remained poorly understood as Jak2 deficiency leads to embryonic lethality. Here we established Jak2 deficiency in adult Cre(+/+)Jak2(fl/fl) mice by tamoxifen induction. Loss of Jak2 significantly impaired DC development as manifested by reduced BMDC yield, smaller spleen size and reduced percentage of DCs in total splenocytes. Jak2 was also crucial for the capacity of DCs to mediate innate immune response. Jak2(-/-) DCs were less potent in response to inflammatory stimuli and showed reduced capacity to secrete proinflammatory cytokines such as TNFalpha and IL-12. As a result, Jak2(-/-) mice were defective for the early clearance of Listeria after infection. However, their potency to mediate adaptive immune response was not affected. Unlike DCs, Jak2(-/-) macrophages showed similar capacity secretion of proinflammatory cytokines, suggesting that Jak2 selectively modulates innate immune response in a DC-dependent manner. Consistent with these results, Jak2(-/-) mice were remarkably resistant to lethal dose of LPS-induced septic shock, a deadly sepsis characterized by the excessive innate immune response, and adoptive transfer of normal DCs restored their susceptibility to LPS-induced septic shock. Mechanistic studies revealed that Jak2/SATA5 signaling is pivotal for DC development and maturation, while the capacity for DCs secretion of proinflammatory cytokines is regulated by both Jak2/STAT5 and Jak2/STAT6 signaling.

  15. Randomized comparison of single dose of recombinant human IL-12 versus placebo for restoration of hematopoiesis and improved survival in rhesus monkeys exposed to lethal radiation

    PubMed Central

    2014-01-01

    Background The hematopoietic syndrome of the acute radiation syndrome (HSARS) is a life-threatening condition in humans exposed to total body irradiation (TBI); no drugs are approved for treating this condition. Recombinant human interleukin-12 (rHuIL-12) is being developed for HSARS mitigation under the FDA Animal Rule, where efficacy is proven in an appropriate animal model and safety is demonstrated in humans. Methods In this blinded study, rhesus monkeys (9 animals/sex/dose group) were randomized to receive a single subcutaneous injection of placebo (group 1) or rHuIL-12 at doses of 50, 100, 250, or 500 ng/kg (groups 2–5, respectively), without antibiotics, fluids or blood transfusions, 24–25 hours after TBI (700 cGy). Results Survival rates at Day 60 were 11%, 33%, 39%, 39%, and 50% for groups 1–5, respectively (log rank p < 0.05 for each dose vs. control). rHuIL-12 also significantly reduced the incidences of severe neutropenia, severe thrombocytopenia, and sepsis (positive hemoculture). Additionally, bone marrow regeneration following TBI was significantly greater in monkeys treated with rHuIL-12 than in controls. Conclusions Data from this study demonstrate that a single injection of rHuIL-12 delivered one day after TBI can significantly increase survival and reduce radiation-induced hematopoietic toxicity and infections. These data significantly advance development of rHuIL-12 toward approval under the Animal Rule as an effective stand-alone medical countermeasure against the lethal effects of radiation exposure. PMID:24708888

  16. Judged Lethality

    DTIC Science & Technology

    1980-12-01

    as automobile accidents and heart attacks . Approach In two experiments, estimates of lethality were elicited in four ways: (1) direct estimates of...31 6,813 2,500 Strokes 11,011 4,648 181 24,758 11,765 Heart Attacks 13,011 3,666 131 27,477 16,250 Cancer 10,889 10,475 160 21,749 37,500 Coefficient...Each Group Experiment 1 Rank of Statistical Cause of Death Lethality Rate Always Underestimated Cancer 20 Heart Attack 19 Stroke 18 Pregnancy 12

  17. Practical applications of internal dose calculations

    SciTech Connect

    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 describes 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.

  18. 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.

  19. 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

  20. 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

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

    2013-05-01

    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 (0.6×LD50 or 300mg/kg, sc) or peanut oil (vehicle; 0.5ml/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.

  1. 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

  2. Increased Expression of Connective Tissue Growth Factor (CTGF) in Multiple Organs After Exposure of Non-Human Primates (NHP) to Lethal Doses of Radiation.

    PubMed

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

    2015-11-01

    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. These 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.

  3. Effect of Linezolid on the 50% Lethal Dose and 50% Protective Dose in Treatment of Infections by Gram-Negative Pathogens in Naive and Immunosuppressed Mice and on the Efficacy of Ciprofloxacin in an Acute Murine Model of Septicemia

    PubMed Central

    Marra, Andrea; Lamb, Lucinda; Medina, Ivette; George, David; Gibson, Glenn; Hardink, Joel; Rugg, Jady; Van Deusen, Jeffrey

    2012-01-01

    Murine models of infection were used to study the effect of linezolid on the virulence of Gram-negative bacteria and to assess potential pharmacodynamic interactions with ciprofloxacin in the treatment of these infections, prompted by observations from a recent clinical trial. Naive and immunosuppressed mice were challenged with Klebsiella pneumoniae 53A1109, K. pneumoniae GC6658, and Pseudomonas aeruginosa UC12120 in acute sepsis and pulmonary infection models, using different serial dilutions of these pathogens (groups of 8 animals each). Linezolid (100 mg/kg/dose) was administered orally at 0.5 and 4.0 h postchallenge in the sepsis model and at 4 h postchallenge followed by 2 days of twice-daily treatment in the pulmonary model. Further, ciprofloxacin alone and in combination with oral linezolid was investigated in the sepsis model. Survival was assessed for 4 and 10 days postchallenge in the systemic and respiratory models, respectively. The data were fitted to a nonlinear regression analysis to determine 50% lethal doses (LD50s) and 50% protective doses (PD50s). A clinically relevant, high-dose regimen of linezolid had no significant effect on LD50 in these models. This lack of effect was independent of immune status. A combination of oral ciprofloxacin with linezolid yielded lower PD50s than oral ciprofloxacin alone (ciprofloxacin in combination, 8.4 to 32.7 mg/kg; oral ciprofloxacin, 39.4 to 88.3 mg/kg). Linezolid did not improve the efficacy of subcutaneous ciprofloxacin (ciprofloxacin in combination, 2.0 to 2.4 mg/kg; subcutaneous ciprofloxacin, 2.0 to 2.8 mg/kg). In conclusion, linezolid does not seem to potentiate infections caused by Gram-negative pathogens or to interact antagonistically with ciprofloxacin. PMID:22710118

  4. Lethal mutagenesis of viruses.

    PubMed

    Perales, Celia; Martín, Verónica; Domingo, Esteban

    2011-11-01

    Lethal mutagenesis aims at extinguishing viruses by increased mutagenesis prompted by virus-specific mutagenic agents, mainly nucleoside analogues. It is derived from the error threshold relationship of quasispecies theory, and it is slowly finding its way towards a clinical application. We summarize the current situation of research in this field of antiviral therapy. Copyright © 2011 Elsevier B.V. All rights reserved.

  5. Hsa-miR-520d-5p promotes survival in human dermal fibroblasts exposed to a lethal dose of UV irradiation

    PubMed Central

    Ishihara, Yoshitaka; Tsuno, Satoshi; Ping, Bingqiong; Ashizaki, Taichiro; Nakashima, Masahiro; Miura, Keigo; Miura, Yugo; Yamashita, Taro; Hasegawa, Junichi; Miura, Norimasa

    2016-01-01

    We previously reported that hsa-miR-520d-5p is functionally involved in the induction of the epithelial–mesenchymal transition and stemness-mediated processes in normal cells and cancer cells, respectively. On the basis of the synergistic effect of p53 upregulation and demethylation induced by 520d-5p, the current study investigated the effect of this miRNA on apoptotic induction by ultraviolet B (UVB) light in normal human dermal fibroblast (NHDF) cells. 520d-5p was lentivirally transfected into NHDF cells either before or after a lethal dose of UVB irradiation (302 nm) to assess its preventive or therapeutic effects, respectively. The methylation level, gene expression, production of type I collagen and cell cycle distribution were estimated in UV-irradiated cells. NHDF cells transfected with 520d-5p prior to UVB irradiation had apoptotic characteristics, and the transfection exerted no preventive effects. However, transfection with 520d-5p into NHDF cells after UVB exposure resulted in the induction of reprogramming in damaged fibroblasts, the survival of CD105-positive cells, an extended cell lifespan and prevention of cellular damage or malfunction; these outcomes were similar to the effects observed in 520d-5p-transfected NHDF cells (520d/NHDF). The gene expression of c-Abl (Abelson murine leukemia viral oncogene homolog 1), ATR (ataxia telangiectasia and Rad3-related protein), and BRCA1 (breast cancer susceptibility gene I) in transfectants was transcriptionally upregulated in order. These mechanistic findings indicate that ATR-dependent DNA damage repair was activated under this stressor. In conclusion, 520d-5p exerted a therapeutic effect on cells damaged by UVB and restored them to a normal senescent state following functional restoration via survival of CD105-positive cells through c-Abl-ATR-BRCA1 pathway activation, p53 upregulation, and demethylation. PMID:28721278

  6. Key Technologies for Ultra High Dose CMOS Applications

    SciTech Connect

    Jeon, Y.; Koo, I.; Singh, V.; Oh, J.; Jin, S.; Lee, J.; Rouh, K.; Ju, M.; Jeon, S.; Ku, J.; Lee, S. B.; Lee, S. W.; Ok, M. T.; Butterbaugh, J.; Lee, A.; Kim, K.; Lee, S. W.; Ju, K. J.; Park, J. W.

    2008-11-03

    The trend towards shrinking advanced microelectronic Logic and DRAM devices will require ultra high dose implantation. One ultra high dose application in DRAM, being rapidly adopted in production is Dual Poly Gate (DPG). Three main challenges existed for the adoption of this high dose dual poly gate (DPG) doping applications: monitoring of high dose implantation, photoresist stripping and maintaining high throughput. In this paper we present how these challenges have been addressed. VSEA's plasma doping (PLAD) tool offers several unique advantages for DPG applications. When compared to conventional or molecular beam line implanters or other immersion techniques, PLAD delivers 3 to 7 times higher throughput (compared to traditional ion implanter) without dopant penetration through the thin doped polysilicon layer into the gate oxide. It also improves P{sup +} poly silicon DPG device properties at superior throughput. In this work we demonstrate how hot spray photoresist strip processing eliminates the need for multiple-tools required for wet+ash+wet process. In addition to PLAD's patented in-situ dose control metrology we also demonstrate an ex-situ high dose implantation metrology using spectroscopic ellipsometer (SE) and spectroscopic reflectometer (SR). The technique shows good correlation (R{sup 2}{approx}0.99) between implant dose and damaged layer thickness.

  7. Toll-like receptor 2- and 6-mediated stimulation by macrophage-activating lipopeptide 2 induces lipopolysaccharide (LPS) cross tolerance in mice, which results in protection from tumor necrosis factor alpha but in only partial protection from lethal LPS doses.

    PubMed

    Deiters, Ursula; Gumenscheimer, Marina; Galanos, Chris; Mühlradt, Peter F

    2003-08-01

    Patients or experimental animals previously exposed to lipopolysaccharide (LPS) become tolerant to further LPS challenge. We investigated the potential of the macrophage-activating lipopeptide 2 (MALP-2) to induce in vivo cross tolerance to tumor necrosis factor alpha (TNF-alpha) and LPS. MALP-2-induced tolerance could be of practical interest, as MALP-2 proved much less pyrogenic in rabbits than LPS. Whereas LPS signals via Toll-like receptor 4 (TLR4), MALP-2 uses TLR2 and TLR6. LPS-mediated cytokine release was studied in mice pretreated with intraperitoneal injections of MALP-2. No biologically active TNF-alpha could be detected in the serum of MALP-2-treated animals when challenged with LPS 24 or 72 h later, whereas suppression of LPS-dependent interleukin (IL)-6 lasted for only 24 h. Protection from lethal TNF-alpha shock was studied in galactosamine-treated mice. Dose dependently, MALP-2 prevented death from lethal TNF-alpha doses in TLR4(-/-) but not in TLR2(-/-) mice, with protection lasting from 5 to 24 h. To assay protection from LPS, mice were pretreated with MALP-2 doses of up to 10 micro g. Five and 24 h later, the animals were simultaneously sensitized and challenged by intravenous coinjection of galactosamine and a lethal dose of 50 ng of LPS. There was only limited protection (four of seven mice survived) when mice were challenged 5 h after MALP-2 pretreatment, and no protection when mice were challenged at later times. The high effectiveness of MALP-2 in suppressing TNF-alpha, the known ways of biological inactivation, and low pyrogenicity make MALP-2 a potential candidate for clinical use.

  8. Combined high pressure and temperature induced lethal and sublethal injury of Lactococcus lactis--application of multivariate statistical analysis.

    PubMed

    Kilimann, K V; Hartmann, C; Delgado, A; Vogel, R F; Gänzle, M G

    2006-05-25

    It was the aim of this work to determine the combined effects of pressure, temperature, and co-solutes on Lactococcus lactis, and to detect correlations between culture-dependent and culture-independent methods for assessment of cellular viability and sublethal injury. Therefore, the pressure induced inactivation of L. lactis MG 1363 was investigated in buffer and in buffer with 1.5 M sucrose or 4 M NaCl at a pressure range of 0.1 to 500 MPa and a temperature range of 5 to 50 degrees C. The inactivation was characterised by viable cell counts, stress resistant cell counts, membrane integrity, metabolic activity, and the activity of the multi-drug-resistance transport enzyme LmrP. L. lactis was most resistant to pressure application at 20-30 degrees C. Sucrose protected towards inactivation at any temperature, NaCl provided protection at high temperatures only. By using Principal Component Analysis, correlations were detected between viable cell counts and metabolic activity as well as stress resistant cell counts and LmrP activity. In conclusion, the pressure-inactivation of L. lactis is strongly temperature dependent, baroprotection by sucrose occurs at any temperature but the baroprotective effects of NaCl is temperature dependent. Further on, a combination of two experimental methods fully describe lethal and sublethal injury of pressure treated cells. These simplification of data acquisition and model development facilitates the establishment of pressure processes in food technology.

  9. Acquisition of lethal doses of Beauveria bassiana conidia by western flower thrips, Frankliniella occidentalis, exposed to foliar spray residues of formulated and unformulated conidia.

    PubMed

    Ugine, Todd A; Wraight, Stephen P; Sanderson, John P

    2005-09-01

    Secondary acquisition of Beauveria bassiana conidia was recorded on the whole bodies and selected body parts of second-instar nymphs and adult female western flower thrips exposed to foliar spray residues of three differently formulated conidial preparations, for 24 h. Conidia were formulated in emulsifiable oil or with clay (wettable powder), or were essentially unformulated conidia (technical grade powder suspended in water with a surfactant). Formulation had no significant effect on dose acquisition and no effect on virulence of acquired conidia. The mean nymphal LC50/LD50 was 116 conidia/mm2 and 52conidia/insect, respectively; the values for adults were 19 conidia/mm2 and 5conidia/insect. Greatest numbers of conidia were recorded on the legs and abdomens of nymphs and on the legs, wings, and thoraces of adults. As would be expected, numbers of conidia acquired increased with residue concentration (application rate). However, an inverse relationship was noted between acquisition rate (conidia acquired/total conidia applied) and residue concentration. The mechanism underlying this response was not determined. However, there was no indication that any body parts (e.g., tarsi) became saturated with spores, which suggests that either the thrips were repelled by the conidial residues or that as the concentrations of conidia on the substrate increased, conidia somehow became more difficult to acquire. Slopes of the LC probit regressions were lower than those of the LD regressions (mean 1.14 vs 1.78), suggesting that the low slopes often obtained in fungal pathogen assays could be partly an artifact of unequal rates of dose acquisition at low vs high application rates.

  10. Distributed Operating System Experiment (DOSE) Application Installation Manual

    DTIC Science & Technology

    1990-02-01

    uses the Cronus distrib- uted environment developed by BBN Systems and Technologies Corporation for the Rome Air Devel- opment Center, Rome, NY. f...and any other machine that has UNIX (or UNIX-like) as the constituent operating system for Cronus .-, T nual is recommended reading before installing...the application. 1.2 RE UIRE S ’" The following describes the minimum requirements needed before installing the DOSE application: 1. Cronus (release 1.3

  11. 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.

  12. Biologically effective doses from californium-252 intracavitary applications.

    PubMed

    Iyer, P S

    1975-02-01

    Californium-252 which emits fission neutrons and gamma rays is being investigated for applications in brachytherapy. From available experimental results, a value of 6.2 had been arrived at as the RBE for cell killing of californium neutrons relative to radium gavva rays for intracavitary applications based on the revised Manchester system of loading. The LET distributions as well as the ratio of neutron to gamma dose-rates have been estimated and are found to remain almost constant in the volume of interest around such applications.

  13. Mask model calibration for MPC applications utilizing shot dose assignment

    NASA Astrophysics Data System (ADS)

    Bork, Ingo; Buck, Peter; Paninjath, Sankaranarayanan; Mishra, Kushlendra; Bürgel, Christian; Standiford, Keith; Chua, Gek Soon

    2014-10-01

    Shrinking feature sizes and the need for tighter CD (Critical Dimension) control require the introduction of new technologies in mask making processes. One of those methods is the dose assignment of individual shots on VSB (Variable Shaped Beam) mask writers to compensate CD non-linearity effects and improve dose edge slope. Using increased dose levels only for most critical features, generally only for the smallest CDs on a mask, the change in mask write time is minimal while the increase in image quality can be significant. However, this technology requires accurate modeling of the mask effects, especially the CD/dose dependencies. This paper describes a mask model calibration flow for Mask Process Correction (MPC) applications with shot dose assignment. The first step in the calibration flow is the selection of appropriate test structures. For this work, a combination of linespace patterns as well as a series of contact patterns are used for calibration. Features sizes vary from 34 nm up to several micrometers in order to capture a wide range of CDs and pattern densities. After mask measurements are completed the results are carefully analyzed and measurements very close to the process window limitation and outliers are removed from the data set. One key finding in this study is that by including patterns exposed at various dose levels the simulated contours of the calibrated model very well match the SEM contours even if the calibration was based entirely on gauge based CD values. In the calibration example shown in this paper, only 1D line and space measurements as well as 1D contact measurements are used for calibration. However, those measurements include patterns exposed at dose levels between 75% and 150% of the nominal dose. The best model achieved in this study uses 2 e-beam kernels and 4 kernels for the simulation of development and etch effects. The model error RMS on a large range of CD down to 34 nm line CD is 0.71 nm. The calibrated model is then

  14. Evaluating the validity and applicable domain of the toxic load model: impact of concentration vs. time profile on inhalation lethality of hydrogen cyanide.

    PubMed

    Sweeney, Lisa M; Sommerville, Douglas R; Channel, Stephen R; Sharits, Brian C; Gargas, Nathan M; Gut, Chester P

    2015-04-01

    The ten Berge model (or "toxic load" model) is often used to estimate the acute toxicity for varying combinations of inhaled concentration and duration. Expressed as C(n) × t = toxic load (TL), TLs are assumed constant for various combinations of concentration (C) and time (t). Experimental data in a recent acute inhalation study of rats exposed to time-varying concentrations of hydrogen cyanide (HCN) supported the validity of the toxic load model except under very brief, discontinuous, high concentration exposures. In the present investigation, experiments were conducted to extend the evaluation of the applicable domain of the model for acute lethality of HCN in the rat (cumulative exposure range of 2900-11,000 ppm min). The lethality of HCN over very short (< 5 min) durations of high concentrations did not conform to the toxic load model. A value of n=1.57 was determined for uninterrupted exposures ⩾ 5 min. For 30-min exposures, the presence or absence of a gap between two exposure pulses of different concentrations, the relative duration, relative height, and the ordering of the pulses (low then high, vs. high then low) did not appear to have a meaningful impact on the toxic load required for median lethality. Copyright © 2015 Elsevier Inc. All rights reserved.

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

    PubMed

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

    2009-09-01

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

  16. Evaluation of the radioprotective effect of the leaf extract of Syzygium cumini (Jamun) in mice exposed to a lethal dose of gamma-irradiation.

    PubMed

    Jagetia, Ganesh Chandra; Baliga, Manjeshwar Shrinath

    2003-06-01

    The effects of various concentrations (5, 10, 20, 30, 40, 50, 60, and 80 mg/kg body weight (b.wt.) of the leaf extracts of Syzygium cumini Linn. and Eugenia cumini (SCE, black plum, Jamun, family Myrtaceae) on the radiation-induced sickness and mortality in mice exposed to 10 Gy gamma-irradiation were studied. The treatment of mice with different doses of SCE, consecutively for five days before irradation, delayed the onset of mortality and reduced the symptoms of radiation sickness when compared with the nondrug-treated irradiated controls. All doses of SCE provied protection against the gastrointestinal death increasing the survival by 66.66% after treatment with 20, 30, and 40 mg/kg SCE versus a 12% survival in the irradiated control group (oil + irradiation). Similarly, SCE provided protection against the radiation-induced bone marrow death in mice treated with 10-60 mg/kg b.wt. of SCE. However, the best protection was obtained for 30 mg/kg b.wt. SCE, where the number of, survivors after 30 days post-irradiation was highest (41.66%) when compared with the other doses of SCE.

  17. Hyperimmune intravenous immunoglobulin containing high titers of pandemic H1N1 hemagglutinin and neuraminidase antibodies provides dose-dependent protection against lethal virus challenge in SCID mice.

    PubMed

    Hohenadl, Christine; Wodal, Walter; Kerschbaum, Astrid; Fritz, Richard; Howard, M Keith; Farcet, Maria R; Portsmouth, Daniel; McVey, John K; Baker, Donald A; Ehrlich, Hartmut J; Barrett, P Noel; Kreil, Thomas R

    2014-04-16

    Convalescent plasma and fractionated immunoglobulins have been suggested as prophylactic or therapeutic interventions during an influenza pandemic. Intravenous immunoglobulin (IVIG) preparations manufactured from human plasma collected before the 2009 H1N1 influenza pandemic, and post-pandemic hyperimmune (H)-IVIG preparations were characterized with respect to hemagglutination inhibition (HI), microneutralization (MN) and neuraminidase-inhibiting (NAi) antibody titers against pandemic H1N1 (pH1N1) and seasonal H1N1 (sH1N1) viruses. The protective efficacy of the IVIG and H-IVIG preparations was evaluated in a SCID mouse challenge model.Substantial levels of HI, MN and NAi antibodies against pH1N1 (GMTs 1:45, 1:204 and 1: 727, respectively) and sH1N1 (GMTs 1:688, 1:4,946 and 1:312, respectively) were present in pre-pandemic IVIG preparations. In post-pandemic H-IVIG preparations, HI, MN and NAi antibody GMTs against pH1N1 were 1:1,280, 1:11,404 and 1:2,488 (28-, 56- and 3.4-fold enriched), respectively, compared to pre-pandemic IVIG preparations (p < 0.001). Post-pandemic H-IVIG (HI titer 1:1,280) provided complete protection from lethality of SCID mice against pH1N1 challenge (100% of mice survived for 29 days post-challenge). Pre-pandemic IVIG (HI titer 1:70) did not provide significant protection against pH1N1 challenge (50% of mice survived 29 days post-challenge compared to 40% survival in the buffer control group). There was a highly significant correlation between circulating in vivo HI and MN antibody titers and survival (p < 0001). The substantial enrichment of HA- and NA-specific antibodies in H-IVIG and the efficacious protection of SCID mice against challenge with pH1N1 suggests H-IVIG as a promising intervention against pandemic influenza for immunocompromised patients and other risk groups.

  18. Hyperimmune intravenous immunoglobulin containing high titers of pandemic H1N1 hemagglutinin and neuraminidase antibodies provides dose-dependent protection against lethal virus challenge in SCID mice

    PubMed Central

    2014-01-01

    Background Convalescent plasma and fractionated immunoglobulins have been suggested as prophylactic or therapeutic interventions during an influenza pandemic. Findings Intravenous immunoglobulin (IVIG) preparations manufactured from human plasma collected before the 2009 H1N1 influenza pandemic, and post-pandemic hyperimmune (H)-IVIG preparations were characterized with respect to hemagglutination inhibition (HI), microneutralization (MN) and neuraminidase-inhibiting (NAi) antibody titers against pandemic H1N1 (pH1N1) and seasonal H1N1 (sH1N1) viruses. The protective efficacy of the IVIG and H-IVIG preparations was evaluated in a SCID mouse challenge model. Substantial levels of HI, MN and NAi antibodies against pH1N1 (GMTs 1:45, 1:204 and 1: 727, respectively) and sH1N1 (GMTs 1:688, 1:4,946 and 1:312, respectively) were present in pre-pandemic IVIG preparations. In post-pandemic H-IVIG preparations, HI, MN and NAi antibody GMTs against pH1N1 were 1:1,280, 1:11,404 and 1:2,488 (28-, 56- and 3.4-fold enriched), respectively, compared to pre-pandemic IVIG preparations (p < 0.001). Post-pandemic H-IVIG (HI titer 1:1,280) provided complete protection from lethality of SCID mice against pH1N1 challenge (100% of mice survived for 29 days post-challenge). Pre-pandemic IVIG (HI titer 1:70) did not provide significant protection against pH1N1 challenge (50% of mice survived 29 days post-challenge compared to 40% survival in the buffer control group). There was a highly significant correlation between circulating in vivo HI and MN antibody titers and survival (p < 0001). Conclusion The substantial enrichment of HA- and NA-specific antibodies in H-IVIG and the efficacious protection of SCID mice against challenge with pH1N1 suggests H-IVIG as a promising intervention against pandemic influenza for immunocompromised patients and other risk groups. PMID:24739285

  19. 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, R.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.

  20. Prediction of protein-peptide interactions: application of the XPairIt API to anthrax lethal factor and substrates

    NASA Astrophysics Data System (ADS)

    Hurley, Margaret M.; Sellers, Michael S.

    2013-05-01

    As software and methodology develop, key aspects of molecular interactions such as detailed energetics and flexibility are continuously better represented in docking simulations. In the latest iteration of the XPairIt API and Docking Protocol, we perform a blind dock of a peptide into the cleavage site of the Anthrax lethal factor (LF) metalloprotein. Molecular structures are prepared from RCSB:1JKY and we demonstrate a reasonably accurate docked peptide through analysis of protein motion and, using NCI Plot, visualize and characterize the forces leading to binding. We compare our docked structure to the 1JKY crystal structure and the more recent 1PWV structure, and discuss both captured and overlooked interactions. Our results offer a more detailed look at secondary contact and show that both van der Waals and electrostatic interactions from peptide residues further from the enzyme's catalytic site are significant.

  1. Lethal Airpower and Intervention

    DTIC Science & Technology

    1996-06-01

    of similar proportions in Bosnia might have fatally undermined the NATO policy there, bringing an ignominious end to OPERATION DELIBERATE FORCE...Progress Lethality COG Amenable to Bombing Too Lethal at Low End of Conflict Spectrum Global Reacli—Global Power Tempo 105 For a more complete...element of a winning strategy at the high end of the intervention spectrum—war-fighting. Humanitarian Interests and Lethal Airpower. Humanitarian

  2. 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

  3. Effective dose efficiency: an application-specific metric of quality and dose for digital radiography.

    PubMed

    Samei, Ehsan; Ranger, Nicole T; Dobbins, James T; Ravin, Carl E

    2011-08-21

    The detective quantum efficiency (DQE) and the effective DQE (eDQE) are relevant metrics of image quality for digital radiography detectors and systems, respectively. The current study further extends the eDQE methodology to technique optimization using a new metric of the effective dose efficiency (eDE), reflecting both the image quality as well as the effective dose (ED) attributes of the imaging system. Using phantoms representing pediatric, adult and large adult body habitus, image quality measurements were made at 80, 100, 120 and 140 kVp using the standard eDQE protocol and exposures. ED was computed using Monte Carlo methods. The eDE was then computed as a ratio of image quality to ED for each of the phantom/spectral conditions. The eDQE and eDE results showed the same trends across tube potential with 80 kVp yielding the highest values and 120 kVp yielding the lowest. The eDE results for the pediatric phantom were markedly lower than the results for the adult phantom at spatial frequencies lower than 1.2-1.7 mm(-1), primarily due to a correspondingly higher value of ED per entrance exposure. The relative performance for the adult and large adult phantoms was generally comparable but affected by kVps. The eDE results for the large adult configuration were lower than the eDE results for the adult phantom, across all spatial frequencies (120 and 140 kVp) and at spatial frequencies greater than 1.0 mm(-1) (80 and 100 kVp). Demonstrated for chest radiography, the eDE shows promise as an application-specific metric of imaging performance, reflective of body habitus and radiographic technique, with utility for radiography protocol assessment and optimization.

  4. The short term effects of a supra-lethal dose of irradiation and changes in the environmental temperature on the growth of tail bones of the mouse.

    PubMed

    Al-Hilli, F; Wright, E A

    1983-12-01

    The growth and histological features of the tail vertebrae of young mice (31 day old) were observed for 48 h after transference from a cold (8 degrees) to a hot (33 degrees) environment. Some mice received a massive (5000 rad) dose of X-ray to the tail. Less than 2 h after housing the animals in the heat there was a period of very rapid growth lasting 12 h after which time growth slowed but was still much greater than the animals in the cold. Animals whose tails were irradiated (and also put in the heat) showed the same rapid growth for 12 h but after this growth ceased. Evidence is provided which shows that the initial rapid growth in the heat is due to an abnormal increase in the linear dimensions of the hypertrophic cells of the growth plate. This is most marked in the hot-irradiated animals.

  5. A novel dose uncertainty model and its application for dose verification.

    PubMed

    Jin, Hosang; Chung, Heetaek; Liu, Chihray; Palta, Jatinder; Suh, Tae-Suk; Kim, Siyong

    2005-06-01

    Based on statistical approach, a novel dose uncertainty model was introduced considering both nonspatial and spatial dose deviations. Non-space-oriented uncertainty is mainly caused by dosimetric uncertainties, and space-oriented dose uncertainty is the uncertainty caused by all spatial displacements. Assuming these two parts are independent, dose difference between measurement and calculation is a linear combination of nonspatial and spatial dose uncertainties. Two assumptions were made: (1) the relative standard deviation of nonspatial dose uncertainty is inversely proportional to the dose standard deviation sigma, and (2) the spatial dose uncertainty is proportional to the gradient of dose. The total dose uncertainty is a quadratic sum of the nonspatial and spatial uncertainties. The uncertainty model provides the tolerance dose bound for comparison between calculation and measurement. In the statistical uncertainty model based on a Gaussian distribution, a confidence level of 3sigma theoretically confines 99.74% of measurements within the bound. By setting the confidence limit, the tolerance bound for dose comparison can be made analogous to that of existing dose comparison methods (e.g., a composite distribution analysis, a gamma test, a chi evaluation, and a normalized agreement test method). However, the model considers the inherent dose uncertainty characteristics of the test points by taking into account the space-specific history of dose accumulation, while the previous methods apply a single tolerance criterion to the points, although dose uncertainty at each point is significantly different from others. Three types of one-dimensional test dose distributions (a single large field, a composite flat field made by two identical beams, and three-beam intensity-modulated fields) were made to verify the robustness of the model. For each test distribution, the dose bound predicted by the uncertainty model was compared with simulated measurements. The simulated

  6. A novel dose uncertainty model and its application for dose verification

    SciTech Connect

    Jin Hosang; Chung Heetaek; Liu Chihray; Palta, Jatinder; Suh, Tae-Suk; Kim, Siyong

    2005-06-15

    Based on statistical approach, a novel dose uncertainty model was introduced considering both nonspatial and spatial dose deviations. Non-space-oriented uncertainty is mainly caused by dosimetric uncertainties, and space-oriented dose uncertainty is the uncertainty caused by all spatial displacements. Assuming these two parts are independent, dose difference between measurement and calculation is a linear combination of nonspatial and spatial dose uncertainties. Two assumptions were made: (1) the relative standard deviation of nonspatial dose uncertainty is inversely proportional to the dose standard deviation {sigma}, and (2) the spatial dose uncertainty is proportional to the gradient of dose. The total dose uncertainty is a quadratic sum of the nonspatial and spatial uncertainties. The uncertainty model provides the tolerance dose bound for comparison between calculation and measurement. In the statistical uncertainty model based on a Gaussian distribution, a confidence level of 3{sigma} theoretically confines 99.74% of measurements within the bound. By setting the confidence limit, the tolerance bound for dose comparison can be made analogous to that of existing dose comparison methods (e.g., a composite distribution analysis, a {gamma} test, a {chi} evaluation, and a normalized agreement test method). However, the model considers the inherent dose uncertainty characteristics of the test points by taking into account the space-specific history of dose accumulation, while the previous methods apply a single tolerance criterion to the points, although dose uncertainty at each point is significantly different from others. Three types of one-dimensional test dose distributions (a single large field, a composite flat field made by two identical beams, and three-beam intensity-modulated fields) were made to verify the robustness of the model. For each test distribution, the dose bound predicted by the uncertainty model was compared with simulated measurements. The

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

    SciTech Connect

    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); 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.

  8. Analysis of cell cycle regulated and regulating proteins following exposure of lung derived cells to sub-lethal doses of a-rays

    NASA Astrophysics Data System (ADS)

    Trani, D.; Claudio, P. P.; Cassone, M.; Lucchetti, C.; D'Agostino, L.; Caputi, M.; Giordano, A.

    Introduction Since the last century mankind had to face an increased exposure to man made and natural sources of radiation Radiation represents a therapeutic instrument for radiosensitive cancers as well as a cytotoxic agent for normal human tissues The effects of prolonged exposure to low doses of high energy radiation are still not well-known at the molecular and clinical level Understanding their molecular effects will aid in developing more tailored therapeutic strategies as well as implementing radio-protective measures essential prerequisite for the long-time permanence of men in space Objective of the study The general aim of this study was to evaluate the susceptibility and the response of lung epithelial cells to DNA damage induced by ionizing radiations We decided to study a panel of epithelial bronchial cell lines because of their fast-growth rate and their prominent exposure to both environmental and medical radiations The specific objective of our study was to qualitatively and semi-quantitatively assess the involvement and behaviour of selected genes in DNA damage DNA-repair mechanisms and apoptosis which follow radiation exposure with the aim to determine the involvement of the most promising targets for the early detection of radiation-mediated lung damage before chronic disease develops Methods Four epithelial cell lines one normal and three neoplastic were selected in order to detect and compare survival cell cycle and protein expression differences related to their different genetic asset

  9. 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

    SciTech Connect

    Morita, Akinori; Ariyasu, Shinya; Wang, Bing; Asanuma, Tetsuo; Onoda, Takayoshi; Sawa, Akiko; Tanaka, Kaoru; Takahashi, Ippei; Togami, Shotaro; Nenoi, Mitsuru; Inaba, Toshiya; Aoki, Shin

    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 mice 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. AS-2 also

  10. 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.

  11. Efficacy of single dose of a bivalent vaccine containing inactivated Newcastle disease virus and reassortant highly pathogenic avian influenza H5N1 virus against lethal HPAI and NDV infection in chickens.

    PubMed

    Lee, Dong-Hun; Park, Jae-Keun; Kwon, Jung-Hoon; Yuk, Seong-Su; Erdene-Ochir, Tseren-Ochir; Jang, Yo-Han; Seong, Baik-Lin; Lee, Joong-Bok; Park, Seung-Yong; Choi, In-Soo; Song, Chang-Seon

    2013-01-01

    Highly pathogenic avian influenza (HPAI) and Newcastle disease (ND) are 2 devastating diseases of poultry, which cause great economic losses to the poultry industry. In the present study, we developed a bivalent vaccine containing antigens of inactivated ND and reassortant HPAI H5N1 viruses as a candidate poultry vaccine, and we evaluated its immunogenicity and protective efficacy in specific pathogen-free chickens. The 6:2 reassortant H5N1 vaccine strain containing the surface genes of the A/Chicken/Korea/ES/2003(H5N1) virus was successfully generated by reverse genetics. A polybasic cleavage site of the hemagglutinin segment was replaced by a monobasic cleavage site. We characterized the reverse genetics-derived reassortant HPAI H5N1 clade 2.5 vaccine strain by evaluating its growth kinetics in eggs, minimum effective dose in chickens, and cross-clade immunogenicity against HPAI clade 1 and 2. The bivalent vaccine was prepared by emulsifying inactivated ND (La Sota strain) and reassortant HPAI viruses with Montanide ISA 70 adjuvant. A single immunization with this vaccine induced high levels of hemagglutination-inhibiting antibody titers and protected chickens against a lethal challenge with the wild-type HPAI and ND viruses. Our results demonstrate that the bivalent, inactivated vaccine developed in this study is a promising approach for the control of both HPAI H5N1 and ND viral infections.

  12. HDRMC, an accelerated Monte Carlo dose calculator for high dose rate brachytherapy with CT-compatible applicators

    SciTech Connect

    Chibani, Omar C-M Ma, Charlie

    2014-05-15

    Purpose: To present a new accelerated Monte Carlo code for CT-based dose calculations in high dose rate (HDR) brachytherapy. The new code (HDRMC) accounts for both tissue and nontissue heterogeneities (applicator and contrast medium). Methods: HDRMC uses a fast ray-tracing technique and detailed physics algorithms to transport photons through a 3D mesh of voxels representing the patient anatomy with applicator and contrast medium included. A precalculated phase space file for the{sup 192}Ir source is used as source term. HDRM is calibrated to calculated absolute dose for real plans. A postprocessing technique is used to include the exact density and composition of nontissue heterogeneities in the 3D phantom. Dwell positions and angular orientations of the source are reconstructed using data from the treatment planning system (TPS). Structure contours are also imported from the TPS to recalculate dose-volume histograms. Results: HDRMC was first benchmarked against the MCNP5 code for a single source in homogenous water and for a loaded gynecologic applicator in water. The accuracy of the voxel-based applicator model used in HDRMC was also verified by comparing 3D dose distributions and dose-volume parameters obtained using 1-mm{sup 3} versus 2-mm{sup 3} phantom resolutions. HDRMC can calculate the 3D dose distribution for a typical HDR cervix case with 2-mm resolution in 5 min on a single CPU. Examples of heterogeneity effects for two clinical cases (cervix and esophagus) were demonstrated using HDRMC. The neglect of tissue heterogeneity for the esophageal case leads to the overestimate of CTV D90, CTV D100, and spinal cord maximum dose by 3.2%, 3.9%, and 3.6%, respectively. Conclusions: A fast Monte Carlo code for CT-based dose calculations which does not require a prebuilt applicator model is developed for those HDR brachytherapy treatments that use CT-compatible applicators. Tissue and nontissue heterogeneities should be taken into account in modern HDR

  13. Assessment of patient and occupational dose in established and new applications of MDCT fluoroscopy.

    PubMed

    Joemai, Raoul M S; Zweers, Dirk; Obermann, Wim R; Geleijns, Jacob

    2009-04-01

    This study aimed to assess patient dose and occupational dose in established and new applications of MDCT fluoroscopy. Electronic personal dosimeters were used to measure occupational dose equivalent. Effective patient dose was derived from the recorded dose-length product. Acquisition parameters that were observed during CT fluoroscopy (CTF) provided the basis for the estimation of an entrance skin dose profile. Two hundred ten CT-guided interventional procedures were included in the study. The median effective patient dose was 10 mSv (range, 0.1-235 mSv; 107 procedures). The median peak entrance skin dose was 0.4 Sv (0.1-2.1 Sv; 27 procedures). From 547 measurements of occupational dose equivalent, a median occupational effective dose of 3 muSv per procedure was derived for the interventional radiologists and 0.4 muSv per procedure for the assisting radiologists and radiology technologists. The estimated maximum occupational effective dose reached 0.4 mSv. The study revealed high effective patient doses, up to 235 mSv, mainly for relatively new applications such as CTF-guided radiofrequency ablations using MDCT, vertebroplasty, and percutaneous ethanol injections of tumors. Entrance doses were occasionally in the range of the warning level for deterministic skin effects but were always below the threshold for serious deterministic effects. The complexity of the procedure, expected benefits of the treatment, and general health state of the patient contribute to the justification of observed high effective patient doses.

  14. 3D-printed applicators for high dose rate brachytherapy: Dosimetric assessment at different infill percentage.

    PubMed

    Ricotti, Rosalinda; Vavassori, Andrea; Bazani, Alessia; Ciardo, Delia; Pansini, Floriana; Spoto, Ruggero; Sammarco, Vittorio; Cattani, Federica; Baroni, Guido; Orecchia, Roberto; Jereczek-Fossa, Barbara Alicja

    2016-12-01

    Dosimetric assessment of high dose rate (HDR) brachytherapy applicators, printed in 3D with acrylonitrile butadiene styrene (ABS) at different infill percentage. A low-cost, desktop, 3D printer (Hamlet 3DX100, Hamlet, Dublin, IE) was used for manufacturing simple HDR applicators, reproducing typical geometries in brachytherapy: cylindrical (common in vaginal treatment) and flat configurations (generally used to treat superficial lesions). Printer accuracy was investigated through physical measurements. The dosimetric consequences of varying the applicator's density by tuning the printing infill percentage were analysed experimentally by measuring depth dose profiles and superficial dose distribution with Gafchromic EBT3 films (International Specialty Products, Wayne, NJ). Dose distributions were compared to those obtained with a commercial superficial applicator. Measured printing accuracy was within 0.5mm. Dose attenuation was not sensitive to the density of the material. Surface dose distribution comparison of the 3D printed flat applicators with respect to the commercial superficial applicator showed an overall passing rate greater than 94% for gamma analysis with 3% dose difference criteria, 3mm distance-to-agreement criteria and 10% dose threshold. Low-cost 3D printers are a promising solution for the customization of the HDR brachytherapy applicators. However, further assessment of 3D printing techniques and regulatory materials approval are required for clinical application. Copyright © 2016 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

  15. Dosimetric optimization of a conical breast brachytherapy applicator for improved skin dose sparing

    SciTech Connect

    Yang Yun; Rivard, Mark J.

    2010-11-15

    Purpose: Both the AccuBoost D-shaped and round applicators have been dosimetrically characterized and clinically used to treat patients with breast cancer. While the round applicators provide conformal dose coverage, under certain clinical circumstances the breast skin dose may be higher than preferred. The purpose of this study was to modify the round applicators to minimize skin dose while not substantially affecting dose uniformity within the target volume and reducing the treatment time. Methods: In order to irradiate the intended volume while sparing critical structures such as the skin, the current round applicator design has been augmented through the addition of an internal truncated cone (i.e., frustum) shield. Monte Carlo methods and clinical constraints were used to design the optimal cone applicator. With the cone applicator now defined as the entire assembly including the surrounding tungsten-alloy shell holding the HDR {sup 192}Ir source catheter, the applicator height was reduced to diminish the treatment time while minimizing skin dose. Monte Carlo simulation results were validated using both radiochromic film and ionization chamber measurements based on established techniques. Results: The optimal cone applicators diminished the maximum skin dose by 15%-32% (based on the applicator diameter and breast separation) with the tumor dose reduced by less than 3% for a constant exposure time. Furthermore, reduction in applicator height diminished the treatment time by up to 30%. Radiochromic film and ionization chamber dosimetric results in phantom agreed with Monte Carlo simulation results typically within 3%. Larger differences were outside the treatment volume in low dose regions or associated with differences between the measurement and Monte Carlo simulation environments. Conclusions: A new radiotherapy treatment device was developed and dosimetrically characterized. This set of applicators significantly reduces the skin dose and treatment time while

  16. Dosimetric optimization of a conical breast brachytherapy applicator for improved skin dose sparing.

    PubMed

    Yang, Yun; Rivard, Mark J

    2010-11-01

    Both the AccuBoost D-shaped and round applicators have been dosimetrically characterized and clinically used to treat patients with breast cancer. While the round applicators provide conformal dose coverage, under certain clinical circumstances the breast skin dose may be higher than preferred. The purpose of this study was to modify the round applicators to minimize skin dose while not substantially affecting dose uniformity within the target volume and reducing the treatment time. In order to irradiate the intended volume while sparing critical structures such as the skin, the current round applicator design has been augmented through the addition of an internal truncated cone (i.e., frustum) shield. Monte Carlo methods and clinical constraints were used to design the optimal cone applicator. With the cone applicator now defined as the entire assembly including the surrounding tungsten-alloy shell holding the HDR 192Ir source catheter, the applicator height was reduced to diminish the treatment time while minimizing skin dose. Monte Carlo simulation results were validated using both radiochromic film and ionization chamber measurements based on established techniques. The optimal cone applicators diminished the maximum skin dose by 15%-32% (based on the applicator diameter and breast separation) with the tumor dose reduced by less than 3% for a constant exposure time. Furthermore, reduction in applicator height diminished the treatment time by up to 30%. Radiochromic film and ionization chamber dosimetric results in phantom agreed with Monte Carlo simulation results typically within 3%. Larger differences were outside the treatment volume in low dose regions or associated with differences between the measurement and Monte Carlo simulation environments. A new radiotherapy treatment device was developed and dosimetrically characterized. This set of applicators significantly reduces the skin dose and treatment time while retaining uniform target dose.

  17. High-dose acetaminophen inhibits the lethal effect of doxorubicin in HepG2 cells: the role of P-glycoprotein and mitogen-activated protein kinase p44/42 pathway.

    PubMed

    Manov, Irena; Bashenko, Yulia; Eliaz-Wolkowicz, Anat; Mizrahi, Meital; Liran, Oded; Iancu, Theodore C

    2007-09-01

    Doxorubicin (DOX) is a widely used chemotherapeutic drug for human hepatocellular carcinoma (HCC). A major limitation to its effectiveness is the development of multidrug resistance of cancer cells. In clinical trials, patients with advanced HCC were treated with high-dose acetaminophen (HAAP) in an effort to improve the antitumor activity of chemotherapeutics. In this study, we investigated the effect of concomitant treatment of DOX and HAAP on hepatoma-derived HepG2 cells. Viability, cell cycle distribution, and ultrastructure were examined. Unexpectedly, HAAP, when added to DOX-exposed cells, increased cell viability, released cell cycle arrest, and decreased apoptosis. To elucidate the mechanisms by which HAAP reduces the DOX lethal effect to HepG2 cells, we investigated the multidrug resistance P-glycoprotein (P-gp) and p44/42-mitogen-activated protein kinase (MAPK) pathways. The P-gp function was enhanced by DOX and HAAP, and it was further stimulated during combined treatment, leading to decreased DOX retention. Verapamil (VRP), when added to DOX + HAAP exposure, increased DOX accumulation and restored DOX-induced toxicity. The increased phospho-p44/42-MAPK level in DOX-exposed cells was inhibited by HAAP. In addition, suppression of p44/42 activation by the p44/42-MAPK inhibitor 2'-amino-3'-methoxyflavone (PD98059) blocked DOX-induced apoptosis. These findings suggest that the antagonistic effect of concomitant DOX + HAAP treatment occurs as a result of interactive stimulation of P-gp, generating decreased intracellular drug concentrations. Furthermore, inhibition of the p44/42-MAPK phosphorylation by HAAP could abolish the DOX-induced cell death pathway. Thus, combined treatment by DOX + HAAP, intended to improve chemotherapeutic efficacy, could have an opposite effect facilitating cancer cell survival.

  18. Evaluating sub-lethal effects of orchard-applied pyrethroids using video-tracking software to quantify honey bee behaviors.

    PubMed

    Ingram, Erin M; Augustin, Julie; Ellis, Marion D; Siegfried, Blair D

    2015-09-01

    Managed honey bee, Apis mellifera L., colonies are contracted to pollinate fruit and nut orchards improving crop quality and yield. Colonies placed in orchards are potentially exposed to pyrethroid insecticides used for broad-spectrum pest control. Pyrethroids have been reported to pose minimal risk to bees due to their low application rates in the field and putative repellent properties. This repellency is believed to alter foraging behavior with the benefit of preventing bees from encountering a lethal dose in the field. However, sub-lethal exposure to pyrethroids may adversely impact bee behavior potentially resulting in social dysfunction or disruption of foraging. This study quantified behaviors associated with sub-lethal exposure to orchard-applied pyrethroids including, lambda-cyhalothrin, esfenvalerate, and permethrin, using video tracking software, Ethovision XT (Noldus Information Technologies). Bee locomotion, social interaction, and time spent near a food source were measured over a 24-h period. Bees treated with a pyrethroid traveled 30-71% less than control bees. Social interaction time decreased by 43% for bees treated with a high sub-lethal dose of esfenvalerate. Bees exposed to a high sub-lethal dose of permethrin spent 67% less time in social interaction and spent more than 5 times as long in the food zone compared to control bees.

  19. Influence of metal of the applicator on the dose distribution during brachytherapy.

    PubMed

    Wu, Chin-Hui; Shiau, An-Cheng; Liao, Yi-Jen; Lin, Hsin-Yu; Liu, Yen-Wan Hsueh; Hsu, Shih-Ming

    2014-01-01

    This study explores how the metal materials of the applicator influence the dose distribution when performing brachytherapy for cervical cancer. A pinpoint ionization chamber, Monte Carlo code MCNPX, and treatment planning system are used to evaluate the dose distribution for a single Ir-192 source positioned in the tandem and ovoid. For dose distribution in water with the presence of the tandem, differences among measurement, MCNPX calculation and treatment planning system results are <5%. For dose distribution in water with the presence of the ovoid, the MCNPX result agrees with the measurement. But the doses calculated from treatment planning system are overestimated by up to a factor of 4. This is due to the shielding effect of the metal materials in the applicator not being considered in the treatment planning system. This result suggests that the treatment planning system should take into account corrections for the metal materials of the applicator in order to improve the accuracy of the radiation dose delivered.

  20. Fast, three-dimensional, MR Imaging for polymer gel dosimetric applications involving high dose and steep dose gradients

    NASA Astrophysics Data System (ADS)

    Sandilos, Panagiotis; Baras, Panagiotis; Georgiou, Evangelos; Dardoufas, Konstantinos; Karaiskos, Pantelis; Papagiannis, Panagiotis; Paschalis, Theodoros; Tatsis, Elias; Torrens, Michael; Vlahos, Lampros

    2006-12-01

    Polymer gels constitute water equivalent integrating detectors, which, combined with magnetic resonance imaging (MRI), can provide accurate three dimensional (3D) dose distributions in contemporary radiotherapy applications where the small field dimensions and steep dose gradients induce limitations to conventional dosimeters. One of the main obstacles for adapting the method for routine use in the clinical setting is the cost effectiveness of the MRI readout method. Currently, optimized Carr-Purcell-Meiboom-Gill (CPMG) multiple spin echo imaging pulse sequences are commonly used which however result in long imaging times. This work evaluates the efficiency of 3D, dual-echo, k-space segmented turbo spin echo (TSE) scanning sequences for accurate dosimetry with sub-millimetre spatial resolution in strenuous radiation therapy applications. PABIG polymer gel dosimeters were irradiated with an 192Ir High Dose Rate brachytherapy source, the 4 mm and 8 mm collimator helmets of a gamma knife unit and a custom made x-knife collimator of 1 cm diameter. Profile and dose distribution measurements using TSE are benchmarked against corresponding findings obtained by the commonly used, but time consuming, CPMG sequence as well as treatment planning calculations, Monte Carlo (MC) simulations and film measurements. The implementation of a high Turbo factor was found to provide comparable accuracy, allowing a 64-fold MRI scan acceleration compared to conventional multi-echo sequences. The availability of TSE sequences in typical MRI installations greatly facilitates the introduction of polymer gel dosimetry in the clinical environment as a practicable tool for the determination of full 3D dose distributions in contemporary radiotherapy applications.

  1. Dose Modification Factor Analysis of Multi-Lumen Brachytherapy Applicator with Monte Carlo Simulation

    NASA Astrophysics Data System (ADS)

    Williams, Eric Alan

    Multi-lumen applicators like the Contura (SenoRx, Inc.) are used in partial breast irradiation (PBI) brachytherapy in instances where asymmetric dose distributions are desired, for example, when the applicator surface-to-skin thickness is small (<7mm). In these instances, the air outside the patient and the lung act as a poor scattering medium, scattering less dose back into the breast tissue which affects the dose distribution. Many commercial treatment planning systems do not correct for tissue heterogeneity, which results in inaccuracies in the planned dose distribution. This deviation has been quantified as the dose modification factor (DMF), equal to the ratio of the dose rate at 1cm beyond the applicator surface, with homogenous medium, to the dose rate at 1cm with heterogeneous medium. This investigation intends to model the Contura applicator with the Monte Carlo N-Particle code (MCNP, Los Alamos National Labs), determine a DMF through simulation, and correlate to previous measurements. Taking all geometrical considerations into account, an accurate model of the Contura balloon applicator was created in MCNP. This model was used to run simulations of symmetric and asymmetric plans. The dose modification factor was found to be dependent on the simulated water phantom geometry, with cuboid geometry yielding a max DMF of 1.0664. The same measurements taken using a spherical geometry water phantom gave a DMF of 1.1221. It was also seen that the difference in DMF between symmetric and asymmetric plans using the Contura applicator is minimal.

  2. 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.

  3. A broadly applicable function for describing luminescence dose response

    SciTech Connect

    Burbidge, C. I.

    2015-07-28

    The basic form of luminescence dose response is investigated, with the aim of developing a single function to account for the appearance of linear, superlinear, sublinear, and supralinear behaviors and variations in saturation signal level and rate. A function is assembled based on the assumption of first order behavior in different major factors contributing to measured luminescence-dosimetric signals. Different versions of the function are developed for standardized and non-dose-normalized responses. Data generated using a two trap two recombination center model and experimental data for natural quartz are analyzed to compare results obtained using different signals, measurement protocols, pretreatment conditions, and radiation qualities. The function well describes a range of dose dependent behavior, including sublinear, superlinear, supralinear, and non-monotonic responses and relative response to α and β radiation, based on change in relative recombination and trapping probability affecting signals sourced from a single electron trap.

  4. Lethal multiple pterygium syndrome

    PubMed Central

    Joshi, Tulika; Noor, Nazia Nagori; Kural, Moolraj; Tripathi, Amita

    2016-01-01

    The multiple pterygium syndrome is consist of wide range of fetal malformations which have a genetic linkage. A defect in embryonic acetylcholine receptor which can be inherited as autosomal recessive, autosomal dominant, or X-linked fashion is the cause of this syndrome. We present a sporadic case of lethal multiple pterygium syndrome. PMID:27843868

  5. HDR Brachytherapy Dose Distribution is Influenced by the Metal Material of the Applicator.

    PubMed

    Wu, Chin-Hui; Liao, Yi-Jen; Shiau, An-Cheng; Lin, Hsin-Yu; Hsueh Liu, Yen-Wan; Hsu, Shih-Ming

    2015-12-11

    Applicators containing metal have been widely used in recent years when applying brachytherapy to patients with cervical cancer. However, the high dose rate (HDR) treatment-planning system (TPS) that is currently used in brachytherapy still assumes that the treatment environment constitutes a homogeneous water medium and does not include a dose correction for the metal material of the applicator. The primary purpose of this study was to evaluate the HDR (192)Ir dose distribution in cervical cancer patients when performing brachytherapy using a metal-containing applicator. Thermoluminescent dosimeter (TLD) measurements and Monte Carlo N-Particle eXtended (MCNPX) code were used to explore the doses to the rectum and bladder when using a Henschke applicator containing metal during brachytherapy. When the applicator was assumed to be present, the absolute dose difference between the TLD measurement and MCNPX simulation values was within approximately 5%. A comparison of the MCNPX simulation and TPS calculation values revealed that the TPS overestimated the International Commission of Radiation Units and Measurement (ICRU) rectum and bladder reference doses by 57.78% and 49.59%, respectively. We therefore suggest that the TPS should be modified to account for the shielding effects of the applicator to ensure the accuracy of the delivered doses.

  6. HDR Brachytherapy Dose Distribution is Influenced by the Metal Material of the Applicator

    PubMed Central

    Wu, Chin-Hui; Liao, Yi-Jen; Shiau, An-Cheng; Lin, Hsin-Yu; Hsueh Liu, Yen-Wan; Hsu, Shih-Ming

    2015-01-01

    Applicators containing metal have been widely used in recent years when applying brachytherapy to patients with cervical cancer. However, the high dose rate (HDR) treatment-planning system (TPS) that is currently used in brachytherapy still assumes that the treatment environment constitutes a homogeneous water medium and does not include a dose correction for the metal material of the applicator. The primary purpose of this study was to evaluate the HDR 192Ir dose distribution in cervical cancer patients when performing brachytherapy using a metal-containing applicator. Thermoluminescent dosimeter (TLD) measurements and Monte Carlo N-Particle eXtended (MCNPX) code were used to explore the doses to the rectum and bladder when using a Henschke applicator containing metal during brachytherapy. When the applicator was assumed to be present, the absolute dose difference between the TLD measurement and MCNPX simulation values was within approximately 5%. A comparison of the MCNPX simulation and TPS calculation values revealed that the TPS overestimated the International Commission of Radiation Units and Measurement (ICRU) rectum and bladder reference doses by 57.78% and 49.59%, respectively. We therefore suggest that the TPS should be modified to account for the shielding effects of the applicator to ensure the accuracy of the delivered doses. PMID:26658746

  7. 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

  8. Anthrax lethal factor inhibition.

    PubMed

    Shoop, W L; Xiong, Y; Wiltsie, J; Woods, A; Guo, J; Pivnichny, J V; Felcetto, T; Michael, B F; Bansal, A; Cummings, R T; Cunningham, B R; Friedlander, A M; Douglas, C M; Patel, S B; Wisniewski, D; Scapin, G; Salowe, S P; Zaller, D M; Chapman, K T; Scolnick, E M; Schmatz, D M; Bartizal, K; MacCoss, M; Hermes, J D

    2005-05-31

    The primary virulence factor of Bacillus anthracis is a secreted zinc-dependent metalloprotease toxin known as lethal factor (LF) that is lethal to the host through disruption of signaling pathways, cell destruction, and circulatory shock. Inhibition of this proteolytic-based LF toxemia could be expected to provide therapeutic value in combination with an antibiotic during and immediately after an active anthrax infection. Herein is shown the crystal structure of an intimate complex between a hydroxamate, (2R)-2-[(4-fluoro-3-methylphenyl)sulfonylamino]-N-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetamide, and LF at the LF-active site. Most importantly, this molecular interaction between the hydroxamate and the LF active site resulted in (i) inhibited LF protease activity in an enzyme assay and protected macrophages against recombinant LF and protective antigen in a cell-based assay, (ii) 100% protection in a lethal mouse toxemia model against recombinant LF and protective antigen, (iii) approximately 50% survival advantage to mice given a lethal challenge of B. anthracis Sterne vegetative cells and to rabbits given a lethal challenge of B. anthracis Ames spores and doubled the mean time to death in those that died in both species, and (iv) 100% protection against B. anthracis spore challenge when used in combination therapy with ciprofloxacin in a rabbit "point of no return" model for which ciprofloxacin alone provided 50% protection. These results indicate that a small molecule, hydroxamate LF inhibitor, as revealed herein, can ameliorate the toxemia characteristic of an active B. anthracis infection and could be a vital adjunct to our ability to combat anthrax.

  9. In contrast to conventional inactivated influenza vaccines, 4xM2e.HSP70c fusion protein fully protected mice against lethal dose of H1, H3 and H9 influenza A isolates circulating in Iran

    SciTech Connect

    Ebrahimi, Seyyed Mahmoud; Dabaghian, Mehran; Tebianian, Majid

    2012-08-15

    Ideal vaccines against influenza viruses should elicit not only a humoral response, but also a cellular response. Mycobacterium tuberculosis HSP70 (mHSP70) have been found to promote immunogenic APCs function, elicit a strong cytotoxic T lymphocyte (CTL) response, and prevent the induction of tolerance. Moreover, it showed linkage of antigens to the C-terminus of mHSP70 (mHSP70c) can represent them as vaccines resulted in more potent, protective antigen specific responses in the absence of adjuvants or complex formulations. Hence, recombinant fusion protein comprising C-terminus of mHSP70 genetically fused to four tandem repeats of the ectodomain of the conserved influenza matrix protein M2 (M2e) was expressed in Escherichia coli, purified under denaturing condition, refolding, and then confirmed by SDS-PAGE, respectively. The recombinant fusion protein, 4xM2e.HSP70c, retained its immunogenicity and displayed the protective epitope of M2e by ELISA and FITC assays. A prime-boost administration of 4xM2e.HSP70c formulated in F105 buffer by intramuscular route in mice (Balb/C) provided full protection against lethal dose of mouse-adapted H1N1, H3N2, or H9N2 influenza A isolates from Iran compared to 0-33.34% survival rate of challenged unimmunized and immunized mice with the currently in use conventional vaccines designated as control groups. However, protection induced by immunization with 4xM2e.HSP70c failed to prevent weight loss in challenged mice; they experienced significantly lower weight loss, clinical symptoms and higher lung viral clearance in comparison with protective effects of conventional influenza vaccines in challenged mice. These data demonstrate that C-terminal domain of mHSP70 can be a superior candidate to deliver the adjuvant function in M2e-based influenza A vaccine in order to provide significant protection against multiple influenza A virus strains.

  10. In contrast to conventional inactivated influenza vaccines, 4xM2e.HSP70c fusion protein fully protected mice against lethal dose of H1, H3 and H9 influenza A isolates circulating in Iran.

    PubMed

    Ebrahimi, Seyyed Mahmoud; Dabaghian, Mehran; Tebianian, Majid; Jazi, Mohammad Hossein Zabeh

    2012-08-15

    Ideal vaccines against influenza viruses should elicit not only a humoral response, but also a cellular response. Mycobacterium tuberculosis HSP70 (mHSP70) have been found to promote immunogenic APCs function, elicit a strong cytotoxic T lymphocyte (CTL) response, and prevent the induction of tolerance. Moreover, it showed linkage of antigens to the C-terminus of mHSP70 (mHSP70c) can represent them as vaccines resulted in more potent, protective antigen specific responses in the absence of adjuvants or complex formulations. Hence, recombinant fusion protein comprising C-terminus of mHSP70 genetically fused to four tandem repeats of the ectodomain of the conserved influenza matrix protein M2 (M2e) was expressed in Escherichia coli, purified under denaturing condition, refolding, and then confirmed by SDS-PAGE, respectively. The recombinant fusion protein, 4xM2e.HSP70c, retained its immunogenicity and displayed the protective epitope of M2e by ELISA and FITC assays. A prime-boost administration of 4xM2e.HSP70c formulated in F105 buffer by intramuscular route in mice (Balb/C) provided full protection against lethal dose of mouse-adapted H1N1, H3N2, or H9N2 influenza A isolates from Iran compared to 0-33.34% survival rate of challenged unimmunized and immunized mice with the currently in use conventional vaccines designated as control groups. However, protection induced by immunization with 4xM2e.HSP70c failed to prevent weight loss in challenged mice; they experienced significantly lower weight loss, clinical symptoms and higher lung viral clearance in comparison with protective effects of conventional influenza vaccines in challenged mice. These data demonstrate that C-terminal domain of mHSP70 can be a superior candidate to deliver the adjuvant function in M2e-based influenza A vaccine in order to provide significant protection against multiple influenza A virus strains.

  11. 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.

  12. High-dose processing and application to Korean space foods

    NASA Astrophysics Data System (ADS)

    Song, Beom-Seok; Park, Jin-Gyu; Park, Jae-Nam; Han, In-Jun; Choi, Jong-il; Kim, Jae-Hun; Byun, Myung-Woo; Kang, Sang-Wook; Choi, Gi-Hyuk; Lee, Ju-Woon

    2009-07-01

    Nutrition bar, Ramen (ready-to-cook noodle), and two Korean traditional foods ( Kimchi, fermented vegetable; Sujeonggwa, cinnamon beverage) have been developed as space foods using high-dose gamma irradiation. Addition of calcium lactate and vitamin C, a mild heating, deep-freezing, and gamma irradiation at 25 kGy were conducted to prepare Kimchi as a ready-to-eat space food. Sterilization of Space Kimchi (SK) was confirmed by a microbiological test. The hardness of the Space Kimchi was lower than the untreated Kimchi (CON), but higher than the irradiated only Kimchi. Sensory attributes of the SK were similar to CON, and maintained during preservation at 35 °C for 30 days. The optimal doses for eliminating the contaminated microbes and maintaining the qualities of the Nutrition bars, Ramen, and Sujeonggwa were determined at 15, 10 and 6 kGy, respectively. All the Korean space food were certificated for use in space flight conditions of 30 days by the Russian Institute for Biomedical Problems.

  13. 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.

  14. Comparison of dose calculation algorithms for colorectal cancer brachytherapy treatment with a shielded applicator

    SciTech Connect

    Yan Xiangsheng; Poon, Emily; Reniers, Brigitte; Vuong, Te; Verhaegen, Frank

    2008-11-15

    Colorectal cancer patients are treated at our hospital with {sup 192}Ir high dose rate (HDR) brachytherapy using an applicator that allows the introduction of a lead or tungsten shielding rod to reduce the dose to healthy tissue. The clinical dose planning calculations are, however, currently performed without taking the shielding into account. To study the dose distributions in shielded cases, three techniques were employed. The first technique was to adapt a shielding algorithm which is part of the Nucletron PLATO HDR treatment planning system. The isodose pattern exhibited unexpected features but was found to be a reasonable approximation. The second technique employed a ray tracing algorithm that assigns a constant dose ratio with/without shielding behind the shielding along a radial line originating from the source. The dose calculation results were similar to the results from the first technique but with improved accuracy. The third and most accurate technique used a dose-matrix-superposition algorithm, based on Monte Carlo calculations. The results from the latter technique showed quantitatively that the dose to healthy tissue is reduced significantly in the presence of shielding. However, it was also found that the dose to the tumor may be affected by the presence of shielding; for about a quarter of the patients treated the volume covered by the 100% isodose lines was reduced by more than 5%, leading to potential tumor cold spots. Use of any of the three shielding algorithms results in improved dose estimates to healthy tissue and the tumor.

  15. The application of high dose food irradiation in South Africa

    NASA Astrophysics Data System (ADS)

    de Bruyn, Ingrid Nine

    2000-03-01

    During the 1950s to the end of the 1970s the United States Army developed the basic methodology to produce shelf-stable irradiated meat, seafood and poultry products. These products are normally packed without gravy, sauce or brine, as liquid is not required to sterilize the product as in the canning process. This leads to the distinctive "dried cooked" taste normally associated with roasts opposed to the casserole taste usually associated with tinned meats. The Biogam group at the Atomic Energy Corporation of South Africa is currently producing shelf-stable irradiated meats on a commercial basis. The meats are cooked, chilled, portioned, vacuum packed and irradiated to the required minimum dose of 45 kGy at a temperature of between -20 and -40°C to ensure absolute sterility even under tropical conditions. The product is packaged in a high quality four layer laminate pouch and will therefore not rust or burst even under adverse weather conditions and can be guaranteed for more than two years as long as the integrity of the packaging is maintained. Safari operators in remote parts of Africa, mountaineers, yachtsmen, canoeists and geological survey teams currently use shelf-stable irradiated meat products produced in South Africa.

  16. Single versus multichannel applicator in high-dose-rate vaginal brachytherapy optimized by inverse treatment planning

    PubMed Central

    Constantinescu, Camelia; Hassouna, Ashraf H.; Eltaher, Maha M.; Ghassal, Noor M.; Awad, Nesreen A.

    2014-01-01

    Purpose To retrospectively compare the potential dosimetric advantages of a multichannel vaginal applicator vs. a single channel one in intracavitary vaginal high-dose-rate (HDR) brachytherapy after hysterectomy, and evaluate the dosimetric advantage of fractional re-planning. Material and methods We randomly selected 12 patients with endometrial carcinoma, who received adjuvant vaginal cuff HDR brachytherapy using a multichannel applicator. For each brachytherapy fraction, two inverse treatment plans (for central channel and multichannel loadings) were performed and compared. The advantage of fractional re-planning was also investigated. Results Dose-volume-histogram (DVH) analysis showed limited, but statistically significant difference (p = 0.007) regarding clinical-target-volume dose coverage between single and multichannel approaches. For the organs-at-risk rectum and bladder, the use of multichannel applicator demonstrated a noticeable dose reduction, when compared to single channel, but statistically significant for rectum only (p = 0.0001). For D2cc of rectum, an average fractional dose of 6.1 ± 0.7 Gy resulted for single channel vs. 5.1 ± 0.6 Gy for multichannel. For D2cc of bladder, an average fractional dose of 5 ± 0.9 Gy occurred for single channel vs. 4.9 ± 0.8 Gy for multichannel. The dosimetric benefit of fractional re-planning was demonstrated: DVH analysis showed large, but not statistically significant differences between first fraction plan and fractional re-planning, due to large inter-fraction variations for rectum and bladder positioning and filling. Conclusions Vaginal HDR brachytherapy using a multichannel vaginal applicator and inverse planning provides dosimetric advantages over single channel cylinder, by reducing the dose to organs at risk without compromising the target volume coverage, but at the expense of an increased vaginal mucosa dose. Due to large inter-fraction dose variations, we recommend individual fraction treatment plan

  17. Single versus multichannel applicator in high-dose-rate vaginal brachytherapy optimized by inverse treatment planning.

    PubMed

    Bahadur, Yasir A; Constantinescu, Camelia; Hassouna, Ashraf H; Eltaher, Maha M; Ghassal, Noor M; Awad, Nesreen A

    2015-01-01

    To retrospectively compare the potential dosimetric advantages of a multichannel vaginal applicator vs. a single channel one in intracavitary vaginal high-dose-rate (HDR) brachytherapy after hysterectomy, and evaluate the dosimetric advantage of fractional re-planning. We randomly selected 12 patients with endometrial carcinoma, who received adjuvant vaginal cuff HDR brachytherapy using a multichannel applicator. For each brachytherapy fraction, two inverse treatment plans (for central channel and multichannel loadings) were performed and compared. The advantage of fractional re-planning was also investigated. Dose-volume-histogram (DVH) analysis showed limited, but statistically significant difference (p = 0.007) regarding clinical-target-volume dose coverage between single and multichannel approaches. For the organs-at-risk rectum and bladder, the use of multichannel applicator demonstrated a noticeable dose reduction, when compared to single channel, but statistically significant for rectum only (p = 0.0001). For D2cc of rectum, an average fractional dose of 6.1 ± 0.7 Gy resulted for single channel vs. 5.1 ± 0.6 Gy for multichannel. For D2cc of bladder, an average fractional dose of 5 ± 0.9 Gy occurred for single channel vs. 4.9 ± 0.8 Gy for multichannel. The dosimetric benefit of fractional re-planning was demonstrated: DVH analysis showed large, but not statistically significant differences between first fraction plan and fractional re-planning, due to large inter-fraction variations for rectum and bladder positioning and filling. Vaginal HDR brachytherapy using a multichannel vaginal applicator and inverse planning provides dosimetric advantages over single channel cylinder, by reducing the dose to organs at risk without compromising the target volume coverage, but at the expense of an increased vaginal mucosa dose. Due to large inter-fraction dose variations, we recommend individual fraction treatment plan optimization.

  18. The lethality test system

    SciTech Connect

    Parsons, W.M.; Sims, J.R.; Parker, J.V.

    1986-11-01

    The Lethality Test System (LTS), presently under construction at Los Alamos, is an electromagnetic launcher facility designed to perform impact experiments at velocities up to 15 km/s. The launcher is a 25 mm round bore, plasma armature railgun extending 22 m in length. Preinjection is accomplished with a two-stage light gas gun capable of 7 km/s. The railgun power supply utilized traction motors, vacuum interrupters, and pulse transformers. The design of these traction motors, vacuum interrupters and pulse transformers are detailed.

  19. Application of jade samples for high-dose dosimetry using the EPR technique.

    PubMed

    Teixeira, Maria Inês; Melo, Adeilson P; Ferraz, Gilberto M; Caldas, Linda V E

    2010-01-01

    The dosimeter characteristics of jade samples were studied for application in high-dose dosimetry. Jade is the common denomination of two silicates: jadeite and actinolite. The EPR spectra of different jade samples were obtained after irradiation with absorbed doses of 100 Gy up to 20 kGy. The jade samples present signals that increase with the absorbed dose (g-factors around 2.00); they can be attributed to electron centers. The EPR spectra obtained for the USA jade samples and their main dosimetric properties as reproducibility, calibration curves and energy dependence were investigated.

  20. Computed tomography radiation dose optimization: scanning protocols and clinical applications of automatic exposure control.

    PubMed

    Kalra, Mannudeep K; Naz, Nausheen; Rizzo, Stefania M R; Blake, Michael A

    2005-01-01

    As multi-detector-row computed tomography (CT) technology evolves, manifold applications of CT scanning have been adopted in clinical practice and optimization of scanning protocols to comply with an "as low as reasonably achievable" radiation dose have become more complex. Automatic exposure control techniques, which have been recently introduced on most state-of-the-art CT equipment, aid in radiation dose optimization at a selected image quality. The present article reviews the fundamentals of automatic exposure control techniques in CT, along with the scanning protocols and associated radiation dose reduction.

  1. Mechanism by which caffeine potentiates lethality of nitrogen mustard.

    PubMed Central

    Lau, C C; Pardee, A B

    1982-01-01

    Caffeine is synergistic with many DNA-damaging agents in increasing lethality to mammalian cells. The mechanism is not well understood. Our results show that caffeine potentiates the lethality of the nitrogen mustard 2-chloro-N-(2-chloroethyl)-N-methylethanamine (HN2) by inducing damaged cells to undergo mitosis before properly repairing lesions in their DNA. Treatment with low doses of HN2 (0.5 microM for 1 hr) caused little lethality in baby hamster kidney cells (90% survival). These cells were arrested in G2 shortly after treatment with HN2 as shown by flow microfluorimetry and autoradiography. After an arrest of 6 hr, HN2-treated cells began to move into mitosis and from then on behaved like normal cells. Repair synthesis was shown to continue during the G2 arrest by using synchronized cells pulse labeled with [3H]thymidine after HN2 treatment and autoradiography. Caffeine (2mM) increased the lethality of HN2 by 5- to 10-fold. It prevented the G2 arrest. Caffeine did not prevent these HN2-treated cells from entering or completing S phase but rather allowed them to divide without finishing the repair processes and as a consequence caused nuclear fragmentation after mitosis. Caffeine-induced nuclear fragmentation and enhanced lethality were proportional, as shown with dose--response curves and time dependence. In addition, both lethality and nuclear fragmentation were abolished by low doses of cycloheximide, an inhibitor of protein synthesis. Images PMID:6953438

  2. Influence of Metal of the Applicator on the Dose Distribution during Brachytherapy

    PubMed Central

    Wu, Chin-Hui; Shiau, An-Cheng; Liao, Yi-Jen; Lin, Hsin-Yu

    2014-01-01

    This study explores how the metal materials of the applicator influence the dose distribution when performing brachytherapy for cervical cancer. A pinpoint ionization chamber, Monte Carlo code MCNPX, and treatment planning system are used to evaluate the dose distribution for a single Ir-192 source positioned in the tandem and ovoid. For dose distribution in water with the presence of the tandem, differences among measurement, MCNPX calculation and treatment planning system results are <5%. For dose distribution in water with the presence of the ovoid, the MCNPX result agrees with the measurement. But the doses calculated from treatment planning system are overestimated by up to a factor of 4. This is due to the shielding effect of the metal materials in the applicator not being considered in the treatment planning system. This result suggests that the treatment planning system should take into account corrections for the metal materials of the applicator in order to improve the accuracy of the radiation dose delivered. PMID:25133789

  3. Dose verification of single shot gamma knife applications using VIPAR polymer gel and MRI

    NASA Astrophysics Data System (ADS)

    Karaiskos, P.; Petrokokkinos, L.; Tatsis, E.; Angelopoulos, A.; Baras, P.; Kozicki, M.; Papagiannis, P.; Rosiak, J. M.; Sakelliou, L.; Sandilos, P.; Vlachos, L.

    2005-03-01

    This work describes an experimental procedure with potential to assess the overall accuracy associated with gamma knife clinical applications, from patient imaging and dosimetry planning to patient positioning and dose delivery using the automated positioning system of a Leksell Gamma Knife model C. The VIPAR polymer gel-MRI dosimetry method is employed due to its inherent three-dimensional feature and linear dose response over the range of gamma knife applications. Different polymer gel vials were irradiated with single shot gamma knife treatment plans using each of the four available collimator helmets to deliver a maximum dose of 30 Gy. Percentage relative dose results are presented not only in the form of one-dimensional profiles but also planar isocontours and isosurfaces in three dimensions. Experimental results are compared with corresponding Gammaplan treatment planning system calculations as well as acceptance test radiochromic film measurements. A good agreement, within the experimental uncertainty, is observed between measured and expected dose distributions. This experimental uncertainty is of the order of one imaging pixel in the MRI gel readout session (<1 mm) and allows for the verification of single shot gamma knife applications in terms of acceptance specifications for precision in beam alignment and accuracy. Averaging net R2 results in the dose plateau of the 4 mm and 18 mm collimator irradiated gel vials, which were MR scanned in the same session, provides a crude estimate of the 4 mm output factor which agrees within errors with the default value of 0.870.

  4. Survival of lethal poxvirus infection in mice depends on TLR9, and therapeutic vaccination provides protection

    PubMed Central

    Samuelsson, Christofer; Hausmann, Jürgen; Lauterbach, Henning; Schmidt, Michaela; Akira, Shizuo; Wagner, Hermann; Chaplin, Paul; Suter, Mark; O’Keeffe, Meredith; Hochrein, Hubertus

    2008-01-01

    Poxviruses such as the causative agent of smallpox have developed multiple strategies to suppress immune responses, including the suppression of DC activation. Since poxviruses are large DNA viruses, we hypothesized that their detection by DCs may involve the endosomal DNA recognition receptor TLR9. Indeed, we have shown here that DC recognition of ectromelia virus (ECTV), the causative agent of mousepox, completely depended on TLR9. The importance of TLR9 was highlighted by the fact that mice lacking TLR9 showed drastically increased susceptibility to infection with ECTV. In contrast, we found that the strongly attenuated poxvirus modified vaccinia virus Ankara (MVA) activated DCs by both TLR9-dependent and -independent pathways. We therefore tested whether we could use the broader induction of immune responses by MVA to protect mice from a lethal infection with ECTV. Indeed, MVA given at the same time as a lethal dose of ECTV protected mice from death. Importantly, MVA also rescued TLR9-deficient mice if administered 2 full days after an otherwise lethal infection with ECTV. Therefore, these data suggest an essential role for TLR9 in the defense against poxviruses. In addition, postexposure application of MVA may protect against lethal poxvirus infection. PMID:18398511

  5. Non-Lethal Chemical Weapons

    DTIC Science & Technology

    2003-04-01

    AU/ACSC/1636/2003-04 AIR COMMAND AND STAFF COLLEGE AIR UNIVERSITY Non- Lethal Chemical Weapons LESTER A. WEILACHER...Non- Lethal Chemical Weapons 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER 5e. TASK NUMBER 5f...of the United States government. ii EL 664 (AY03) Issue Analysis, “Non- Lethal Chemical Weapons” Submitted by Major JR Weilacher, 03-1636E, 11

  6. The Lethality Test System

    NASA Astrophysics Data System (ADS)

    Parsons, W. M.; Sims, J. R.; Parker, J. V.

    1986-11-01

    The Lethality Test System (LTS) under construction at Los Alamos is an electromagnetic launcher facility designed to perform impact experiments at velocities up to 15 km/sec. The launcher is a 25 mm round bore, plasma armature railgun 22 m in length. Preinjection is accomplished with a two-stage light gas gun capable of 7 km/sec. The railgun power supply utilizes traction motors, vacuum interrupters, and pulse transformers. An assembly of 28 traction motors, equipped with flywheels, stores approximately 80 MJ at 92 percent of full speed and energizes the primary windings of three pulse transformers at a current of 50 kA. At peak current an array of vacuum interrupters disconnects the transformer primary windings and forces the current to flow in the secondary windings. The secondary windings are connected to the railgun, and by staging the vacuum interrupter openings, a 1-1.3 MA ramped current waveform will be delivered to the railgun.

  7. Lethality test system

    SciTech Connect

    Parsons, W.M.; Sims, J.R.; Parker, J.V.

    1986-01-01

    The Lethality Test System (LTS), presently under construction at Los Alamos, is an electromagnetic launcher facility designed to perform impact experiments at velocities up to 15 km/s. The launcher is a 25 mm round bore, plasma armature railgun extending 22 m in length. Preinjection is accomplished with a two-stage gas gun capable of 7 km/s. The railgun power supply utilizes traction motors, vacuum interrupters, and pulse transformers. An assembly of 28 traction motors, equipped with flywheels, stores approximately 80 MJ at 92% of full speed and energizes the primary windings of three pulse transformers at a current of 50 kA. At peak current an array of vacuum interrupters disconnects the transformer primary windings and forces the current to flow in the secondary windings. The secondary windings are connected to the railgun, and by staging the vacuum interrupter openings, a 1 MA to 1.3 MA ramped current waveform will be delivered to the railgun.

  8. Heterogeneity of Lethals in a "Simple" Lethal Complementation Group

    PubMed Central

    Janca, Frank C.; Woloshyn, Effie P.; Nash, David

    1986-01-01

    Of 24 ethyl methanesulphonate-induced, recessive-lethal mutations in the region 9E1-9F13 of the X chromosome of Drosophila melanogaster , eight fall into a typically homogeneous lethal complementation group associated with the raspberry (ras) locus. Mutations in this group have previously been shown to be pleiotropic, affecting not only ras but also two other genetic entities, gua1 and pur1, which yield auxotrophic mutations.—The eight new mutations have been characterized phenotypically in double heterozygotes with gua1, pur1 and ras mutations. Despite their homogeneity in lethal complementation tests, the mutations prove quite diverse. For example, two mutations have little or no effect on eye color in double heterozygotes with ras2 . The differences between the lethals are allele-specific and cannot be explained as a trivial outcome of a hypomorphic series.—Taken alone, the lethal complementation studies mask the complexity of the locus and the diversity of its recessive lethal alleles. By extension, we argue that the general use of lethal saturation studies provides an unduly simplified image of genetic organization. We suggest that the reason why recessive lethal mutations rarely present complex complementation patterns is that complex loci tend to produce mutations that affect several subfunctions. PMID:3080355

  9. Clinical implementation of a novel applicator in high-dose-rate brachytherapy treatment of esophageal cancer

    PubMed Central

    Hansen, Jorgen L.; Bhagwat, Mandar S.; O'Farrell, Desmond A.; Friesen, Scott; Harris, Thomas C.; Damato, Antonio L.; Cormack, Robert A.; Martin, Neil E.; Devlin, Phillip M.

    2016-01-01

    Purpose In this study, we present the clinical implementation of a novel transoral balloon centering esophageal applicator (BCEA) and the initial clinical experience in high-dose-rate (HDR) brachytherapy treatment of esophageal cancer, using this applicator. Material and methods Acceptance testing and commissioning of the BCEA were performed prior to clinical use. Full performance testing was conducted including measurements of the dimensions and the catheter diameter, evaluation of the inflatable balloon consistency, visibility of the radio-opaque markers, congruence of the markers, absolute and relative accuracy of the HDR source in the applicator using the radiochromic film and source position simulator, visibility and digitization of the applicator on the computed tomography (CT) images under the clinical conditions, and reproducibility of the offset. Clinical placement of the applicator, treatment planning, treatment delivery, and patient's response to the treatment were elaborated as well. Results The experiments showed sub-millimeter accuracy in the source positioning with distal position at 1270 mm. The digitization (catheter reconstruction) was uncomplicated due to the good visibility of markers. The treatment planning resulted in a favorable dose distribution. This finding was pronounced for the treatment of the curvy anatomy of the lesion due to the improved repeatability and consistency of the delivered fractional dose to the patient, since the radioactive source was placed centrally within the lumen with respect to the clinical target due to the five inflatable balloons. Conclusions The consistency of the BCEA positioning resulted in the possibility to deliver optimized non-uniform dose along the catheter, which resulted in an increase of the dose to the cancerous tissue and lower doses to healthy tissue. A larger number of patients and long-term follow-up will be required to investigate if the delivered optimized treatment can lead to improved

  10. Ocular tissue concentrations of mitomycin C with variable dose and duration of application time in rabbits.

    PubMed

    Hara, T; Shirato, S; Suzuki, Y

    1998-01-01

    We measured mitomycin C (MMC) concentrations in ocular tissues in rabbits with variable dose (0.1, 0.2, or 0.4 mg) and duration of application time (1, 3, or 5 minutes) of MMC using high-performance liquid chromatography. Mitomycin C concentrations at the administered site after single subconjunctival application of MMC and after irrigation showed significant correlation with dose and duration of time of application. By multiple regression analysis, MMC concentrations (microg/g) at the conjunctiva were described as -6.73 + 67.4 x Dose (mg) + 1.66 x Time (minutes) (R2 0.65); at the sclera, -1.85 + 38.2 x Dose + 0.927 x Time (R2 0.63); at the cornea, -0.727 + 8.44 x Dose (R2 0.46). With a 0.2-mg MMC dose, in all three application times (1, 3, or 5 minutes), MMC concentrations in the conjunctiva at the administered quadrant were three times higher than in the neighboring quadrants and 6 to 7 times higher than in the opposite quadrant. In the sclera, MMC concentrations were 3.5 times higher than in the neighboring sites and over 8 to 9 times higher than in the opposite site. In the cornea, MMC concentrations were 2 to 3 times higher than in the neighboring sites and opposite site. In the iris-ciliary body, MMC concentrations were 0.61 microg/g at the administered site with 0.2 mg for 3-minute application, 2 times higher than in neighboring sites, and 2 times higher than in opposite sites.

  11. An evaluation of the TSE MR sequence for time efficient data acquisition in polymer gel dosimetry of applications involving high doses and steep dose gradients

    SciTech Connect

    Baras, P.; Seimenis, I.; Sandilos, P.; Vlahos, L.; Bieganski, T.; Georgiou, E.; Pantelis, E.; Papagiannis, P.; Sakelliou, L.

    2005-11-15

    The use of magnetic resonance imaging as a readout method for polymer gel dosimetry commonly involves long imaging sessions, particularly when high spatial resolution is required in all three dimensions, for the investigation of dose distributions with steep dose gradients and stringent dose delivery specifications. In this work, a volume selective turbo spin echo (TSE) pulse sequence is compared to the established Carr-Purcell-Meiboom-Gill (CPMG) multiecho acquisition with regard to providing accurate dosimetric results in significantly reduced imaging times. Polyethylene glycol diacrylate based (PABIG) gels were irradiated and subsequently scanned to obtain R2 relaxation rate measurements, using a CPMG multiecho sequence and a dual echo TSE utilizing an acceleration (turbo) factor of 64. R2 values, plotted against corresponding Monte Carlo dose calculations, provided calibration data of PABIG gels dose response over a wide dose range. A linear R2 versus dose relationship was demonstrated for both sequences with TSE results presenting reduced dose sensitivity. Although TSE data were found to deviate from linearity at lower doses compared to CPMG data, a relatively wide dynamic dose range of response extending up to approximately 100 Gy was observed for both sequences. The TSE and CPMG sequences were evaluated with a brachytherapy irradiation using a high dose rate {sup 192}Ir source and a gamma knife stereotactic radiosurgery irradiation with a single 4 mm collimator helmet shot. Dosimetric results obtained with the TSE and CPMG are shown to compare equally well with the expected dose distributions for these irradiations. The 60-fold scan time reduction achieved with TSE implies that this sequence could prove to be a useful tool for the introduction of polymer gel dosimetry in clinical radiation therapy applications involving high doses and steep dose gradients.

  12. 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

  13. Calculation of patient effective dose and scattered dose for dental mobile fluoroscopic equipment: application of the Monte Carlo simulation.

    PubMed

    Lee, Boram; Lee, Jungseok; Kang, Sangwon; Cho, Hyelim; Shin, Gwisoon; Lee, Jeong-Woo; Choi, Jonghak

    2013-01-01

    The objective of this study was to evaluate the patient effective dose and scattered dose from recently developed dental mobile equipment in Korea. The MCNPX 2.6 (Los Alamos National Laboratory, USA) was used in a Monte Carlo simulation to calculate both the effective and scattered doses. The MCNPX code was constructed identically as in the general use of equipment and the effective dose and scattered dose were calculated using the KTMAN-2 digital phantom. The effective dose was calculated as 906 μSv. The equivalent doses per organ were calculated via the MCNPX code, and were 32 174 and 19 μSv in the salivary gland and oesophagus, respectively. The scattered dose of 22.5-32.6 μSv of the tube side at 25 cm from the centre in anterior and posterior planes was measured as 1.4-3 times higher than the detector side of 10.5-16.0 μSv.

  14. Local application of low-dose insulin in improving wound healing after deep burn surgery

    PubMed Central

    Wang, Chejiang; Wang, Jiazhe; Feng, Jianke

    2016-01-01

    The clinical effects of local application of low-dose insulin in improving wound healing after deep burn self-skin transplantation surgery were examined. Fifty-eight patients with deep burns were selected and randomly divided into 3 groups. In the blank control group, normal saline was injected to the subcutaneous tissue of wounds; in large dose insulin group, 1.0 µ long-term suspended zinc insulin was locally injected; and in the low-dose insulin group, 0.1 µ long-term suspended zinc insulin was locally injected. The healing effects were compared. After 7 and 14 days of treatments, wound surface area in the low-dose group was significantly smaller than in the other groups, and differences were statistically significant (P<0.05); wound healing duration and infection rate for patients in the low-dose group were significantly lower, class A healing rate was significantly improved, and the differences were statistically significant (P<0.05). Insulin resistance index (HOMA-IR) in the low-dose group was significantly lower, insulin secretion index (HOMA-β) and the insulin sensitivity index (HOMA-ISI) significantly increased. The expression levels of vascular endothelial growth factor and tumor necrosis factor-α in local tissue for the low-dose group were significantly higher than those in the other two groups. Differences were statistically significant (P<0.05). In conclusion, local application of low-dose insulin can effectively improve wound healing after deep burn surgeries. PMID:27698753

  15. 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.

  16. APPLICATION AND USE OF DOSE ESTIMATING EXPOSURE MODEL (DEEM) FOR DOSE COMPARISONS AFTER EXPOSURE TO TRICHLOROETHYLENE (TCE)

    EPA Science Inventory

    Route-to-route extrapolations are a crucial step in many risk assessments. Often the doses which result In toxicological end points in one route must be compared with doses resulting from typical environmental exposures by another route. In this case we used EPA's Dose Estimati...

  17. APPLICATION AND USE OF DOSE ESTIMATING EXPOSURE MODEL (DEEM) FOR ROUTE TO ROUTE DOSE COMPARISONS AFTER EXPOSURE TO TRICHLOROETHYLENE (TCE)

    EPA Science Inventory

    Route-to-route extrapolations are a crucial step in many risk assessments. Often the doses which result In toxicological end points in one route must be compared with doses resulting from typical environmental exposures by another route. In this case we used EPA's Dose Estimati...

  18. APPLICATION AND USE OF DOSE ESTIMATING EXPOSURE MODEL (DEEM) FOR ROUTE TO ROUTE DOSE COMPARISONS AFTER EXPOSURE TO TRICHLOROETHYLENE (TCE)

    EPA Science Inventory

    Route-to-route extrapolations are a crucial step in many risk assessments. Often the doses which result In toxicological end points in one route must be compared with doses resulting from typical environmental exposures by another route. In this case we used EPA's Dose Estimati...

  19. APPLICATION AND USE OF DOSE ESTIMATING EXPOSURE MODEL (DEEM) FOR DOSE COMPARISONS AFTER EXPOSURE TO TRICHLOROETHYLENE (TCE)

    EPA Science Inventory

    Route-to-route extrapolations are a crucial step in many risk assessments. Often the doses which result In toxicological end points in one route must be compared with doses resulting from typical environmental exposures by another route. In this case we used EPA's Dose Estimati...

  20. CYTOKINE PROFILING FOR CHEMICAL SENSITIZERS: APPLICATION OF THE RIBONUCLEASE PROTECTION ASSAY AND EFFECT OF DOSE

    EPA Science Inventory

    Cytokine Profiling for Chemical Sensitizers: Application of the Ribonuclease Protection Assay and Effect of Dose. L.M. Plitnick1, S.E. Loveless3, G.S. Ladics3, M.P. Holsapple4, M.J. Selgrade2, D.M. Sailstad2 and R.J. Smialowicz2. 1UNC, Curriculum in Toxicology, Chapel Hill, NC a...

  1. CYTOKINE PROFILING FOR CHEMICAL SENSITIZERS: APPLICATION OF THE RIBONUCLEASE PROTECTION ASSAY AND EFFECT OF DOSE

    EPA Science Inventory

    Cytokine Profiling for Chemical Sensitizers: Application of the Ribonuclease Protection Assay and Effect of Dose. L.M. Plitnick1, S.E. Loveless3, G.S. Ladics3, M.P. Holsapple4, M.J. Selgrade2, D.M. Sailstad2 and R.J. Smialowicz2. 1UNC, Curriculum in Toxicology, Chapel Hill, NC a...

  2. Reduction of the rectal dose in gynecological brachytherapy: modification to the Fletcher-Suit applicator.

    PubMed

    Rosenblatt, E; Cederbaum, M; Yereslav, N; Kuten, A

    1996-01-01

    The dose to the anterior rectal wall is a known limiting factor for the delivery of radical doses of radiation to the uterine cervix with brachytherapy. We developed a modification to the Fletcher-Suit afterloading applicator, consisting of two small inflatable balloons attached to the posterior end of each colpostat. The balloons are connected to catheters that emerge from the vagina attached to the colpostat's handles. The balloons were affixed to the colpostats with a plastic adaptor and are inserted empty. After an anterior radiograph is taken, the balloons are filled with radiological contrast material and a lateral orthogonal film is made. This lateral film taken with the balloons filled with contrast typically shows a significant posterior displacement of the anterior rectal wall away from the vaginal sources. The International Commission on Radiation Units (ICRU) rectal point is then determined 5 mm beyond the posterior boundary of the opacified balloons. We have performed 90 applications using this device, including brachytherapy applications for cervical cancer, as well as vaginal applications for endometrial carcinoma following TAH-BSO. On average, the ICRU rectal point was displaced 14 mm away from the colpostats, thus reducing the dose rate by 60% and resulting in an average dose sparing of about 1000 cGy to the anterior rectal wall.

  3. Bleomycin: female-specific dominant lethal effects in mice.

    PubMed

    Sudman, P D; Rutledge, J C; Bishop, J B; Generoso, W M

    1992-12-01

    Limited comparative data in mice indicate that chemical mutagens that induce dominant lethal mutations in males are not necessarily effective in females, but those which are effective in females are generally equally or more effective in males. Recently, however, a few chemicals have been identified that are female-specific with respect to induction of dominant lethal mutations. The antitumor antibiotic adriamycin is among them. Another antitumor antibiotic, bleomycin was examined for its ability to induce dominant lethal mutations in the reproductive cells of male and female mice. No dominant lethal or cytotoxic effects were observed in males treated with bleomycin, even at a maximum tolerated dose. In females, on the other hand, a dose nearly 1/4 of that used in males induced not only a high level of dominant lethal mutations but also killed oocytes in certain stages of follicular development. The effectiveness of bleomycin in inducing dominant lethal mutations in mouse oocytes makes it a valuable tool for investigating whether gonadal transport, inherent differences in the configuration of chromatin in the germ cells of the two sexes or other factors are responsible for the differential susceptibility to bleomycin, which implies potential gender-specific genetic risk in cancer chemotherapy.

  4. 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

  5. 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

  6. Application of Dempster-Shafer theory in dose response outcome analysis

    NASA Astrophysics Data System (ADS)

    Chen, Wenzhou; Cui, Yunfeng; He, Yanyan; Yu, Yan; Galvin, James; Hussaini, Yousuff M.; Xiao, Ying

    2012-09-01

    The Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) reviews summarize the currently available three-dimensional dose/volume/outcome data from multi-institutions and numerous articles to update and refine the normal tissue dose/volume tolerance guidelines. As pointed out in the review, the data have limitations and even some inconsistency. However, with the help of new physical and statistical techniques, the information in the review could be updated so that patient care can be continually improved. The purpose of this work is to demonstrate the application of a mathematical theory, the Dempster-Shafer theory, in dose/volume/outcome data analysis. We applied this theory to the original data obtained from published clinical studies describing dose response for radiation pneumonitis. Belief and plausibility concepts were introduced for dose response evaluation. We were also able to consider the uncertainty and inconsistency of the data from these studies with Yager's combination rule, a special methodology of Dempster-Shafer theory, to fuse the data at several specific doses. The values of belief and plausibility functions were obtained at the corresponding doses. Then we applied the Lyman-Kutcher-Burman (LKB) model to fit these values and a belief-plausibility range was obtained. This range could be considered as a probability range to assist physicians and treatment planners in determining acceptable dose-volume constraints. Finally, the parameters obtained from the LKB model fitting were compared with those in Emami and Burman's papers and those from other frequentist statistics methods. We found that Emami and Burman's parameters are within the belief-plausibility range we calculated by the Dempster-Shafer theory.

  7. 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.

  8. Application of solid state integrating dosemeters to the determination of biologically equivalent doses in space.

    PubMed

    Yasuda, H

    2002-01-01

    If the biological responses are well approximated by the efficiencies of solid-state integrating dosemeters (SSID), the biologically equivalent doses can be simply estimated using SSID. For demonstrating the applicability of this method to space radiation dosimetry, biologically equivalent doses for two biological endpoints (enzyme inactivation and cell survival) were evaluated in the 8.8 d Shuttle-Mir mission (STS-89) using three commercial thermoluminescence dosemeters: Mg2SiO4:Tb, BeO:Na and 7LiF:Mg,Ti. The approximate biologically equivalent doses at two positions in the Spacehab module were found to be significantly different for trypsin inactivation, whereas they were almost identical for mammalian cell survival.

  9. Mixed-effects Gaussian process functional regression models with application to dose-response curve prediction.

    PubMed

    Shi, J Q; Wang, B; Will, E J; West, R M

    2012-11-20

    We propose a new semiparametric model for functional regression analysis, combining a parametric mixed-effects model with a nonparametric Gaussian process regression model, namely a mixed-effects Gaussian process functional regression model. The parametric component can provide explanatory information between the response and the covariates, whereas the nonparametric component can add nonlinearity. We can model the mean and covariance structures simultaneously, combining the information borrowed from other subjects with the information collected from each individual subject. We apply the model to dose-response curves that describe changes in the responses of subjects for differing levels of the dose of a drug or agent and have a wide application in many areas. We illustrate the method for the management of renal anaemia. An individual dose-response curve is improved when more information is included by this mechanism from the subject/patient over time, enabling a patient-specific treatment regime.

  10. Radiation crosslinking of CMC-Na at low dose and its application as substitute for hydrogel

    NASA Astrophysics Data System (ADS)

    Liu, Pengfei; Peng, Jing; Li, Jiuqiang; Wu, Jilan

    2005-04-01

    The slight radiation-crosslinked CMC-Na as a substitute for hydrogel was prepared by gamma irradiation below gelation dose. The effects of various parameters such as absorbed dose, concentration of inorganic salts, pH, swelling temperature and swelling time on the swelling ratio in water were investigated in detail. This kind of slight crosslinked CMC-Na showed good water absorption below 60°C, whereas, it became solution when heated up to 70°C. Such CMC-Na gel is different from the true gel that is insoluble in boiled water; nevertheless, it can be used as hydrogel at room temperature and produced at low dose. Due to its low cost, it might be useful for its application in agriculture or others.

  11. 2005 Non-Lethal Defense VI Symposium

    DTIC Science & Technology

    2005-03-16

    Untitled Document 2005 Non Lethal Defense VI Symposium.html[8/22/2016 9:24:13 AM] Non- Lethal Defense "VI" Symposium “Non- Lethal Weapon Options in...Current and Desired Capabilities Forum Army Non- Lethal Requirements, Brigadier General Coker, USA, TRADOC Successful Non- Lethal Illegal Alien...Interdiction Case, Rear Admiral Kunkle, USCG, Non Lethal IPT Member Luncheon Keynote Speaker, by Lieutenant General Jan Huly, USMC, Deputy Commandant for Plans

  12. A generic TG-186 shielded applicator for commissioning model-based dose calculation algorithms for high-dose-rate (192) Ir brachytherapy.

    PubMed

    Ma, Yunzhi; Vijande, Javier; Ballester, Facundo; Carlsson Tedgren, Åsa; Granero, Domingo; Haworth, Annette; Mourtada, Firas; Fonseca, Gabriel Paiva; Zourari, Kyveli; Papagiannis, Panagiotis; Rivard, Mark J; Siebert, Frank André; Sloboda, Ron S; Smith, Ryan; Chamberland, Marc J P; Thomson, Rowan M; Verhaegen, Frank; Beaulieu, Luc

    2017-07-19

    A joint working group was created by the American Association of Physicists in Medicine (AAPM), the European Society for Radiotherapy and Oncology (ESTRO), and the Australasian Brachytherapy Group (ABG) with the charge, among others, to develop a set of well-defined test case plans and perform model-based dose calculation algorithms (MBDCA) dose calculations and comparisons. Its main goal is to facilitate a smooth transition from the AAPM Task Group No. 43 (TG-43) dose calculation formalism, widely being used in clinical practice for brachytherapy, to the one proposed by Task Group No. 186 (TG-186) for MBDCAs. To do so, in this work a hypothetical, generic high-dose rate (HDR) (192) Ir shielded applicator has been designed and benchmarked. A generic HDR (192) Ir shielded applicator was designed based on three commercially available gynecological applicators as well as a virtual cubic water phantom that can be imported into any DICOM-RT compatible treatment planning system (TPS). The absorbed dose distribution around the applicator with the TG-186 (192) Ir source located at one dwell position at its center was computed using two commercial TPSs incorporating MBDCAs (Oncentra(®) Brachy with Advanced Collapsed-cone Engine, ACE(™) , and BrachyVision ACUROS(™) ) and state-of-the-art Monte Carlo (MC) codes, including ALGEBRA, BrachyDose, egs_brachy, Geant4, MCNP6, and Penelope2008. TPS-based volumetric dose distributions for the previously reported "source centered in water" and "source displaced" test cases, and the new "source centered in applicator" test case, were analyzed here using the MCNP6 dose distribution as a reference. Volumetric dose comparisons of TPS results against results for the other MC codes were also performed. Distributions of local and global dose difference ratios are reported. The local dose differences among MC codes are comparable to the statistical uncertainties of the reference datasets for the "source centered in water" and "source

  13. 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.

  14. Application of Bayes theorem to aminoglycoside-associated nephrotoxicity: comparison of extended-interval dosing, individualized pharmacokinetic monitoring, and multiple-daily dosing.

    PubMed

    Kim, Myong-Jin; Bertino, Joseph S; Erb, Tara A; Jenkins, Paul L; Nafziger, Anne N

    2004-07-01

    The objective of this study was to examine the incidence of aminoglycoside-associated nephrotoxicity related to extended-interval dosing, individualized pharmacokinetic monitoring, and multiple-daily dosing by applying Bayes theorem. An electronic literature search of MEDLINE (1966-2003) and a manual search of references from published meta-analyses and review articles were performed. Studies using extended-interval dosing, individualized pharmacokinetic monitoring, or multiple-daily dosing and reported aminoglycoside-associated nephrotoxicity for patients > or = 16 years of age were included. Quality scores were assigned based on the rigor of definition of aminoglycoside-associated nephrotoxicity, duration of therapy, and length of follow-up of renal function after completion of therapy. Inclusion criteria were then based on these quality scores. Quantitative data on the incidence of aminoglycoside-associated nephrotoxicity were abstracted. Twelve extended-interval dosing studies (n = 916), 10 individualized pharmacokinetic monitoring studies (n = 2066), and 27 multiple-daily dosing studies (n = 4251) met the inclusion criteria. Prior probabilities of aminoglycoside-associated nephrotoxicity were derived from a combination of a review of published studies and expert judgment. The maximum densities for the final posterior probabilities of aminoglycoside-associated nephrotoxicity for extended-interval dosing, individualized pharmacokinetic monitoring, and multiple-daily dosing were located at 12% to 13%, 10% to 11%, and 13% to 14%, respectively. Application of Bayes theorem demonstrates that aminoglycoside dosing by individualized pharmacokinetic monitoring results in less aminoglycoside-associated nephrotoxicity than extended-interval dosing or multiple-daily dosing.

  15. Application of the optimal design approach to improve a pretransplant drug dose finding design for ciclosporin.

    PubMed

    Hennig, Stefanie; Nyberg, Joakim; Fanta, Samuel; Backman, Janne T; Hoppu, Kalle; Hooker, Andrew C; Karlsson, Mats O

    2012-03-01

    A time and sampling intensive pretransplant test dose design was to be reduced, but at the same time optimized so that there was no loss in the precision of predicting the individual pharmacokinetic (PK) estimates of posttransplant dosing. The following variables were optimized simultaneously: sampling times, ciclosporin dose, time of second dose, infusion duration, and administration order, using a published ciclosporin population PK model as prior information. The original design was reduced from 22 samples to 6 samples/patient and both doses (intravenous oral) were administered within 8 hours. Compared with the prior information given by the published ciclosporin population PK model, the expected standard deviations (SDs) of the individual parameters for clearance and bioavailability could be reduced by, on average, 40% under the optimized sparse designs. The gain of performing the original rich design compared with the optimal reduced design, considering the standard errors of the parameter estimates, was found to be minimal. This application demonstrates, in a practical clinical scenario, how optimal design techniques may be used to improve diagnostic procedures given available software and methods.

  16. The application of cassette dosing for pharmacokinetic screening in small-molecule cancer drug discovery.

    PubMed

    Smith, Nicola F; Raynaud, Florence I; Workman, Paul

    2007-02-01

    Pharmacokinetic evaluation is an essential component of drug discovery and should be conducted early in the process so that those compounds with the best chance of success are prioritized and progressed. However, pharmacokinetic analysis has become a serious bottleneck during the 'hit-to-lead' and lead optimization phases due to the availability of new targets and the large numbers of compounds resulting from advances in synthesis and screening technologies. Cassette dosing, which involves the simultaneous administration of several compounds to a single animal followed by rapid sample analysis by liquid chromatography/tandem mass spectrometry, was developed to increase the throughput of in vivo pharmacokinetic screening. Although cassette dosing is advantageous in terms of resources and throughput, there are possible complications associated with this approach, such as the potential for compound interactions. Following an overview of the cassette dosing literature, this article focuses on the application of the technique in anticancer drug discovery. Specific examples are discussed, including the evaluation of cassette dosing to assess pharmacokinetic properties in the development of cyclin-dependent kinase and heat shock protein 90 inhibitors. Subject to critical analysis and validation in each case, the use of cassette dosing is recommended in appropriate chemical series to enhance the efficiency of drug discovery and reduce animal usage.

  17. Application of mathematical model to multiple-dose experimental chemotherapy for fatal murine pneumonia.

    PubMed Central

    Hishikawa, T; Kusunoki, T; Tsuchiya, K; Uzuka, Y; Sakamoto, T; Nagatake, T; Matsumoto, K

    1991-01-01

    Two beta-lactam antibiotics, cefazolin and cefmenoxime, were administered for 7 days to mice with pneumonia caused by Klebsiella pneumoniae by using dosage regimens that would simulate multiple dosing in usual clinical treatments at dosing intervals of 8 or 12 h. Viable numbers of the bacteria in the lungs were measured at 12- or 24-h intervals. The mathematical model established in a previous single-dose study was applied in this study to explain the time courses of the changes in bacterial count over 7 days. However, because the error in viable count measurements was larger than that in the previous study, the time course of the changes in mean viable count was not regular and the viable count reduction rate changed during multiple dosing, and therefore it was difficult to explain the time course by repeated application of the mathematical model described previously. This study suggests that the changes in pharmacokinetic and pharmacodynamic parameters during multiple dosing need to be considered. PMID:1929244

  18. [Application of adaptive iterative dose reduction technique in CT enterography in diagnosing Crohn disease].

    PubMed

    Lian, Yanbang; Cao, Wuteng; Zhu, Shanshan; Lin, Yanghao; Liu, Dechao; Wang, Xinhua; Qiu, Jianping; Zhou, Zhiyang

    2014-07-01

    To evaluate the application of low-dose CT enterography with adaptive iterative dose reduction(AIDR) technique in diagnosing Crohn's disease. Retrospective analysis was performed on 26 patients diagnosed as Crohn's disease by the multidisciplinary team in our hospital. Low-dose CT enterography with 640-slice MDCT was performed on these 26 patients using adaptive iterative dose reduction(AIDR) technique. Characteristics of Crohn's disease in CT enterography images were independently analyzed by two radiologists who were experienced in Crohn's disease with calculating the total radiation dosage. The radiation dosage of 26 patients ranged from 5.58 to 12.90 [mean (9.00±2.00)] mSv, which was lower than conventional scan (around 15 mSv) known from the literatures. According to the images of CT enterography of 26 cases, bowel wall thickening with abnormal enhancement and lymphadenectasis were found in 25 cases with total 109 segmental bowel wall thickening. Among 25 thickening cases, enterostenosis was found in 16 cases, stratification enhancement in 12 cases and comb sign in 14 cases. Besides, it was found that 8 cases with hyperdense fat on the mesenteric side, 7 cases with intestinal fistula, 6 cases with abdominal cavity abscess, and 3 cases with anal fistula. CT enterography of Crohn's disease with adaptive iterative dose reduction technique is an effective method to evaluate Crohn's disease without compromising image quality with reduced radiation dosage.

  19. Lethality and entropy of protein interaction networks.

    PubMed

    Manke, Thomas; Demetrius, Lloyd; Vingron, Martin

    2005-01-01

    We characterize protein interaction networks in terms of network entropy. This approach suggests a ranking principle, which strongly correlates with elements of functional importance, such as lethal proteins. Our combined analysis of protein interaction networks and functional profiles in single cellular yeast and multi-cellular worm shows that proteins with large contribution to network entropy are preferentially lethal. While entropy is inherently a dynamical concept, the present analysis incorporates only structural information. Our result therefore highlights the importance of topological features, which appear as correlates of an underlying dynamical property, and which in turn determine functional traits. We argue that network entropy is a natural extension of previously studied observables, such as pathway multiplicity and centrality. It is also applicable to networks in which the processes can be quantified and therefore serves as a link to study questions of structural and dynamical robustness in a unified way.

  20. Lethal post-tonsillectomy hemorrhage.

    PubMed

    Windfuhr, Jochen P

    2003-12-01

    Post-tonsillectomy hemorrhage (PTH) seems to be a rare but unavoidable complication. Due to the frequency of performed tonsillectomies, it can be estimated that a certain amount may result in a lethal outcome. This study was undertaken to evaluate the clinical features of these rare cases. Retrospective case series of five patients with lethal post-tonsillectomy hemorrhage are reported after they had undergone tonsillectomy by four different surgeons. The relevant literature was reviewed. The youngest patient was 42 months and the oldest almost 13 years old. All patients were male. Three patients had left the hospital against surgeon's recommendation 5 days following tonsillectomy. Preceding episodes of bleeding prior to the lethal bleeding occurred in two patients. Lethal PTH occurred in four patients within 5-9 days, the latest bleeding 39 days after surgery. In the literature, lethal PTH was described for eight patients since 1958. The youngest patient was 4 years, the oldest 18 years old (mean: 8.6 years; median: 6.5 years). In three patients, lethal PTH occurred on the day of surgery and the latest bleeding 54 days after surgery. Due to the paucity of reports, little reliable information can be obtained from the literature. It remains unclear, whether or not this reflects the true incidence of this complication. The experience with the five reported cases suggests, that immediate surgical treatment may have avoided lethal outcome in most cases. Therefore, a close postoperative follow-up is advisable to detect any episode of bleeding as soon as possible which should be referred to a specialist. Certainly, the collected data do not suffice to establish general guidelines, indicating that further collection of cases is required to assess characteristics of lethal PTH.

  1. 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.

  2. Comparative study of the assay of Artemia salina L. and the estimate of the medium lethal dose (LD50 value) in mice, to determine oral acute toxicity of plant extracts.

    PubMed

    Logarto Parra, A; Silva Yhebra, R; Guerra Sardiñas, I; Iglesias Buela, L

    2001-09-01

    Artemia salina L. (Artemiidae), the brine shrimp larva, is an invertebrate used in the alternative test to determine toxicity of chemical and natural products. In this study the Medium Lethal Concentrations (LC50 value) of 20 plant extracts, Aloe vera (L.) Burm. F. (Aloeaceae), Artemisia absinthium L. (Asteraceae); Citrus aurantium L. (Rutaceae); Cymbopogon citratus (DC. Ex Nees) Stapf (Poaceae); Datura stramonium L. (Solanaceae); Justicia pectoralis Jacq. (Acanthaceae); Musa x paradisiaca L. (Musaceae); Ocimum basilicum L.; O. gratissimum L.; O. tenuiflorum L. (Lamiaceae); Pimenta dioica (L.) Merr. (Myrtaceae); Piper auritum Kunth (Piperaceae); Plantago major L. (Plantaginaceae); Plectranthus amboinicus (Lour.) Spreng. (Lamiaceae); Ruta graveolens L. (Rutaceae); Senna alata (L.) Roxb. (Fabaceae); Stachytarpheta jamaicensis (L.) Vahl (Verbenaceae); and Thuja occidentalis L. (Cupressaceae), were determined using Artemia salina L. (Artemiidae), with the objective of relating the results to the LD50 values reported in mice (tested at three concentrations: 10, 100, and 1000 microg/mL, for each extract). We found good correlation between the in vivo and the in vitro tests (r = 0.85 p < 0.05), and this method is a useful tool for predicting oral acute toxicity in plant extracts.

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

    SciTech Connect

    Sinha, Neeharika; Cifter, Gizem; Sajo, Erno; Kumar, Rajiv; Sridhar, Srinivas; Nguyen, Paul L.; Cormack, Robert A.; Makrigiorgos, G. Mike; Ngwa, Wilfred

    2015-02-01

    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 the 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 application with

  4. Application of the new MultiTrans SP3 radiation transport code in BNCT dose planning.

    PubMed

    Kotiluoto, P; Hiisamäki, P; Savolainen, S

    2001-09-01

    Dose planning in boron neutron capture therapy (BNCT) is a complex problem and requires sophisticated numerical methods. In the framework of the Finnish BNCT project, new deterministic three-dimensional radiation transport code MultiTrans SP3 has been developed at VTT Chemical Technology, based on a novel application of the tree multigrid technique. To test the applicability of this new code in a realistic BNCT dose planning problem, cylindrical PMMA (polymethyl-methacrylate) phantom was chosen as a benchmark case. It is a convenient benchmark, as it has been modeled by several different codes, including well-known DORT and MCNP. Extensive measured data also exist. In this paper, a comparison of the new MultiTrans SP3 code with other methods is presented for the PMMA phantom case. Results show that the total neutron dose rate to ICRU adult brain calculated by the MultiTrans SP3 code differs less than 4% in 2 cm depth in phantom (in thermal maximum) from the DORT calculation. Results also show that the calculated 197Au(n,gamma) and 55Mn(n,gamma) reaction rates in 2 cm depth in phantom differ less than 4% and 1% from the measured values, respectively. However, the photon dose calculated by the MultiTrans SP3 code seems to be incorrect in this PMMA phantom case, which requires further studying. As expected, the deterministic MultiTrans SP3 code is over an order of magnitude faster than stochastic Monte Carlo codes (with similar resolution), thus providing a very efficient tool for BNCT dose planning.

  5. 3D image-based adapted high-dose-rate brachytherapy in cervical cancer with and without interstitial needles: measurement of applicator shift between imaging and dose delivery

    PubMed Central

    Thunberg, Per; With, Anders; Mordhorst, Louise Bohr; Persliden, Jan

    2017-01-01

    Purpose Using 3D image-guided adaptive brachytherapy for cervical cancer treatment, it often means that patients are transported and moved during the treatment procedure. The purpose of this study was to determine the intra-fractional longitudinal applicator shift in relation to the high risk clinical target volume (HR-CTV) by comparing geometries at imaging and dose delivery for patients with and without needles. Material and methods Measurements were performed in 33 patients (71 fractions), where 25 fractions were without and 46 were with interstitial needles. Gold markers were placed in the lower part of the cervix as a surrogate for HR-CTV, enabling distance measurements between HR-CTV and the ring applicator. Shifts of the applicator relative to the markers were determined using planning computed tomography (CT) images used for planning, and the radiographs obtained at dose delivery. Differences in the physical D90 for HR-CTV due to applicator shifts were simulated individually in the treatment planning system to provide the relative dose variation. Results The maximum distances of the applicator shifts, in relation to the markers, were 3.6 mm (caudal), and –2.5 mm (cranial). There was a significant displacement of –0.7 mm (SD = 0.9 mm) without needles, while with needles there was no significant shift. The relative dose variation showed a significant increase in D90 HR-CTV of 1.6% (SD = 2.6%) when not using needles, and no significant dose variation was found when using needles. Conclusions The results from this study showed that there was a small longitudinal displacement of the ring applicator and a significant difference in displacement between using interstitial needles or not. PMID:28344604

  6. 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.

  7. Sub-lethal toxicity of the antiparasitic abamectin on earthworms and the application of neutral red retention time as a biomarker.

    PubMed

    Jensen, John; Diao, Xiaoping; Scott-fordsmand, Janeck J

    2007-06-01

    The antiparasitic abamectin has been proven effective against both endo- and ectoparasites of farm animals and hence used widely in animal husbandry. It may enter the soil environment with the excreta of treated animals. Very little information is available with regard to the sub-lethal effects of abamectin on soil invertebrates, such as earthworms. The objective of this study was to evaluate the toxic effect of abamectin on earthworms, using Eisenia fetida, by analyzing changes in the survival, growth, reproduction and cocoon hatchability of exposed earthworms. Furthermore, a biomarker of the lysosomal membrane stability, measured by neutral red retention time (NRR-time), was also applied. Abamectin showed significant toxicity on the growth of earthworms with increasing concentrations up to 5mg/kg. The most sensitive parameter was reproduction (cocoons production and hatchability) and NRR-time. The number of cocoons was reduced at concentrations above 0.25mg/kg and no cocoons were present at the highest concentration of 5mg/kg. Cocoons exposed to abamectin exhibited a reduced hatching success at concentrations above 1.5mg/kg. The NRR-time was reduced significantly at exposure concentrations of abamectin above 0.25mg/kg. The change in lysosomal membrane stability showed a good correlation with reproduction and may hence be a potential predicator of the effects on earthworm populations.

  8. 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.

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

    SciTech Connect

    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: 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. 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

  10. Application of Low-dose Stereoradiography in In Vivo Vertebral Morphologic Measurements: Comparison With Computed Tomography.

    PubMed

    Pasha, Saba; Schlösser, Tom; Zhu, Xiaowei; Mellor, Xochitl; Castelein, René; Flynn, John

    2017-06-30

    Though computed tomography (CT) and 3 dimensional (3D) reconstruction of the spine and ribcage are powerful techniques for detailed monitoring of spinal growth and surgical planning of patients, drawbacks can arise. We explored the application of low-dose stereoradiography of the spine to calculate distinct morphologic parameters of the vertebral body in a juvenile patient population with early-onset scoliosis or congenital scoliosis. This study compares the 3D vertebral morphology measurements using low-dose stereoradiography with the currently accepted imaging modality for such measurements, CT scans. A total of 86 vertebrae of 6 patients with early-onset scoliosis and 3 patients with congenital scoliosis, age ranged between 7.8 and 12.5 years, who had both thoracic spine CT scan and low-dose stereoradiography of the spine were included. 3D reconstructions of CT and low-dose stereoradiography were generated. Using previously validated image processing techniques, vertebral anterior (A), posterior (P), left (L), and right (R) heights, superior and inferior endplates depth and width (S-D, I-D, S-W, I-W) were measured on the CTs' 3D reconstructions and were compared with the same parameters measured on low-dose stereoradiography reconstructions using a postprocessing custom code. The agreement between the 2 techniques in measurement of the vertebral morphology was assessed using the Bland-Altman plots. No significant difference was observed in the A, P, L, R, S-W, and I-W between the stereoradiography and CT measurements (P>0.05). S-D and I-D were significantly greater in low-dose stereoradiography measurements P<0.05. Bland-Altman plots showed an agreement between the stereoradiography and CT techniques in vertebral height measurements (A, P, L, R); however, larger measurement bias and greater limits of agreement in S-D, I-D, S-W, and I-W measurements were shown. In vivo measurements of the vertebral heights using low-dose stereoradiography 3D reconstructions were

  11. Evaluation of low energy electron beam dose application by means of a portable optical device

    NASA Astrophysics Data System (ADS)

    Reitzig, Manuela; Winkler, Martin; Härtling, Thomas; Röder, Olaf; Opitz, Jörg

    2014-11-01

    We present our recent development concerning the evaluation of a low energy dose application to electron beam responding materials with a simple portable optical device. Electron beam irradiation is a promising option to sterilize sensitive and high performance products or surfaces at a low temperature and without moisture. Especially in the fields of the food industry and medicine, regulations regarding sterility are increasingly tightened. Because of this, a secure proof for electron-beam-assisted sterilization is required. However, no nondestructive and in situ method exists up until now. Our approach to provide a secure proof of sterilization is to place a suitable marker material based on rare-earth-doped phosphors inside or on the top of the packaging material of the respective product. Upon electron irradiation the marker material changes its luminescence properties as a function of the applied energy dose. We verified the energy dependence by means of time-resolved measurements of the luminescence decay of an upconversion phosphor with a portable optical device. In our experimental realization, short laser pulses in the near-infrared range are triggered by a microcontrol unit (MCU) and excite the marker material. The light emitted by the marker is collected in the range between 400 and 1100 nm via a silicon photodiode, processed by the MCU, and analyzed in a Labview program via a single-exponential fit. As a main result, we observe an increasing reduction of the luminescence lifetime with higher dose applications.

  12. A lethal combination for cancer cells: synthetic lethality screenings for drug discovery.

    PubMed

    Ferrari, Elisa; Lucca, Chiara; Foiani, Marco

    2010-11-01

    In recent years, cancer drug discovery has faced the challenging task of integrating the huge amount of information coming from the genomic studies with the need of developing highly selective target-based strategies within the context of tumour cells that experience massive genome instability. The combination between genetic and genomic technologies has been extremely useful and has contributed to efficiently transfer certain approaches typical of basic science to drug discover projects. An example comes from the synthetic lethal approaches, very powerful procedures that employ the rational used by geneticists working on model organisms. Applying the synthetic lethality (SL) screenings to anticancer therapy allows exploiting the typical features of tumour cells, such as genome instability, without changing them, as opposed to the conventional anticancer strategies that aim at counteracting the oncogenic signalling pathways. Recent and very encouraging clinical studies clearly show that certain promising anticancer compounds work through a synthetic lethal mechanism by targeting pathways that are specifically essential for the viability of cancer cells but not of normal cells. Herein we describe the rationale of the synthetic lethality approaches and the potential applications for anticancer therapy.

  13. Passive Immunization against Cachectin/Tumor Necrosis Factor Protects Mice from Lethal Effect of Endotoxin

    NASA Astrophysics Data System (ADS)

    Beutler, B.; Milsark, I. W.; Cerami, A. C.

    1985-08-01

    A highly specific polyclonal rabbit antiserum directed against murine cachectin/tumor necrosis factor (TNF) was prepared. When BALB/c mice were passively immunized with the antiserum or with purified immune globulin, they were protected against the lethal effect of the endotoxin lipopolysaccharide produced by Escherichia coli. The prophylactic effect was dose-dependent and was most effective when the antiserum was administered prior to the injection of the endotoxin. Antiserum to cachectin/TNF did not mitigate the febrile response of endotoxin-treated animals, and very high doses of endotoxin could overcome the protective effect. The median lethal dose of endotoxin in mice pretreated with 50 microliters of the specific antiserum was approximately 2.5 times greater the median lethal dose for controls given nonimmune serum. The data suggest that cachectin/TNF is one of the principal mediators of the lethal effect of endotoxin.

  14. 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.

  15. How and When Do Insects Rely on Endogenous Protein and Lipid Resources during Lethal Bouts of Starvation? A New Application for 13C-Breath testing.

    PubMed

    McCue, Marshall D; Guzman, R Marena; Passement, Celeste A; Davidowitz, Goggy

    2015-01-01

    Most of our understanding about the physiology of fasting and starvation comes from studies of vertebrates; however, for ethical reasons, studies that monitor vertebrates through the lethal endpoint are scant. Insects are convenient models to characterize the comparative strategies used to cope with starvation because they have diverse life histories and have evolved under the omnipresent challenge of food limitation. Moreover, we can study the physiology of starvation through its natural endpoint. In this study we raised populations of five species of insects (adult grasshoppers, crickets, cockroaches, and larval beetles and moths) on diets labeled with either 13C-palmitic acid or 13C-leucine to isotopically enrich the lipids or the proteins in their bodies, respectively. The insects were allowed to become postabsorptive and then starved. We periodically measured the δ13C of the exhaled breath to characterize how each species adjusted their reliance on endogenous lipids and proteins as energy sources. We found that starving insects employ a wide range of strategies for regulating lipid and protein oxidation. All of the insects except for the beetle larvae were capable of sharply reducing reliance on protein oxidation; however, this protein sparing strategy was usually unsustainable during the entire starvation period. All insects increased their reliance on lipid oxidation, but while some species (grasshoppers, cockroaches, and beetle larvae) were still relying extensively on lipids at the time of death, other species (crickets and moth larvae) allowed rates of lipid oxidation to return to prestarvation levels. Although lipids and proteins are critical metabolic fuels for both vertebrates and insects, insects apparently exhibit a much wider range of strategies for rationing these limited resources during starvation.

  16. How and When Do Insects Rely on Endogenous Protein and Lipid Resources during Lethal Bouts of Starvation? A New Application for 13C-Breath testing

    PubMed Central

    McCue, Marshall D.; Guzman, R. Marena; Passement, Celeste A.; Davidowitz, Goggy

    2015-01-01

    Most of our understanding about the physiology of fasting and starvation comes from studies of vertebrates; however, for ethical reasons, studies that monitor vertebrates through the lethal endpoint are scant. Insects are convenient models to characterize the comparative strategies used to cope with starvation because they have diverse life histories and have evolved under the omnipresent challenge of food limitation. Moreover, we can study the physiology of starvation through its natural endpoint. In this study we raised populations of five species of insects (adult grasshoppers, crickets, cockroaches, and larval beetles and moths) on diets labeled with either 13C-palmitic acid or 13C-leucine to isotopically enrich the lipids or the proteins in their bodies, respectively. The insects were allowed to become postabsorptive and then starved. We periodically measured the δ13C of the exhaled breath to characterize how each species adjusted their reliance on endogenous lipids and proteins as energy sources. We found that starving insects employ a wide range of strategies for regulating lipid and protein oxidation. All of the insects except for the beetle larvae were capable of sharply reducing reliance on protein oxidation; however, this protein sparing strategy was usually unsustainable during the entire starvation period. All insects increased their reliance on lipid oxidation, but while some species (grasshoppers, cockroaches, and beetle larvae) were still relying extensively on lipids at the time of death, other species (crickets and moth larvae) allowed rates of lipid oxidation to return to prestarvation levels. Although lipids and proteins are critical metabolic fuels for both vertebrates and insects, insects apparently exhibit a much wider range of strategies for rationing these limited resources during starvation. PMID:26465334

  17. Lethal Amanita species in China.

    PubMed

    Cai, Qing; Cui, Yang-Yang; Yang, Zhu L

    2016-09-01

    Lethal amanitas (Amanita sect. Phalloideae) cause many casualties worldwide. Recent molecular phylogenetic studies revealed diverse lethal Amanita spp. in China. Here a 5-gene phylogeny (nuc rDNA region encompassing the internal transcribed spacers 1 and 2 with the 5.8S rDNA, the D1-D3 domains of nuc 28S rDNA, and partial RNA polymerase II second largest subunit, translation elongation factor 1-α and β-tubulin genes) is used to investigate the phylogenetic lineages and species delimitation in this section. Thirteen species are recognized, including four new species, namely A. griseorosea, A. molliuscula, A. parviexitialis, and A. subfuliginea They are documented with morphological, multigene phylogenetic, and ecological evidence, line drawings, and photographs and compared with similar species. A key to the Chinese lethal Amanita species is provided.

  18. Considerations in the application of the electronic dosimeter to dose of record

    SciTech Connect

    Swinth, K.L.

    1997-12-01

    This report describes considerations for application of the electronic dosimeter (ED) as a measurement device for the dose of record (primary dosimetry). EDs are widely used for secondary dosimetry and advances in their reliability and capabilities have resulted in interest in their use to meet the needs of both primary and secondary dosimetry. However, the ED is an active device and more complex than the thermoluminescent and film dosimeters now in use for primary dosimetry. The user must evaluate the ED in terms of reliability, serviceability and radiations detected its intended application(s). If an ED is selected for primary dosimetry, the user must establish methods both for controlling the performance of the ED to ensure long term reliability of the measurements and for their proper use as a primary dosimeter. Regulatory groups may also want to develop methods to ensure adequate performance of the ED for dose of record. The purpose of the report is to provide an overview of considerations in the use of the ED for primary dosimetry. Considerations include recognizing current limitations, type testing of EDs, testing by the user, approval performance testing, calibration, and procedures to integrate the dosimeter into the users program.

  19. Synthetic lethal interactions for the development of cancer therapeutics: biological and methodological advancements.

    PubMed

    Mizuarai, Shinji; Kotani, Hidehito

    2010-12-01

    Synthetic lethal interaction is defined as a combination of two mutations that is lethal when present in the same cell; each individual mutation is non-lethal. Synthetic lethal interactions attract attention in cancer research fields since the discovery of synthetic lethal genes with either oncogenes or tumor suppressor genes (TSGs) provides novel cancer therapeutic targets. Due to the selective lethal effect on cancer cells harboring specific genetic alterations, it is expected that targeting synthetic lethal genes would provide wider therapeutic windows compared with cytotoxic chemotherapeutics. Here, we review the current status of the application of synthetic lethal screening in cancer research fields from biological and methodological viewpoints. Very recent studies seeking to identify synthetic lethal genes with K-RAS and p53, which are known to be the most frequently occurring oncogenes and TSGs, respectively, are introduced. Among the accumulating amount of research on synthetic lethal interactions, the synthetic lethality between BRCA1/2 and PARP1 inhibition has been clinically proven. Thus, both preclinical and clinical data showing a preferential anti-tumor effect on BRCA1/2 deficient tumors by a PARP1 inhibitor are the best examples of the synthetic lethal approach of cancer therapeutics. Finally, methodological progress regarding synthetic lethal screening, including barcode shRNA screening and in vivo synthetic lethal screening, is described. Given the fact that an increasing number of synthetic lethal genes for major cancerous genes have been validated in preclinical studies, this intriguing approach awaits clinical verification of preferential benefits for cancer patients with specific genetic alterations as a clear predictive factor for tumor response.

  20. 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

  1. Fast on-site Monte Carlo tool for dose calculations in CT applications.

    PubMed

    Chen, Wei; Kolditz, Daniel; Beister, Marcel; Bohle, Robert; Kalender, Willi A

    2012-06-01

    Monte Carlo (MC) simulation is an established technique for dose calculation in diagnostic radiology. The major drawback is its high computational demand, which limits the possibility of usage in real-time applications. The aim of this study was to develop fast on-site computed tomography (CT) specific MC dose calculations by using a graphics processing unit (GPU) cluster. GPUs are powerful systems which are especially suited to problems that can be expressed as data-parallel computations. In MC simulations, each photon track is independent of the others; each launched photon can be mapped to one thread on the GPU, thousands of threads are executed in parallel in order to achieve high performance. For further acceleration, the authors considered multiple GPUs. The total computation was divided into different parts which can be calculated in parallel on multiple devices. The GPU cluster is an MC calculation server which is connected to the CT scanner and computes 3D dose distributions on-site immediately after image reconstruction. To estimate the performance gain, the authors benchmarked dose calculation times on a 2.6 GHz Intel Xeon 5430 Quad core workstation equipped with two NVIDIA GeForce GTX 285 cards. The on-site calculation concept was demonstrated for clinical and preclinical datasets on CT scanners (multislice CT, flat-detector CT, and micro-CT) with varying geometry, spectra, and filtration. To validate the GPU-based MC algorithm, the authors measured dose values on a 64-slice CT system using calibrated ionization chambers and thermoluminesence dosimeters (TLDs) which were placed inside standard cylindrical polymethyl methacrylate (PMMA) phantoms. The dose values and profiles obtained by GPU-based MC simulations were in the expected good agreement with computed tomography dose index (CTDI) measurements and reference TLD profiles with differences being less than 5%. For 10(9) photon histories simulated in a 256 × 256 × 12 voxel thorax dataset with voxel

  2. Automated high-dose rate brachytherapy treatment planning for a single-channel vaginal cylinder applicator

    NASA Astrophysics Data System (ADS)

    Zhou, Yuhong; Klages, Peter; Tan, Jun; Chi, Yujie; Stojadinovic, Strahinja; Yang, Ming; Hrycushko, Brian; Medin, Paul; Pompos, Arnold; Jiang, Steve; Albuquerque, Kevin; Jia, Xun

    2017-06-01

    High dose rate (HDR) brachytherapy treatment planning is conventionally performed manually and/or with aids of preplanned templates. In general, the standard of care would be elevated by conducting an automated process to improve treatment planning efficiency, eliminate human error, and reduce plan quality variations. Thus, our group is developing AutoBrachy, an automated HDR brachytherapy planning suite of modules used to augment a clinical treatment planning system. This paper describes our proof-of-concept module for vaginal cylinder HDR planning that has been fully developed. After a patient CT scan is acquired, the cylinder applicator is automatically segmented using image-processing techniques. The target CTV is generated based on physician-specified treatment depth and length. Locations of the dose calculation point, apex point and vaginal surface point, as well as the central applicator channel coordinates, and the corresponding dwell positions are determined according to their geometric relationship with the applicator and written to a structure file. Dwell times are computed through iterative quadratic optimization techniques. The planning information is then transferred to the treatment planning system through a DICOM-RT interface. The entire process was tested for nine patients. The AutoBrachy cylindrical applicator module was able to generate treatment plans for these cases with clinical grade quality. Computation times varied between 1 and 3 min on an Intel Xeon CPU E3-1226 v3 processor. All geometric components in the automated treatment plans were generated accurately. The applicator channel tip positions agreed with the manually identified positions with submillimeter deviations and the channel orientations between the plans agreed within less than 1 degree. The automatically generated plans obtained clinically acceptable quality.

  3. Automated high-dose rate brachytherapy treatment planning for a single-channel vaginal cylinder applicator.

    PubMed

    Zhou, Yuhong; Klages, Peter; Tan, Jun; Chi, Yujie; Stojadinovic, Strahinja; Yang, Ming; Hrycushko, Brian; Medin, Paul; Pompos, Arnold; Jiang, Steve; Albuquerque, Kevin; Jia, Xun

    2017-02-28

    High dose rate (HDR) brachytherapy treatment planning is conventionally performed manually and/or with aids of preplanned templates. In general the standard of care would be elevated by conducting an automated process to improve treatment planning efficiency, eliminate human error, and reduce plan quality variations. Thus, our group is developing AutoBrachy, an automated HDR brachytherapy planning suite of modules used to augment a clinical treatment planning system. This paper describes our proof-of-concept module for vaginal cylinder HDR planning that has been fully developed. After a patient CT scan is acquired, the cylinder applicator is automatically segmented using image-processing techniques. The target CTV is generated based on physician-specified treatment depth and length. Locations of the dose calculation point, apex point and vaginal surface point, as well as the central applicator channel coordinates, and the corresponding dwell positions are determined according to their geometric relationship with the applicator and written to a structure file. Dwell times are computed through iterative quadratic optimization techniques. The planning information is then transferred to the treatment planning system through a DICOM-RT interface. The entire process was tested for nine patients. The AutoBrachy cylindrical applicator module was able to generate treatment plans for these cases with clinical grade quality. Computation times varied between 1 to 3 minutes on an Intel Xeon CPU E3-1226 v3 processor. All geometric components in the automated treatment plans were generated accurately. The applicator channel tip positions agreed with the manually identified positions with submillimeter deviations and the channel orientations between the plans agreed within less than 1 degree. The automatically generated plans obtained clinically acceptable quality.

  4. Lethal mutagenesis in a structured environment.

    PubMed

    Steinmeyer, Shelby H; Wilke, Claus O

    2009-11-07

    We analyze how lethal mutagenesis operates in a compartmentalized host. We assume that different compartments receive different amounts of mutagen and that virions can migrate among compartments. We address two main questions: (1) To what extent can refugia, i.e., compartments that receive little mutagen, prevent extinction? (2) Does migration among compartments limit the effectiveness of refugia? We find that if there is little migration, extinction has to be achieved separately in all compartments. In this case, the total dose of mutagen administered to the host needs to be so high that the mutagen is effective even in the refugia. By contrast, if migration is extensive, then lethal mutagenesis is effective as long as the average growth in all compartments is reduced to below replacement levels. The effectiveness of migration is governed by the ratio of virion replication and death rates, R(0). The smaller R(0), the less migration is necessary to neutralize refugia and the less mutagen is necessary to achieve extinction at high migration rates.

  5. Uncertainties in Assesment of the Vaginal Dose for Intracavitary Brachytherapy of Cervical Cancer using a Tandem-ring Applicator

    SciTech Connect

    Berger, Daniel . E-mail: daniel.berger@akhwien.at; Dimopoulos, Johannes; Georg, Petra; Georg, Dietmar; Poetter, Richard; Kirisits, Christian

    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 points 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.

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

    PubMed

    Candela-Juan, C; Niatsetski, Y; van der Laarse, R; Granero, D; Ballester, F; Perez-Calatayud, J; Vijande, J

    2016-04-01

    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 (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. The penelope2008 MC code was used to optimize dwell positions and dwell times. 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 (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. 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%. The new applicator and the dosimetric data provided here will be a valuable tool in clinical practice, making treatment of

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

    SciTech Connect

    Candela-Juan, C.; Niatsetski, Y.; Laarse, R. van der; Granero, D.; Ballester, F.; Perez-Calatayud, J.; Vijande, J.

    2016-04-15

    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. 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 valuable

  8. [The "lethal white foal" syndrome].

    PubMed

    Blendinger, C; Müller, G; Bostedt, H

    1994-06-01

    The lethal white foal syndrome (congenital intestinal aganglionosis) was diagnosed by history, clinical signs and pathological findings in a female foal, born in March 1992, that was an offspring of two overo-spotted paint horses. The syndrome is a congenital innervation defect of the gastrointestinal tract. A literature review of this condition, relatively unknown in Germany, is given.

  9. 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.

  10. The space-developed dynamic vertical cutoff rigidity model and its applicability to aircraft radiation dose.

    PubMed

    Smart, D F; Shea, M A

    2003-01-01

    We have developed a dynamic geomagnetic vertical cutoff rigidity model that predicts the energetic charged particle transmission through the magnetosphere. Initially developed for space applications, we demonstrate the applicability of this library of cutoff rigidity models for computing aircraft radiation dose. The world grids of vertical cutoff rigidities were obtained by particle trajectory tracing in a magnetospheric model. This reference set of world grids of vertical cutoff rigidities calculated for satellite altitudes covers all magnetic activity levels from super quiet to extremely disturbed (i.e., Kp indices ranging from 0 to 9+) for every three hours in universal time. We utilize the McIlwain "L" parameter as the basis of the interpolation technique to reduce these initial satellite altitude vertical cutoff rigidities to cutoff rigidity values at aircraft altitudes. Published by Elsevier Ltd on behalf of COSPAR.

  11. SynergyFinder: a web application for analyzing drug combination dose-response matrix data.

    PubMed

    Ianevski, Aleksandr; He, Liye; Aittokallio, Tero; Tang, Jing

    2017-08-01

    Rational design of drug combinations has become a promising strategy to tackle the drug sensitivity and resistance problem in cancer treatment. To systematically evaluate the pre-clinical significance of pairwise drug combinations, functional screening assays that probe combination effects in a dose-response matrix assay are commonly used. To facilitate the analysis of such drug combination experiments, we implemented a web application that uses key functions of R-package SynergyFinder, and provides not only the flexibility of using multiple synergy scoring models, but also a user-friendly interface for visualizing the drug combination landscapes in an interactive manner. The SynergyFinder web application is freely accessible at https://synergyfinder.fimm.fi ; The R-package and its source-code are freely available at http://bioconductor.org/packages/release/bioc/html/synergyfinder.html . jing.tang@helsinki.fi.

  12. Personnel neutron dose assessment upgrade: Volume 2, Field neutron spectrometer for health physics applications

    SciTech Connect

    Brackenbush, L.W.; Reece, W.D.; Miller, S.D.; Endres, G.W.R.; Durham, J.S.; Scherpelz, R.I.; Tomeraasen, P.L.; Stroud, C.M.; Faust, L.G.; Vallario, E.J.

    1988-07-01

    Both the (ICRP) and the (NCPR) have recommended an increase in neutron quality factors and the adoption of effective dose equivalent methods. The series of reports entitled Personnel Neutron Dose Assessment Upgrade (PNL-6620) addresses these changes. Volume 1 in this series of reports (Personnel Neutron Dosimetry Assessment) provided guidance on the characteristics, use, and calibration of personnel neutron dosimeters in order to meet the new recommendations. This report, Volume 2: Field Neutron Spectrometer for Health Physics Applications describes the development of a portable field spectrometer which can be set up for use in a few minutes by a single person. The field spectrometer described herein represents a significant advance in improving the accuracy of neutron dose assessment. It permits an immediate analysis of the energy spectral distribution associated with the radiation from which neutron quality factor can be determined. It is now possible to depart from the use of maximum Q by determining and realistically applying a lower Q based on spectral data. The field spectrometer is made up of two modules: a detector module with built-in electronics and an analysis module with a IBM PC/reg sign/-compatible computer to control the data acquisition and analysis of data in the field. The unit is simple enough to allow the operator to perform spectral measurements with minimal training. The instrument is intended for use in steady-state radiation fields with neutrons energies covering the fission spectrum range. The prototype field spectrometer has been field tested in plutonium processing facilities, and has been proven to operate satisfactorily. The prototype field spectrometer uses a /sup 3/He proportional counter to measure the neutron energy spectrum between 50 keV and 5 MeV and a tissue equivalent proportional counter (TEPC) to measure absorbed neutron dose.

  13. Dosimetric characterization and output verification for conical brachytherapy surface applicators. Part II. High dose rate {sup 192}Ir sources

    SciTech Connect

    Fulkerson, Regina K. Micka, John A.; DeWerd, Larry A.

    2014-02-15

    Purpose: Historically, treatment of malignant surface lesions has been achieved with linear accelerator based electron beams or superficial x-ray beams. Recent developments in the field of brachytherapy now allow for the treatment of surface lesions with specialized conical applicators placed directly on the lesion. Applicators are available for use with high dose rate (HDR){sup 192}Ir sources, as well as electronic brachytherapy sources. Part I of this paper discussed the applicators used with electronic brachytherapy sources. Part II will discuss those used with HDR {sup 192}Ir sources. Although the use of these applicators has gained in popularity, the dosimetric characteristics have not been independently verified. Additionally, there is no recognized method of output verification for quality assurance procedures with applicators like these. Methods: This work aims to create a cohesive method of output verification that can be used to determine the dose at the treatment surface as part of a quality assurance/commissioning process for surface applicators used with HDR electronic brachytherapy sources (Part I) and{sup 192}Ir sources (Part II). Air-kerma rate measurements for the {sup 192}Ir sources were completed with several models of small-volume ionization chambers to obtain an air-kerma rate at the treatment surface for each applicator. Correction factors were calculated using MCNP5 and EGSnrc Monte Carlo codes in order to determine an applicator-specific absorbed dose to water at the treatment surface from the measured air-kerma rate. Additionally, relative dose measurements of the surface dose distributions and characteristic depth dose curves were completed in-phantom. Results: Theoretical dose distributions and depth dose curves were generated for each applicator and agreed well with the measured values. A method of output verification was created that allows users to determine the applicator-specific dose to water at the treatment surface based on a

  14. 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.

  15. Low Dose Dexmedetomidine Attenuates Hemodynamic Response to Skull Pin Holder Application

    PubMed Central

    Kondavagilu, Shwethashri Ramaprasannakumar; Pujari, Vinayak Seenappa; Chadalawada, Mohan V. R.; Bevinguddaiah, Yatish

    2017-01-01

    Background: The application of skull pin holder elicits an adverse hemodynamic response that can be deleterious; there are many drugs that have been used to attenuate this response. We have conducted this study to evaluate the efficacy of intravenous (i.v.) dexmedetomidine on attenuation of hemodynamic responses to skull pin head holder application and to compare the effectiveness of two doses of i.v. dexmedetomidine (1 μg/kg and 0.5 μg/kg bolus). Materials and Methods: Ninety American Society of Anesthesiologists physical Status I–III patients undergoing craniotomy were randomized into three groups of thirty each. After intubation, patients in Group A received 1 μg/kg of i.v. dexmedetomidine, Group B received 0.5 μg/kg of i.v. dexmedetomidine, whereas Group C received an equivalent quantity of normal saline. Hemodynamic parameters were monitored regularly after skull pin insertion. Results: There was no significant difference in the monitored hemodynamic parameters among the three groups from baseline until intubation. Heart rate (HR) and mean arterial pressure (MAP) increased significantly at skull pin insertion and subsequent points in Group C, whereas the values decreased in Groups A and B (P < 0.05). Patients in Group A showed a higher and sustained attenuation of MAP. Patients in Group C had a higher incidence of tachycardia and hypertension requiring additional measures to attenuate the response. Conclusions: Dexmedetomidine in either dosage (1 μg/kg or 0.5 μg/kg) was effective in attenuating hemodynamic response to skull pin insertion. Dexmedetomidine in doses of 0.5 μg/kg was as effective in attenuating the HR and MAP response to skull pin insertion as compared to a dose of 1 μg/kg. PMID:28298757

  16. Mechanical Performance of Ferritic Martensitic Steels for High Dose Applications in Advanced Nuclear Reactors

    NASA Astrophysics Data System (ADS)

    Anderoglu, Osman; Byun, Thak Sang; Toloczko, Mychailo; Maloy, Stuart A.

    2013-01-01

    Ferritic/martensitic (F/M) steels are considered for core applications and pressure vessels in Generation IV reactors as well as first walls and blankets for fusion reactors. There are significant scientific data on testing and industrial experience in making this class of alloys worldwide. This experience makes F/M steels an attractive candidate. In this article, tensile behavior, fracture toughness and impact property, and creep behavior of the F/M steels under neutron irradiations to high doses with a focus on high Cr content (8 to 12) are reviewed. Tensile properties are very sensitive to irradiation temperature. Increase in yield and tensile strength (hardening) is accompanied with a loss of ductility and starts at very low doses under irradiation. The degradation of mechanical properties is most pronounced at <0.3 T M ( T M is melting temperature) and up to 10 dpa (displacement per atom). Ferritic/martensitic steels exhibit a high fracture toughness after irradiation at all temperatures even below 673 K (400 °C), except when tested at room temperature after irradiations below 673 K (400 °C), which shows a significant reduction in fracture toughness. Creep studies showed that for the range of expected stresses in a reactor environment, the stress exponent is expected to be approximately one and the steady state creep rate in the absence of swelling is usually better than austenitic stainless steels both in terms of the creep rate and the temperature sensitivity of creep. In short, F/M steels show excellent promise for high dose applications in nuclear reactors.

  17. 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.

  18. Left ventricular function during lethal and sublethal endotoxemia in swine

    SciTech Connect

    Goldfarb, R.D.; Nightingale, L.M.; Kish, P.; Weber, P.B.; Loegering, D.J.

    1986-08-01

    Previous studies suggested that after a median lethal dose (LD50) of endotoxin, cardiac contractility was depressed in nonsurviving dogs. The canine cardiovascular system is unlike humans in that dogs have a hepatic vein sphincter that is susceptible to adrenergic stimulation capable of raising hepatic and splanchnic venous pressures. The authors retested the hypothesis that lethality after endotoxin administration is associated with cardiac contractile depression in pigs, because of the hepatic circulation in this species is similar to that of humans. They compared cardiac mechanical function of pigs administered a high dose (250 g/kg) or a low dose (100 g/kg) endotoxin by use of the slope of the end-systolic pressure-diameter relationship (ESPDR) as well as other measurements of cardiac performance. In all the pigs administered a high dose, ESPDR demonstrated a marked, time-dependent depression whereas we observed no significant ESPDR changes after low endotoxin doses. The other cardiodynamic variables were uninterpretable, due to the significant changes in heart rate, end-diastolic diameter (preload), and aortic diastolic pressure (afterload). Plasma myocardia depressant factor activity accumulated in all endotoxin-administered animals, tending to be greater in the high-dose group. In this group, both subendocardial blood flow and global function were depressed, whereas pigs administered the low dose endotoxin demonstrated slight, but nonsignificant, increases in flow and function. These observations indicate that myocardial contractile depression is associated with a lethal outcome to high doses of endotoxin. Myocardial perfusion was measured using radiolabeled microspheres infused into the left atria.

  19. Effective dose to patient measurements in flat-detector and multislice computed tomography: a comparison of applications in neuroradiology.

    PubMed

    Struffert, Tobias; Hauer, Michael; Banckwitz, Rosemarie; Köhler, Christoph; Royalty, Kevin; Doerfler, Arnd

    2014-06-01

    Flat-detector CT (FD-CT) is used for a variety of applications. Additionally, 3D rotational angiography (3D DSA) is used to supplement digital subtraction angiography (DSA) studies. The aim was to measure and compare the dose of (1) standard DSA and 3D DSA and (2) analogous FD-CT and multislice CT (MSCT) protocols. Using an anthropomorphic phantom, the effective dose to patients (according to ICRP 103) was measured on an MSCT and a flat-detector angiographic system using standard protocols as recommended by the manufacturer. (1) Evaluation of DSA and 3D DSA angiography protocols: ap.-lat. Standard/low-dose series 1/0.8 mSv, enlarged oblique projection 0.3 mSv, 3D DSA 0.9 mSv (limited coverage length 0.3 mSv). (2) Comparison of FD-CT and MSCT: brain parenchyma imaging 2.9 /1.4 mSv, perfusion imaging 2.3/4.2 mSv, temporal bone 0.2 /0.2 mSv, angiography 2.9/3.3 mSv, limited to the head using collimation 0.5/0.5 mSv. The effective dose for an FD-CT application depends on the application used. Using collimation for FD-CT applications, the dose may be reduced considerably. Due to the low dose of 3D DSA, we recommend using this technique to reduce the number of DSA series needed to identify working projections. Effective dose of FD-CT in comparison to MSCT is in comparable range. Collimation decreases the dose of FD-CT effectively. Effective dose of 3-D angiography is identical to 2-D DSA. Different FD-CT programs have different dose.

  20. Application of dose kernel calculation using a simplified Monte Carlo method to treatment plan for scanned proton beams.

    PubMed

    Mizutani, Shohei; Takada, Yoshihisa; Kohno, Ryosuke; Hotta, Kenji; Tansho, Ryohei; Akimoto, Tetsuo

    2016-03-01

    Full Monte Carlo (FMC) calculation of dose distribution has been recognized to have superior accuracy, compared with the pencil beam algorithm (PBA). However, since the FMC methods require long calculation time, it is difficult to apply them to routine treatment planning at present. In order to improve the situation, a simplified Monte Carlo (SMC) method has been introduced to the dose kernel calculation applicable to dose optimization procedure for the proton pencil beam scanning. We have evaluated accuracy of the SMC calculation by comparing a result of the dose kernel calculation using the SMC method with that using the FMC method in an inhomogeneous phantom. The dose distribution obtained by the SMC method was in good agreement with that obtained by the FMC method. To assess the usefulness of SMC calculation in clinical situations, we have compared results of the dose calculation using the SMC with those using the PBA method for three clinical cases of tumor treatment. The dose distributions calculated with the PBA dose kernels appear to be homogeneous in the planning target volumes (PTVs). In practice, the dose distributions calculated with the SMC dose kernels with the spot weights optimized with the PBA method show largely inhomogeneous dose distributions in the PTVs, while those with the spot weights optimized with the SMC method have moderately homogeneous distributions in the PTVs. Calculation using the SMC method is faster than that using the GEANT4 by three orders of magnitude. In addition, the graphic processing unit (GPU) boosts the calculation speed by 13 times for the treatment planning using the SMC method. Thence, the SMC method will be applicable to routine clinical treatment planning for reproduction of the complex dose distribution more accurately than the PBA method in a reasonably short time by use of the GPU-based calculation engine. PACS number(s): 87.55.Gh.

  1. Application of dose kernel calculation using a simplified Monte Carlo method to treatment plan for scanned proton beams.

    PubMed

    Mizutani, Shohei; Takada, Yoshihisa; Kohno, Ryosuke; Hotta, Kenji; Tansho, Ryohei; Akimoto, Tetsuo

    2016-03-08

    Full Monte Carlo (FMC) calculation of dose distribution has been recognized to have superior accuracy, compared with the pencil beam algorithm (PBA). However, since the FMC methods require long calculation time, it is difficult to apply them to routine treatment planning at present. In order to improve the situation, a simplified Monte Carlo (SMC) method has been introduced to the dose kernel calculation applicable to dose optimization procedure for the proton pencil beam scanning. We have evaluated accuracy of the SMC calculation by comparing a result of the dose kernel calculation using the SMC method with that using the FMC method in an inhomogeneous phantom. The dose distribution obtained by the SMC method was in good agreement with that obtained by the FMC method. To assess the usefulness of SMC calculation in clinical situations, we have compared results of the dose calculation using the SMC with those using the PBA method for three clinical cases of tumor treatment. The dose distributions calculated with the PBA dose kernels appear to be homogeneous in the planning target volumes (PTVs). In practice, the dose distributions calculated with the SMC dose kernels with the spot weights optimized with the PBA method show largely inhomogeneous dose distributions in the PTVs, while those with the spot weights optimized with the SMC method have moderately homogeneous distributions in the PTVs. Calculation using the SMC method is faster than that using the GEANT4 by three orders of magnitude. In addition, the graphic processing unit (GPU) boosts the calculation speed by 13 times for the treatment planning using the SMC method. Thence, the SMC method will be applicable to routine clinical treatment planning for reproduction of the complex dose distribution more accurately than the PBA method in a reasonably short time by use of the GPU-based calculation engine.

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

    SciTech Connect

    Chisela, W; Yao, R; Dorbu, G

    2014-06-01

    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 field 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.

  3. Transforming How We Fight Through Effects-Based Operations and Non-Lethal Capabilities

    DTIC Science & Technology

    2004-05-17

    Demonstrating the feasibility of building a self-contained, lightweight, hand- held non- lethal laser system for counter-personnel application. Front- End ...FINAL 3. DATES COVERED (From - To) 4. TITLE AND SUBTITLE Transforming How We Fight Through Effects-Based Operations & Non- 5a. CONTRACT NUMBER Lethal ...threats and challenges. The fact of the matter is, there are no more symmetrical threats at which the U.S. can aim its highly lethal military. Instead

  4. Deformable 3D-2D registration for CT and its application to low dose tomographic fluoroscopy.

    PubMed

    Flach, Barbara; Brehm, Marcus; Sawall, Stefan; Kachelrieß, Marc

    2014-12-21

    Many applications in medical imaging include image registration for matching of images from the same or different modalities. In the case of full data sampling, the respective reconstructed images are usually of such a good image quality that standard deformable volume-to-volume (3D-3D) registration approaches can be applied. But research in temporal-correlated image reconstruction and dose reductions increases the number of cases where rawdata are available from only few projection angles. Here, deteriorated image quality leads to non-acceptable deformable volume-to-volume registration results. Therefore a registration approach is required that is robust against a decreasing number of projections defining the target position. We propose a deformable volume-to-rawdata (3D-2D) registration method that aims at finding a displacement vector field maximizing the alignment of a CT volume and the acquired rawdata based on the sum of squared differences in rawdata domain. The registration is constrained by a regularization term in accordance with a fluid-based diffusion. Both cost function components, the rawdata fidelity and the regularization term, are optimized in an alternating manner. The matching criterion is optimized by a conjugate gradient descent for nonlinear functions, while the regularization is realized by convolution of the vector fields with Gaussian kernels. We validate the proposed method and compare it to the demons algorithm, a well-known 3D-3D registration method. The comparison is done for a range of 4-60 target projections using datasets from low dose tomographic fluoroscopy as an application example. The results show a high correlation to the ground truth target position without introducing artifacts even in the case of very few projections. In particular the matching in the rawdata domain is improved compared to the 3D-3D registration for the investigated range. The proposed volume-to-rawdata registration increases the robustness regarding sparse

  5. Deformable 3D-2D registration for CT and its application to low dose tomographic fluoroscopy

    NASA Astrophysics Data System (ADS)

    Flach, Barbara; Brehm, Marcus; Sawall, Stefan; Kachelrieß, Marc

    2014-12-01

    Many applications in medical imaging include image registration for matching of images from the same or different modalities. In the case of full data sampling, the respective reconstructed images are usually of such a good image quality that standard deformable volume-to-volume (3D-3D) registration approaches can be applied. But research in temporal-correlated image reconstruction and dose reductions increases the number of cases where rawdata are available from only few projection angles. Here, deteriorated image quality leads to non-acceptable deformable volume-to-volume registration results. Therefore a registration approach is required that is robust against a decreasing number of projections defining the target position. We propose a deformable volume-to-rawdata (3D-2D) registration method that aims at finding a displacement vector field maximizing the alignment of a CT volume and the acquired rawdata based on the sum of squared differences in rawdata domain. The registration is constrained by a regularization term in accordance with a fluid-based diffusion. Both cost function components, the rawdata fidelity and the regularization term, are optimized in an alternating manner. The matching criterion is optimized by a conjugate gradient descent for nonlinear functions, while the regularization is realized by convolution of the vector fields with Gaussian kernels. We validate the proposed method and compare it to the demons algorithm, a well-known 3D-3D registration method. The comparison is done for a range of 4-60 target projections using datasets from low dose tomographic fluoroscopy as an application example. The results show a high correlation to the ground truth target position without introducing artifacts even in the case of very few projections. In particular the matching in the rawdata domain is improved compared to the 3D-3D registration for the investigated range. The proposed volume-to-rawdata registration increases the robustness regarding sparse

  6. Dose and cycle of insecticide applications in the control of malaria

    PubMed Central

    Macdonald, G.; Davidson, G.

    1953-01-01

    The authors first review the doses and cycles of application normally recommended in different parts of the world for DDT, BHC, and dieldrin in controlling malaria, and then discuss the experimental evidence concerning their actual efficacy in the field. The irritant effect of the various insecticides is compared, DDT being found the most irritant and dieldrin the least. BHC appears to be highly irritant when solid, but not when vaporized. The problem of the application of residual insecticides to absorbent surfaces, such as mud, is considered; the wettable powders are generally accepted as the most efficient formulation for such surfaces, but even with these a marked loss in toxicity may occur, requiring higher initial doses and more frequent application than on non-absorbent surfaces. With volatile insecticides, such as BHC, some degree of absorption slows down the loss by volatilization, but at the usual field dosages of 0.1 g and 0.2 g of gamma-BHC per m2 the decline in toxicity is still rapid. Experiments have also shown that mixtures of DDT and BHC may, in some circumstances, combine the initial high kill of the latter with the persistent moderate kill of the former. Considering the insecticidal efficiency needed for the control of malaria, the authors find that most natural circumstances would be met by attaining a mortality-rate of about 65% of mosquitos entering treated shelters; 85% mortality would be suitable for the most severe conditions and 65% mortality for controlling moderate transmission by endophilic mosquitos. PMID:13141131

  7. Application of PK/PD Modeling in Veterinary Field: Dose Optimization and Drug Resistance Prediction.

    PubMed

    Ahmad, Ijaz; Huang, Lingli; Hao, Haihong; Sanders, Pascal; Yuan, Zonghui

    2016-01-01

    Among veterinary drugs, antibiotics are frequently used. The true mean of antibiotic treatment is to administer dose of drug that will have enough high possibility of attaining the preferred curative effect, with adequately low chance of concentration associated toxicity. Rising of antibacterial resistance and lack of novel antibiotic is a global crisis; therefore there is an urgent need to overcome this problem. Inappropriate antibiotic selection, group treatment, and suboptimal dosing are mostly responsible for the mentioned problem. One approach to minimizing the antibacterial resistance is to optimize the dosage regimen. PK/PD model is important realm to be used for that purpose from several years. PK/PD model describes the relationship between drug potency, microorganism exposed to drug, and the effect observed. Proper use of the most modern PK/PD modeling approaches in veterinary medicine can optimize the dosage for patient, which in turn reduce toxicity and reduce the emergence of resistance. The aim of this review is to look at the existing state and application of PK/PD in veterinary medicine based on in vitro, in vivo, healthy, and disease model.

  8. Application of PK/PD Modeling in Veterinary Field: Dose Optimization and Drug Resistance Prediction

    PubMed Central

    Ahmad, Ijaz; Huang, Lingli; Hao, Haihong; Sanders, Pascal; Yuan, Zonghui

    2016-01-01

    Among veterinary drugs, antibiotics are frequently used. The true mean of antibiotic treatment is to administer dose of drug that will have enough high possibility of attaining the preferred curative effect, with adequately low chance of concentration associated toxicity. Rising of antibacterial resistance and lack of novel antibiotic is a global crisis; therefore there is an urgent need to overcome this problem. Inappropriate antibiotic selection, group treatment, and suboptimal dosing are mostly responsible for the mentioned problem. One approach to minimizing the antibacterial resistance is to optimize the dosage regimen. PK/PD model is important realm to be used for that purpose from several years. PK/PD model describes the relationship between drug potency, microorganism exposed to drug, and the effect observed. Proper use of the most modern PK/PD modeling approaches in veterinary medicine can optimize the dosage for patient, which in turn reduce toxicity and reduce the emergence of resistance. The aim of this review is to look at the existing state and application of PK/PD in veterinary medicine based on in vitro, in vivo, healthy, and disease model. PMID:26989688

  9. Application of RADTRAN to estimation of doses to persons in enclosed spaces

    SciTech Connect

    Neuhauser, K. S.

    1992-01-01

    The RADTRAN computer code for transportation risk analysis can be used to estimate doses to persons in enclosed volumes. This application was developed in response to a need to examine consequences of a hypothetical container leak during accident-free transportation by cargo air. The original problem addressed tritium containers, but the method can be applied to any gaseous or suspended particulate material potentially released in an airplane or other enclosed area (e.g., warehouse) under accident-free conditions. Such leakage can occur during shipment of any radioactive gas or material with a gaseous phase. Atmospheric dispersion is normally modeled in RADTRAN as a series of downwind isopleths each of which is assigned a dilution factor (also known as time-integrated concentration or X/Q value). These values are located in look-up tables in RADTRAN and are normally taken from externally performed Gaussian dispersion calculations. The dilution factors are used to estimate inhalation dose to persons in the specified downwind areas.

  10. WE-F-201-01: Identify Key Clinical Applications Needing Advanced Dose Calculation in Brachytherapy

    SciTech Connect

    Fulkerson, R.

    2015-06-15

    With the recent introduction of heterogeneity correction algorithms for brachytherapy, the AAPM community is still unclear on how to commission and implement these into clinical practice. The recently-published AAPM TG-186 report discusses important issues for clinical implementation of these algorithms. A charge of the AAPM-ESTRO-ABG Working Group on MBDCA in Brachytherapy (WGMBDCA) is the development of a set of well-defined test case plans, available as references in the software commissioning process to be performed by clinical end-users. In this practical medical physics course, specific examples on how to perform the commissioning process are presented, as well as descriptions of the clinical impact from recent literature reporting comparisons of TG-43 and heterogeneity-based dosimetry. Learning Objectives: Identify key clinical applications needing advanced dose calculation in brachytherapy. Review TG-186 and WGMBDCA guidelines, commission process, and dosimetry benchmarks. Evaluate clinical cases using commercially available systems and compare to TG-43 dosimetry.

  11. Application of IDEAS guidelines: the IDEAS/IAEA intercomparison exercise on internal dose assessment.

    PubMed

    Hurtgen, C; Andrasi, A; Bailey, M R; Birchall, A; Blanchardon, E; Berkovski, V; Castellani, C M; Cruz-Suarez, R; Davis, K; Doerfel, H; Leguen, B; Malatova, I; Marsh, J; Zeger, J

    2007-01-01

    As part of the EU Fifth Framework Programme IDEAS project 'General Guidelines for the Evaluation of Incorporation Monitoring Data', and in collaboration with the International Atomic Energy Agency, a new intercomparison exercise for the assessment of doses from intakes of radionuclides was organised. Several cases were selected, to cover a wide range of practices in the nuclear fuel cycle and medical applications. The cases were: (1) acute intake of HTO, (2) acute inhalation of the fission products 137Cs and 90Sr, (3) acute inhalation of 60Co, (4) repeated intakes of 131I, (5) intake of enriched uranium and (6) single intake of Pu isotopes and 241Am. This intercomparison exercise especially focused on the effect of the Guidelines proposed by the IDEAS project for harmonisation of internal dosimetry.

  12. New allometric scaling relationships and applications for dose and toxicity extrapolation.

    PubMed

    Cao, Qiming; Yu, Jimmy; Connell, Des

    2014-01-01

    Allometric scaling between metabolic rate, size, body temperature, and other biological traits has found broad applications in ecology, physiology, and particularly in toxicology and pharmacology. Basal metabolic rate (BMR) was observed to scale with body size and temperature. However, the mass scaling exponent was increasingly debated whether it should be 2/3, 3/4, or neither, and scaling with body temperature also attracted recent attention. Based on thermodynamic principles, this work reports 2 new scaling relationships between BMR, size, temperature, and biological time. Good correlations were found with the new scaling relationships, and no universal scaling exponent can be obtained. The new scaling relationships were successfully validated with external toxicological and pharmacological studies. Results also demonstrated that individual extrapolation models can be built to obtain scaling exponent specific to the interested group, which can be practically applied for dose and toxicity extrapolations.

  13. Dose Tracker Application for Monitoring Crew Medication Usage, Symptoms, and Adverse Effects During Missions

    NASA Technical Reports Server (NTRS)

    Wotring, Virginia; Smith, LaRona

    2015-01-01

    Medication usage records can be used as a relatively nonintrusive means of monitoring health. This has been attempted previously through crew medical records, but these records are incomplete from the perspective of a research pharmacologist. During the shuttle era, NASA operations did not include routine questioning of crewmembers about their medication use until after missions were complete. The (long!) questionnaire was on paper. Asking crewmembers to recall medication use from weeks before questioning made getting complete and accurate information virtually impossible. This study will document medication usage of crewmembers before and during their missions. It will capture previously unrecorded data regarding medication use during spaceflight, including side effect qualities, frequencies and severities. The research-oriented data will be collected for research purposes, separate from medical records. Dose Tracker employs an iOS application (app) for fast & easy collection of medication usage data from crewmember participants during their missions.

  14. Syn-Lethality: An Integrative Knowledge Base of Synthetic Lethality towards Discovery of Selective Anticancer Therapies

    PubMed Central

    Li, Xue-juan; Mishra, Shital K.; Wu, Min; Zhang, Fan

    2014-01-01

    Synthetic lethality (SL) is a novel strategy for anticancer therapies, whereby mutations of two genes will kill a cell but mutation of a single gene will not. Therefore, a cancer-specific mutation combined with a drug-induced mutation, if they have SL interactions, will selectively kill cancer cells. While numerous SL interactions have been identified in yeast, only a few have been known in human. There is a pressing need to systematically discover and understand SL interactions specific to human cancer. In this paper, we present Syn-Lethality, the first integrative knowledge base of SL that is dedicated to human cancer. It integrates experimentally discovered and verified human SL gene pairs into a network, associated with annotations of gene function, pathway, and molecular mechanisms. It also includes yeast SL genes from high-throughput screenings which are mapped to orthologous human genes. Such an integrative knowledge base, organized as a relational database with user interface for searching and network visualization, will greatly expedite the discovery of novel anticancer drug targets based on synthetic lethality interactions. The database can be downloaded as a stand-alone Java application. PMID:24864230

  15. Application of airborne gamma spectrometric survey data to estimating terrestrial gamma-ray dose rates: an example in California.

    PubMed

    Wollenberg, H A; Revzan, K L; Smith, A R

    1994-01-01

    We examined the applicability of radioelement data from the National Aerial Radiometric Reconnaissance, an element of the National Uranium Resource Evaluation, to estimate terrestrial gamma-ray absorbed dose rates, by comparing dose rates calculated from aeroradiometric surveys of uranium, thorium, and potassium concentrations with dose rates calculated from a radiogeologic data base and the distribution of lithologies in California. Gamma-ray dose rates increase generally from north to south following lithological trends, with low values of 25-30 nGy h-1 in the northernmost 1 x 2 degrees quadrangles between 41 and 42 degrees N to high values of 75-100 nGy h-1 in southeastern California. Lithologic-based estimates of mean dose rates in the quadrangles generally match those from aeroradiometric data, with statewide means of 63 and 60 nGy h-1, respectively. These are intermediate between a population-weighted global average of 51 nGy h-1 reported in 1982 by UNSCEAR and a weighted continental average of 70 nGy h-1, based on the global distribution of rock types. The concurrence of lithologically and aeroradiometrically determined dose rates in California, with its varied geology and topography encompassing settings representative of the continents, indicates that the National Aerial Radiometric Reconnaissance data are applicable to estimates of terrestrial absorbed dose rates from natural gamma emitters.

  16. SU-E-T-10: A Clinical Implementation and the Dosimetric Evidence in High Dose Rate Vaginal Multichannel Applicator Brachytherapy

    SciTech Connect

    Syh, J; Syh, J; Patel, B; Zhang, J; Wu, H; Rosen, L

    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. The 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.

  17. Use of bladder dose points for assessment of the spatial dose distribution in the posterior bladder wall in cervical cancer brachytherapy and the impact of applicator position.

    PubMed

    Nkiwane, Karen S; Pötter, Richard; Fokdal, Lars U; Hoskin, Peter; Pearcey, Robert; Segedin, Barbara; Mahantshetty, Umesh; Kirisits, Christian

    2015-01-01

    To validate the feasibility and use of dose points to characterize the bladder wall dose distribution and investigate potential impact of the applicator position in cervical cancer brachytherapy. One hundred twenty-eight optimized MRI plans were evaluated. The International Commission of Radiation Units and Measurements (ICRU-38) point doses (B(ICRU)), surrogate for bladder base doses, were compared with D(2cc). Vaginal source to superior-anterior border of the symphysis distances were measured and compared within two groups, namely Group 1-B(ICRU)/D(2cc) ≥1 and Group 2-B(ICRU)/D(2cc) <1. Additionally, points at 1.5 and 2 cm cranial to the B(ICRU), parallel to the tandem and the body axis were analyzed. Thirty-seven percent of the patients had the ratio B(ICRU)/D(2cc) of 1 or higher, with the 2cc subvolume at the bladder base (Group 1). In 63%, BICRU/D2cc ratio was lower than 1 and the 2cc, cranial to the bladder base (Group 2). Median vaginal source-to-superior-anterior border of the symphysis line distance was -2 cm (range, -3.7 to +1.2 cm) in Group 1 and +1.8 cm (range, -2 to +4.8 cm) in Group 2 (+ cranial/- caudal direction). There was a high correlation between vaginal sources near the symphysis and the 2cc subvolume at the bladder base. The additional points provided no added value. Location of the 2cc subvolume varies in cervical cancer brachytherapy. Maximum doses are at the bladder base if vaginal sources are also in the vicinity of the bladder base indicated by B(ICRU)/D(2cc) ratio of 1 or higher. Such variation should be considered in dose-effect analyses and intercomparisons, as the same D(2cc) at different bladder locations may correlate with different morbidity profiles and severity Reporting D(2cc) and B(ICRU) doses together therefore remains essential. Copyright © 2015 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

  18. 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

  19. 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.

  20. Application of a generic biosphere model for dose assessments to five European sites.

    PubMed

    Chen, Q; Kowe, R; Mobbs, S F; Pröhl, G; Olyslaegers, G; Zeevaert, T; Kanyar, B; Pinedo, P; Simón, I; Bergström, U; Hallberg, B; Jones, J A; Oatway, W B; Watson, S J

    2006-06-01

    The BIOMOSA (BIOsphere MOdels for Safety Assessment of radioactive waste disposal) project was part of the EC fifth framework research programme. The main goal of this project was to improve the scientific basis for the application of biosphere models in the framework of long-term safety studies of radioactive waste disposal facilities and to enhance the confidence in using biosphere models for performance assessments. The study focused on the development and application of a generic biosphere tool BIOGEM (BIOsphere GEneric Model) using the IAEA BIOMASS reference biosphere methodology, and the comparison between BIOGEM and five site-specific biosphere models. The site-specific models and the generic model were applied to five typical locations in Europe, resulting in estimates of the annual effective individual doses to the critical groups and the ranking of the importance of the exposure pathways for each of the sites. Uncertainty in the results was also estimated by means of stochastic calculations based on variation of the site-specific parameter values. This paper describes the generic model and the deterministic and stochastic results obtained when it was applied to the five sites. Details of the site-specific models and the corresponding results are described in two companion papers. This paper also presents a comparison of the results between the generic model and site-specific models. In general, there was an acceptable agreement of the BIOGEM for both the deterministic and stochastic results with the results from the site-specific models.

  1. Application of RPTEC/TERT1 cells for investigation of repeat dose nephrotoxicity: A transcriptomic study.

    PubMed

    Aschauer, Lydia; Limonciel, Alice; Wilmes, Anja; Stanzel, Sven; Kopp-Schneider, Annette; Hewitt, Philip; Lukas, Arno; Leonard, Martin O; Pfaller, Walter; Jennings, Paul

    2015-12-25

    The kidney is a major target organ for toxicity. Incidence of chronic kidney disease (CKD) is increasing at an alarming rate due to factors such as increasing population age and increased prevalence of heart disease and diabetes. There is a major effort ongoing to develop superior predictive models of renal injury and early renal biomarkers that can predict onset of CKD. In the EU FP7 funded project, Predict-IV, we investigated the human renal proximal tubule cells line, RPTEC/TERT1 for their applicability to long term nephrotoxic mechanistic studies. To this end, we used a tiered strategy to optimise dosing regimes for 9 nephrotoxins. Our final testing protocol utilised differentiated RPTEC/TERT1 cells cultured on filter inserts treated with compounds at both the apical and basolateral side, at concentrations not exceeding IC10, for 14 days in a 24 h repeat application. Transepithelial electrical resistance and supernatant lactate were measured over the duration of the experiments and genome wide transcriptomic profiles were assayed at day 1, 3 and 14. The effect of hypoxia was investigated for a subset of compounds. The transcriptomic data were analysed to investigate compound-specific effects, global responses and mechanistically informative signatures. In addition, several potential clinically useful renal injury biomarkers were identified. Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. Inter-application displacement of brachytherapy dose received by the bladder and rectum of the patients with inoperable cervical cancer

    PubMed Central

    Marosevic, Goran; Ljuca, Dzenita; Osmic, Hasan; Fazlic, Semir; Arsovski, Oliver; Mileusnic, Dusan

    2014-01-01

    Background The aim of the study was to examine on the CT basis the inter-application displacement of the positions D0.1cc, D1cc and D2cc of the brachytherapy dose applied to the bladder and rectum of the patients with inoperable cervical cancer. Patients and methods This prospective study included 30 patients with cervical cancer who were treated by concomitant chemo-radiotherapy. HDR intracavitary brachytherapy was made by the applicators type Fletcher tandem and ovoids. For each brachytherapy application the position D0.1cc was determined of the bladder and rectum that receive a brachytherapty dose. Then, based on the X, Y, and Z axis displacement, inter-application mean X, Y, and Z axis displacements were calculated as well as their displacement vectors (R). It has been analyzed whether there is statistically significant difference in inter-application displacement of the position of the brachytherapy dose D0.1cc, D1cc and D2cc of the bladder and rectum. The ANOVA test and post-hoc analysis by Tukey method were used for testing statistical importance of differences among the groups analyzed. The difference among the groups analyzed was considered significant if p < 0.05. Results There are significant inter-application displacements of the position of the brachytherapy dose D0,1cc, D1cc and D2cc of the bladder and rectum. Conclusions When we calculate the cumulative brachytherapy dose by summing up D0,1cc, D1cc and D2cc of the organs at risk for all the applications, we must bear in mind their inter-application displacement, and the fact that it is less likely that the worst scenario would indeed happen. PMID:24991211

  3. Three-dimensional dose verification of the clinical application of gamma knife stereotactic radiosurgery using polymer gel and MRI

    NASA Astrophysics Data System (ADS)

    Papagiannis, P.; Karaiskos, P.; Kozicki, M.; Rosiak, J. M.; Sakelliou, L.; Sandilos, P.; Seimenis, I.; Torrens, M.

    2005-05-01

    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.

  4. Evaluation of lethality estimates for combustion gases in military scenarios.

    PubMed

    Smith, S M; Stuhmiller, J H; Januszkiewicz, A J

    1996-12-31

    To meet the military objective of determining criteria for incapacitation and lethality from toxic gas exposures, a series of small animal tests and data analyses were conducted. Carbon monoxide (CO), a narcotic gas and nitrogen dioxide (NO2), an irritant gas, along with carbon dioxide (CO2) were tested individually and in the following mixtures: (CO + CO2), (NO2 + CO2) and (NO2 + CO + CO2). A group of six animals was exposed to each of the gases and their combinations, lethality and biophysical data were collected. We conclude that our observations of lethality from single toxic gases can be correlated with a fractional effective dose (FED) description, in which external concentrations are corrected for minute volume changes. Multiple gas exposures clearly demonstrate synergistic effects because lethality rates greatly exceed those expected from statistically independent causes. Simple addition of the FED values, however, overstates the effect and implies a competition between the narcotic and irritant gas effects. The N-Gas model, while being an additive FED model, does not appear to be in a form that could guide the setting of military exposure standards.

  5. 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

    SciTech Connect

    Li, Y; Tian, Z; Hrycushko, B; Jiang, S; Jia, X

    2015-06-15

    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 with 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.

  6. SU-E-T-55: A Novel Applicator for High Dose Rate Brachytherapy Treatments of Ocular Conjunctiva

    SciTech Connect

    Koren, S; Bragilovski, D; Tafo, A Guemnie; Cohen, G

    2015-06-15

    Purpose: To evaluate the clinical feasibility of IntraBeam intra operative kV irradiation beam device for ocular conjunctiva treatments. The Intra-Beam system offers a 4.4 mm diameter needle applicator, that is not suitable for treatment of a large surface with limits access. We propose an adaptor that will answer to this clinical need and provide initial dosimetry. Methods: The dose distribution of the needle applicator is non uniform and hence not suitable for treatment of relatively large surfaces. We designed an adapter to the needle applicator that will filter the X-rays and produce a conformal dose distribution over the treatment area while shielding surfaces to be spared. Dose distributions were simulated using FLUKA is a fully integrated particle physics Monte Carlo simulation package. Results: We designed a wedge applicator made of Polythermide window and stainless steel for collimating. We compare the dose distribution to that of the known needle and surface applicators. Conclusion: Initial dosimetry shows feasibility of this approach. While further refinements to the design may be warranted, the results support construction of a prototype and confirmation of the Monte Carlo dosimetry with measured data.

  7. Virulence Alterations of Tacaribe Virus Infection in Adult Mice: Lethal Model for Fatal Encephalitis.

    DTIC Science & Technology

    1977-03-29

    Selection of lethal substrains of Tacaribe virus strain 11573 was done by successive serial intracerebral (I.c.) passage of the virus in adult mice...calculation of median intracerebral lethal dose values, and by histopathologic changes observed in brains of adult mice. Some of the derived virus substrains...declined with subsequent passages. Clinical signs of infection in adult mice were manifested by a rough hair-coat, ventriflexed posture, diminished

  8. Preclinical dose number and its application in understanding drug absorption risk and formulation design for preclinical species.

    PubMed

    Wuelfing, W Peter; Daublain, Pierre; Kesisoglou, Filippos; Templeton, Allen; McGregor, Caroline

    2015-04-06

    In the drug discovery setting, the ability to rapidly identify drug absorption risk in preclinical species at high doses from easily measured physical properties is desired. This is due to the large number of molecules being evaluated and their high attrition rate, which make resource-intensive in vitro and in silico evaluation unattractive. High-dose in vivo data from rat, dog, and monkey are analyzed here, using a preclinical dose number (PDo) concept based on the dose number described by Amidon and other authors (Pharm. Res., 1993, 10, 264-270). PDo, as described in this article, is simply calculated as dose (mg/kg) divided by compound solubility in FaSSIF (mg/mL) and approximates the volume of biorelevant media per kilogram of animal that would be needed to fully dissolve the dose. High PDo values were found to be predictive of difficulty in achieving drug exposure (AUC)-dose proportionality in in vivo studies, as could be expected; however, this work analyzes a large data set (>900 data points) and provides quantitative guidance to identify drug absorption risk in preclinical species based on a single solubility measurement commonly carried out in drug discovery. Above the PDo values defined, >50% of all in vivo studies exhibited poor AUC-dose proportionality in rat, dog, and monkey, and these values can be utilized as general guidelines in discovery and early development to rapidly assess risk of solubility-limited absorption for a given compound. A preclinical dose number generated by biorelevant dilutions of formulated compounds (formulated PDo) was also evaluated and defines solubility targets predictive of suitable AUC-dose proportionality in formulation development efforts. Application of these guidelines can serve to efficiently identify compounds in discovery that are likely to present extreme challenges with respect to solubility-limited absorption in preclinical species as well as reduce the testing of poor formulations in vivo, which is a key

  9. 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.

  10. Acute toxoplasmosis leads to lethal overproduction of Th1 cytokines.

    PubMed

    Mordue, D G; Monroy, F; La Regina, M; Dinarello, C A; Sibley, L D

    2001-10-15

    Virulence in Toxoplasma gondii is strongly influenced by the genotype of the parasite. Type I strains uniformly cause rapid death in mice regardless of the host genotype or the challenge dose. In contrast, the outcome of infections with type II strains is highly dependent on the challenge dose and the genotype of the host. To understand the basis of acute virulence in toxoplasmosis, we compared low and high doses of the RH strain (type I) and the ME49/PTG strain (type II) of T. gondii in outbred mice. Differences in virulence were reflected in only modestly different growth rates in vivo, and both strains disseminated widely to different tissues. The key difference in the virulent RH strain was the ability to reach high tissue burdens rapidly following a low dose challenge. Lethal infections caused by type I (RH) or type II (PTG) strain infections were accompanied by extremely elevated levels of Th1 cytokines in the serum, including IFN-gamma, TNF-alpha, IL-12, and IL-18. Extensive liver damage and lymphoid degeneration accompanied the elevated levels of cytokines produced during lethal infection. Increased time of survival following lethal infection with the RH strain was provided by neutralization of IL-18, but not TNF-alpha or IFN-gamma. Nonlethal infections with a low dose of type II PTG strain parasites were characterized by a modest induction of Th1 cytokines that led to control of infection and minimal damage to host tissues. Our findings establish that overstimulation of immune responses that are normally necessary for protection is an important feature of acute toxoplasmosis.

  11. Biochemical Changes in Blood Components after Lethal Doses of Radiation.

    DTIC Science & Technology

    1982-10-01

    from the knowledge that ionizing radiation An induce lipid peroxidation (27); this then can affect membrane phospholipase A2 activity (28). Changes in... phospholipase A2 activity could result in changes in arachidonic acid production and the generation of lipoxygenase and cyclooxy- genase products (29...postirradiation. If ionizing radiation does alter phospholipase A2 activity, this would be interesting because the arachidonic acid cascade is a very

  12. Methods of space radiation dose analysis with applications to manned space systems

    NASA Technical Reports Server (NTRS)

    Langley, R. W.; Billings, M. P.

    1972-01-01

    The full potential of state-of-the-art space radiation dose analysis for manned missions has not been exploited. Point doses have been overemphasized, and the critical dose to the bone marrow has been only crudely approximated, despite the existence of detailed man models and computer codes for dose integration in complex geometries. The method presented makes it practical to account for the geometrical detail of the astronaut as well as the vehicle. Discussed are the major assumptions involved and the concept of applying the results of detailed proton dose analysis to the real-time interpretation of on-board dosimetric measurements.

  13. 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.

  14. Construction of a conditional lethal Salmonella mutant via genetic recombination using the ara system and asd gene.

    PubMed

    Kim, Sam Woong; Kang, Ho Young; Hur, Jin; Gal, Sang Wan; Bang, Woo Young; Cho, Kwang-Keun; Kim, Chul Wook; Bahk, Jeong Dong; Lee, John Hwa

    2011-11-01

    In order to construct a conditional lethal Salmonella mutant, an arabinose-regulated recombinant genetic system was used. The Salmonella aspartate semialdehyde dehydrogenase (asd) gene was localized under the control of araC P(araBAD) in a plasmid to create the araC P(araBAD)::asd cassette. The cassette was cloned into a plasmid carrying a p15A replication origin to create the recombinant plasmid pMMP55. The growth of Salmonella MMP10 harboring pMMP55 was dependent on the presence of arabinose. In the presence of arabinose, the Asd deficiency due to chromosomal deletion of asd in the Salmonella host was complemented by the asd gene transcribed and translated under the P(araBAD) promoter and araBAD Shine-Dalgarno (SD) sequence in pMMP55. Growth inhibition of the strain was demonstrated by arabinose depletion in M9 minimal medium, indicating that the strain were unable to grow in an arabinose-limited environment. In addition, the analysis of a 50% lethal dose (LD50) using mice revealed that the strain MMP10 exhibited attenuation by approximately 100-fold relative to that of the unmodified strain. In conclusion, these data suggest that the araC P(araBAD)::asd system developed in this study can be used to construct conditional lethal Salmonella mutants for application as safe, live-attenuated Salmonella vaccines.

  15. [Lethal intravenous infusion of a wound antiseptic containing polyhexanide].

    PubMed

    Wehner, Frank; Wehner, Heinz-Dieter; Schulz, Martin Manfred

    2009-01-01

    Polyhexamethylene biguanide (PHMB) is considered to be highly histocompatible and is one of the most frequently used wound antiseptics. Only one case of intoxication has been reported so far. The present case of a lethal intoxication is the first fatal incident described where causality is substantiated by a temporal coincidence between application and ascertainable organ damage. The laboratory-chemical and histological investigations verified the toxicity of this substance after intravenous application with the main findings being severe hepatic and pancreatic damage.

  16. 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).

  17. Using rule-based shot dose assignment in model-based MPC applications

    NASA Astrophysics Data System (ADS)

    Bork, Ingo; Buck, Peter; Wang, Lin; Müller, Uwe

    2014-10-01

    Shrinking feature sizes and the need for tighter CD (Critical Dimension) control require the introduction of new technologies in mask making processes. One of those methods is the dose assignment of individual shots on VSB (Variable Shaped Beam) mask writers to compensate CD non-linearity effects and improve dose edge slope. Using increased dose levels only for most critical features, generally only for the smallest CDs on a mask, the change in mask write time is minimal while the increase in image quality can be significant. This paper describes a method combining rule-based shot dose assignment with model-based shot size correction. This combination proves to be very efficient in correcting mask linearity errors while also improving dose edge slope of small features. Shot dose assignment is based on tables assigning certain dose levels to a range of feature sizes. The dose to feature size assignment is derived from mask measurements in such a way that shape corrections are kept to a minimum. For example, if a 50nm drawn line on mask results in a 45nm chrome line using nominal dose, a dose level is chosen which is closest to getting the line back on target. Since CD non-linearity is different for lines, line-ends and contacts, different tables are generated for the different shape categories. The actual dose assignment is done via DRC rules in a pre-processing step before executing the shape correction in the MPC engine. Dose assignment to line ends can be restricted to critical line/space dimensions since it might not be required for all line ends. In addition, adding dose assignment to a wide range of line ends might increase shot count which is undesirable. The dose assignment algorithm is very flexible and can be adjusted based on the type of layer and the best balance between accuracy and shot count. These methods can be optimized for the number of dose levels available for specific mask writers. The MPC engine now needs to be able to handle different dose

  18. Spot scanning proton therapy plan assessment: design and development of a dose verification application for use in routine clinical practice

    NASA Astrophysics Data System (ADS)

    Augustine, Kurt E.; Walsh, Timothy J.; Beltran, Chris J.; Stoker, Joshua B.; Mundy, Daniel W.; Parry, Mark D.; Bues, Martin; Fatyga, Mirek

    2016-04-01

    The use of radiation therapy for the treatment of cancer has been carried out clinically since the late 1800's. Early on however, it was discovered that a radiation dose sufficient to destroy cancer cells can also cause severe injury to surrounding healthy tissue. Radiation oncologists continually strive to find the perfect balance between a dose high enough to destroy the cancer and one that avoids damage to healthy organs. Spot scanning or "pencil beam" proton radiotherapy offers another option to improve on this. Unlike traditional photon therapy, proton beams stop in the target tissue, thus better sparing all organs beyond the targeted tumor. In addition, the beams are far narrower and thus can be more precisely "painted" onto the tumor, avoiding exposure to surrounding healthy tissue. To safely treat patients with proton beam radiotherapy, dose verification should be carried out for each plan prior to treatment. Proton dose verification systems are not currently commercially available so the Department of Radiation Oncology at the Mayo Clinic developed its own, called DOSeCHECK, which offers two distinct dose simulation methods: GPU-based Monte Carlo and CPU-based analytical. The three major components of the system include the web-based user interface, the Linux-based dose verification simulation engines, and the supporting services and components. The architecture integrates multiple applications, libraries, platforms, programming languages, and communication protocols and was successfully deployed in time for Mayo Clinic's first proton beam therapy patient. Having a simple, efficient application for dose verification greatly reduces staff workload and provides additional quality assurance, ultimately improving patient safety.

  19. Enantioselective disposition of (R)-salmeterol and (S)-salmeterol in urine following inhaled dosing and application to doping control.

    PubMed

    Jacobson, Glenn A; Hostrup, Morten; Narkowicz, Christian K; Nichols, David S; Haydn Walters, E

    2016-11-07

    Salmeterol (USAN, INN, BAN) is a long-acting beta2-adrenoceptor agonist (LABA) widely used in the treatment of airways disease. Although salmeterol is permitted via inhalation by athletes and supratherapeutic dosing may enhance performance, no urine threshold has been established by the World Anti-Doping Agency (WADA). Salmeterol is a chiral compound consisting of (R)- and (S)-enantiomers, normally administered as racemic (rac-) mixture via inhalation. Levels of rac-salmeterol in urine are often below detectable levels and there is surprisingly little information regarding the enantioselectivity of salmeterol pharmacokinetics. In this study, subjects inhaled either 50 (n = 6) or 200 µg (n = 4; generally regarded as maximum therapeutic dose) of salmeterol and urine was then collected for 24 h and analyzed by enantioselective ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Maximum rac-salmeterol urine concentrations were obtained at 2 h for both doses with medians of 0.084 ng/mL after the 50 µg dose and 2.1 ng/mL after the 200 µg dose, with an individual maximum of 5.7 ng/mL. Levels were detectable at 24 h for both doses. Salmeterol displayed enantioselective pharmacokinetics, with a mean ± SD log (S):(R) = 0.055 ± 0.025 (P < 0.0001) equivalent to (S):(R) of 1.13. In conclusion, rac-salmeterol by inhalation exhibits modest enantioselectivity in urine following single dose administration and can be detected following a single 50 µg dose for up to 24 h after inhalation. The present findings are of relevance if a urine threshold limit is to be introduced for salmeterol on the list of prohibited substances. The application of an enantiomer ratio analysis may offer improved discriminatory detection capability for doping control analysis applications.

  20. Application of Physiologically Based Pharmacokinetic (PBPK) Modeling to Support Dose Selection: Report of an FDA Public Workshop on PBPK

    PubMed Central

    Wagner, C; Zhao, P; Pan, Y; Hsu, V; Grillo, J; Huang, SM; Sinha, V

    2015-01-01

    The US Food and Drug Administration (FDA) public workshop, entitled “Application of Physiologically-based Pharmacokinetic (PBPK) Modeling to Support Dose Selection focused on the role of PBPK in drug development and regulation. Representatives from industry, academia, and regulatory agencies discussed the issues within plenary and panel discussions. This report summarizes the discussions and provides current perspectives on the application of PBPK in different areas, including its utility, predictive performance, and reporting for regulatory submissions. PMID:26225246

  1. Effect of syngeneic marrow injection upon recovery in sub- and near-lethally irradiated mice

    SciTech Connect

    Boggs, S.S.; Boggs, D.R.; Patrene, K.D.

    1989-06-01

    Mice were given sub-lethal (200-600 cGy) or near-lethal (800 cGy) whole body irradiation and the effect of injecting syngeneic marrow on subsequent hematopoietic recovery was studied. Marrow cell injection enhanced erythropoietic recovery after sub-lethal irradiation as reflected in hematocrit values and rate of appearance of /sup 59/Fe-labeled red cells in blood. However, this enhanced erythropoiesis was only seen in the spleen, and /sup 59/Fe uptake in marrow was reduced. When the irradiation dose was kept constant and the marrow dose increased from 10(5) to 10(6) to 10(7) cells, there was a somewhat erratic increase in spleen /sup 59/Fe and a decrease in marrow /sup 59/Fe uptake. When marrow cell number was kept constant and the dose of irradiation was increased from 200 to 400 to 600 to 800 cGy, there was an exponential increase in spleen /sup 59/Fe uptake but the marrow /sup 59/Fe uptake changed from depressed after lower doses to increased after 800 cGy. Cell injection after sub-lethal irradiation did not increase or decrease granulocytopoiesis. Injection of irradiated marrow cells also reduced marrow erythropoiesis and this was evident after both sub- and near-lethal irradiation. However, injection of irradiated cells did not increase splenic erythropoiesis. Following splenectomy, the depressed marrow erythropoiesis attending injection of viable cells was virtually eliminated but no increase was seen. These data suggest that the injection of autologous or syngeneic marrow may not be effective as a means of accelerating hematopoietic recovery after irradiation unless near-lethal or lethal dose have been received.

  2. Development of synthetic lethality anticancer therapeutics.

    PubMed

    Fang, Bingliang

    2014-10-09

    The concept of synthetic lethality (the creation of a lethal phenotype from the combined effects of mutations in two or more genes) has recently been exploited in various efforts to develop new genotype-selective anticancer therapeutics. These efforts include screening for novel anticancer agents, identifying novel therapeutic targets, characterizing mechanisms of resistance to targeted therapy, and improving efficacies through the rational design of combination therapy. This review discusses recent developments in synthetic lethality anticancer therapeutics, including poly ADP-ribose polymerase inhibitors for BRCA1- and BRCA2-mutant cancers, checkpoint inhibitors for p53 mutant cancers, and small molecule agents targeting RAS gene mutant cancers. Because cancers are caused by mutations in multiple genes and abnormalities in multiple signaling pathways, synthetic lethality for a specific tumor suppressor gene or oncogene is likely cell context-dependent. Delineation of the mechanisms underlying synthetic lethality and identification of treatment response biomarkers will be critical for the success of synthetic lethality anticancer therapy.

  3. Application of urea dosing for alkalinity supply during anaerobic digestion of vinasse.

    PubMed

    Boncz, M A; Formagini, E L; Santos, L da S; Marques, R D; Paulo, P L

    2012-01-01

    Pushed by demand for renewable energy, the ethanol industry in Brazil is expanding. However, production of 1 m(3) of ethanol generates around 13 m(3) of liquid residues (vinasse), so this expansion results in an increasing need for a more adequate destination of these residues. Nowadays the vinasse is dispersed on the sugar cane fields in the practice of fertirrigation, but anaerobic digestion of this residue may be a better solution, additionally offering an alternative source of energy, able to complement hydroelectric power supply in the dry season. However, when trying to digest vinasse at reduced hydraulic retention times, complications arise from its strong tendency toward acidification, upsetting the fragile balance of transformations normally occurring under anaerobic conditions. For successful operation of an anaerobic treatment process with acceptable hydraulic residence times, increasing alkalinity levels inside the reactor is neces-sary. In the present work we show that pH regulation by means of urea dosing, in spite of the risk posed by ammonia toxicity towards methanogenic biomass, can be a viable alternative to avoid vinasse acidification. The ammonia formed in urea conversion remains in solution, rather than escaping to the biogas, and so its use as fertiliser can offset its cost of application in the process.

  4. A novel intracavitary applicator design for the treatment of deep vaginal fornices: preliminary dose metrics and geometric analysis

    PubMed Central

    Cormack, Robert A.; Viswanathan, Akila N.

    2015-01-01

    Purpose To investigate the dose distributions associated with a novel balloon sleeve placed over a standard cylinder applicator. Material and methods A computed tomography (CT) scan of a sleeve balloon shaped to inflate into the vaginal fornices was used to digitize 1-, 3-, and 5-catheter configurations. Point doses for rectum, apex, and fornix were calculated and compared to the values associated with a standard cylinder plan not targeting the vaginal fornices. Inflation of the sleeve balloon in the vaginal fornices and dose coverage with constraints to the rectum, bladder, and sigmoid D2cc were evaluated. Results Rectum, apex, and fornix doses were respectively 76%, 119%, and 44% for a standard cylinder; 190%, 310%, and 93% for a 1-catheter configuration; 98%, 109%, and 109% for a 3-catheter configuration; and 91%, 107%, and 96% for the 5-catheter configuration. In a patient analysis, expansion of the sleeve balloon into the vaginal fornices was confirmed. The 5-catheter configurations were associated with best coverage of the fornices and acceptable doses to rectum, bladder, and sigmoid. Conclusions A 1-catheter configuration cannot be used clinically due to high rectal and apex dose. In theoretical analysis, the 3- and 5-catheter configurations showed > 96% coverage to the vaginal fornices with a clinically acceptable rectal dose. In a treatment simulation in a patient, a 5-catheter configuration showed 90% coverage of the fornices with acceptable doses to the organs at risk. The treatment of deep vaginal fornices results in an increased rectal dose compared to a standard cylinder plan. PMID:25829937

  5. Application of Helminth ova infection dose curve to estimate the risks associated with biosolid application on soil.

    PubMed

    Navarro, I; Jiménez, B; Lucario, S; Cifuentes, E

    2009-03-01

    Helminth ova (HO) are the main biological concern when reusing sludge for agricultural production. Worldwide sludge regulations consider a permissible range of 0.25-1 HO/gTS. Such limits are unaffordable to most developing countries, due to high helminth ova content in sludge, and the lack of viable technology to inactivate them as needed. The quantitative microbial risk assessment (QMRA) is a useful tool to estimate the risk of treated sludge, considering feasible and viable limits. QMRA, however, has not been applied before for HO because no dose-infection curve was available. Therefore, the objectives of this paper are: to build up a risk-based model designed for untreated wastewater exposure (i.e., land irrigation) using Ascaris lumbricoides eggs as indicators for HO, and apply the results to assess health risk (i.e., Ascaris lumbricoides infection) associated with consumption of crops grown on biosolid-enriched soil. Data showed that it may be feasible to update HO threshold in biosolids from developing countries without significantly increasing risks. To reduce health risk from HO, it may be wiser to achieve feasible and evidence-based standards, than to set unaffordable limits in these countries. QMRA data suggested additional protection measures, such as biosolid application rates, crop restriction, and produce better washing practices.

  6. Biologically effective dose in fractionated molecular radiotherapy—application to treatment of neuroblastoma with 131I-mIBG

    NASA Astrophysics Data System (ADS)

    Mínguez, Pablo; Gustafsson, Johan; Flux, Glenn; Sjögreen Gleisner, Katarina

    2016-03-01

    In this work, the biologically effective dose (BED) is investigated for fractionated molecular radiotherapy (MRT). A formula for the Lea-Catcheside G-factor is derived which takes the possibility of combinations of sub-lethal damage due to radiation from different administrations of activity into account. In contrast to the previous formula, the new G-factor has an explicit dependence on the time interval between administrations. The BED of tumour and liver is analysed in MRT of neuroblastoma with 131I-mIBG, following a common two-administration protocol with a mass-based activity prescription. A BED analysis is also made for modified schedules, when due to local regulations there is a maximum permitted activity for each administration. Modifications include both the simplistic approach of delivering this maximum permitted activity in each of the two administrations, and also the introduction of additional administrations while maintaining the protocol-prescribed total activity. For the cases studied with additional (i.e. more than two) administrations, BED of tumour and liver decreases at most 12% and 29%, respectively. The decrease in BED of the tumour is however modest compared to the two-administration schedule using the maximum permitted activity, where the decrease compared to the original schedule is 47%.

  7. Empirical Complexities in the Genetic Foundations of Lethal Mutagenesis

    PubMed Central

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

    2013-01-01

    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. PMID:23934886

  8. The Pursuit of Non-Lethal Capabilities

    DTIC Science & Technology

    2002-01-01

    at the upper end of the spectrum. Without non- lethal options, a Marine would potentially have to resort to deadly force or face further risk by...Technologies with a potential for generating non- lethal military capabilities cover a very broad spectrum. At the low end of this spectrum are...systems, these modifications must not in any way reduce the capability of those systems to fire lethal munitions.” This stance incurred much debate

  9. Dose optimisation of antibiotics in children: application of pharmacokinetics/pharmacodynamics in paediatrics

    PubMed Central

    Downes, Kevin J.; Hahn, Andrea; Wiles, Jason; Courter, Joshua D.; Vinks, Alexander A.

    2014-01-01

    The judicious use of antibiotics to combat infections in children relies upon appropriate selection of an agent, dose and duration to maximise efficacy and to minimise toxicity. Critical to dose optimisation is an understanding of the pharmacokinetics and pharmacodynamics of available drugs. Optimal dosing strategies may take advantage of pharmacokinetic/pharmacodynamic (PK/PD) principles so that antibiotic dosing can be individualised to assure effective bacterial killing in patients who have altered pharmacokinetics or who have infections with less susceptible or resistant organisms. This review will outline the fundamentals of antimicrobial pharmacokinetics/pharmacodynamics through discussion of antibacterial agents most often used in children. We aim to highlight the importance of dose optimisation in paediatrics and describe non-conventional dosing strategies that can take advantage of PK/PD principles at the bedside. PMID:24389079

  10. X-ray-induced dominant lethal mutations in mouse oocytes detected by an in vitro assay

    SciTech Connect

    Goldstein, L.S.

    1987-11-01

    Female mice were X-irradiated with 0.5-4.5 Gy 2 h before mating to unirradiated males of the same strain. The dominant lethal frequencies (DLF) were determined by growing the embryos in vitro from the two-cell stage and determining the relative rates of successful embryogenesis to the blastocyst stage and to the trophectoderm outgrowth with proliferated inner cell mass stage. The DLF increased with increasing dose, the two linear aspects having a breakpoint at about 1.5 Gy. The nature of embryo failure was also dose dependent. At doses less than 2.0 Gy embryos failed predominantly after blastocyst formation, but at higher doses the embryos failed both before and after blastocyst formation. Over the dose range tested, the frequency with which lesions leading to dominant lethality were induced (i.e., -ln(1 - DLF)) increased linearly with increasing dose.

  11. Application of EPR dosimetry in bone for ex vivo measurements of doses in radiotherapy patients.

    PubMed

    Krefft, K; Drogoszewska, B; Kaminska, J; Juniewicz, M; Wołąkiewicz, G; Jakacka, I; Ciesielski, B

    2014-11-01

    In the present study, bone samples from three patients treated in radiotherapy facilities in Poland were used for the determination of doses absorbed during radiotherapy. The samples were obtained during surgical treatments of patients performed due to medical indications. For the purpose of retrospective dosimetry, sensitivity of the radiation-induced EPR signal was individually calibrated in the samples by re-irradiation of the samples with known doses. The doses reconstructed in bones extracted within 6 months after irradiation were consistent with those calculated by treatment planning systems. The dose reconstructed in the bone removed 6 y after radiotherapy was ∼14% lower than the calculated one.

  12. Suppression of rice methane production and emission by low dose sulfate application

    NASA Astrophysics Data System (ADS)

    Gauci, V.; Dise, N. B.; Howell, G.

    2006-12-01

    Large individual applications of SO42- (102-103 kg SO42--S/ha) are known to suppress methane emissions from rice paddies by up to ~70%. The application of large quantities of SO42- amendments to rice paddies has therefore been proposed as a greenhouse gas mitigation strategy. In a similar system, natural peatlands, research has established that very low rates of SO4^{2- } deposition (~25 kg SO42--S/ha/yr as small weekly pulses), similar to those of regions experiencing acid rain pollution, suppress methane emissions by as much as 30-40%. It is thought that this is due to stimulation of sulfate-reducing microbial populations that out-compete methane producers for substrates. Given that acid rain S pollution is forecast to increase in Asia, the major rice growing region, we sought to establish the potential for acid rain to suppress CH4 emission from rice agro-ecosystems by experimentally simulating acid rain inputs of S deposition to rice mesocosms in the laboratory. We used soils from Portuguese rice growing regions as they experience low ambient S deposition, and investigated the effect of simulated sulfate deposition (small regular pulses) on CH4 emissions, pore- water concentrations of CH4 and alternate electron acceptors. We also applied an annual dose of S deposition as a single pulse of sulfate to one set of replicate rice mesocosms. After a lag time of 7 weeks, CH4 emission from the mesocosms subjected to the small weekly applications of `acid rain' sulfate as Na2SO4 at a rate of 100 kg SO42- -S/ha/yr (amounting to a total deposition of ~20 kg SO42- -S/ha throughout the 10 week experiment) were reduced below the control by an average of 22%, and as much as 35% on a single date. CH4 emissions from the `single pulse' experiment were significantly suppressed by the applied sulfate as were pore-water CH4 concentrations.

  13. A descriptive and broadly applicable model of therapeutic and stray absorbed dose from 6 to 25 MV photon beams.

    PubMed

    Schneider, Christopher W; Newhauser, Wayne D; Wilson, Lydia J; Schneider, Uwe; Kaderka, Robert; Miljanić, Saveta; Knežević, Željka; Stolarcyzk, Liliana; Durante, Marco; Harrison, Roger M

    2017-07-01

    To develop a simple model of therapeutic and stray absorbed dose for a variety of treatment machines and techniques without relying on proprietary machine-specific parameters. Dosimetry measurements conducted in this study and from the literature were used to develop an analytical model of absorbed dose from a variety of treatment machines and techniques in the 6 to 25 MV interval. A modified one-dimensional gamma-index analysis was performed to evaluate dosimetric accuracy of the model on an independent dataset consisting of measured dose profiles from seven treatment units spanning four manufacturers. The average difference between the calculated and measured absorbed dose values was 9.9% for those datasets on which the model was trained. Additionally, these results indicate that the model can provide accurate calculations of both therapeutic and stray radiation dose from a wide variety of radiotherapy units and techniques. We have developed a simple analytical model of absorbed dose from external beam radiotherapy treatments in the 6 to 25 MV beam energy range. The model has been tested on measured data from multiple treatment machines and techniques, and is broadly applicable to contemporary external beam radiation therapy. © 2017 American Association of Physicists in Medicine.

  14. Lethal Mutagenesis Failure May Augment Viral Adaptation

    PubMed Central

    Paff, Matthew L.; Stolte, Steven P.; Bull, James J.

    2014-01-01

    Lethal mutagenesis, the attempt to extinguish a population by elevating its mutation rate, has been endorsed in the virology literature as a promising approach for treating viral infections. In support of the concept, in vitro studies have forced viral extinction with high doses of mutagenic drugs. However, the one known mutagenic drug used on patients commonly fails to cure infections, and in vitro studies typically find a wide range of mutagenic conditions permissive for viral growth. A key question becomes how subsequent evolution is affected if the viral population is mutated but avoids extinction—Is viral adaptation augmented rather than suppressed? Here we consider the evolution of highly mutated populations surviving mutagenesis, using the DNA phage T7. In assays using inhibitory hosts, whenever resistance mutants were observed, the mutagenized populations exhibited higher frequencies, but some inhibitors blocked plaque formation by even the mutagenized stock. Second, outgrowth of previously mutagenized populations led to rapid and potentially complete fitness recovery but polymorphism was slow to decay, and mutations exhibited inconsistent patterns of change. Third, the combination of population bottlenecks with mutagenesis did cause fitness declines, revealing a vulnerability that was not apparent from mutagenesis of large populations. The results show that a population surviving high mutagenesis may exhibit enhanced adaptation in some environments and experience little negative fitness consequences in many others. PMID:24092771

  15. [Application of half-dose depot long-acting triptorelin in postoperative adjuvant therapy for endometriosis].

    PubMed

    Liu, Xia; Zhang, Hong-xia; Wang, Li-ping; Fu, Wei-ping

    2013-01-15

    To evaluate the efficacy and adverse effects of half-dose depot long-acting triptorelin in the therapy of endometriosis. The efficacy and adverse effects of routine-dose or half-dose triptorelin in postoperative endometriosis patients were prospectively observed. A total of 186 postoperative patients with moderate or severe endometriosis received an intramuscular injection of triptorelin every 28 days for 6 times. They were randomly divided into 3 groups, i.e. half-dose group (n = 99): 1.875 mg each time; "draw-back" group (n = 52): 3.75 mg first time, then 1.875 mg each time; and routine-dose group (n = 35): 3.75 mg each time. Amenorrhea was effectively induced in all patients after the second injection. There was no significant difference in the rate of serum E2 level at Day 28 of every injection below the upper limit of "estrogen threshold (110 - 146 pmol/L)" not stimulating ectopic endometrium proliferation among half-dose group, "draw-back" group and routine-dose group (99% vs 100% and 99.0%, P > 0.05), the percentage of E2 < 37 pmol/L in E2 < 110 pmol/L in half-dose group was significantly lower than that in "draw-back" and routine-dose groups after 2-5(th) injection (69% vs 79% and 85%, P < 0.01), but there was no significant difference after first half-dose and routine-dose injection (71% vs 73%, P > 0.05). No significant difference existed in the rate of pelvic pain relief during the first returning menstruation and the recurrence rate of endometriosis within 1 year postoperation among three groups (both P > 0.05). However, the incidences of menopausal syndrome and severe menopausal syndrome in half-dose group were significantly lower than those in "draw-back" and routine-dose groups (both P < 0.01). And the incompletion rate of six-time drug for severe menopause syndrome was also significantly lower (P < 0.05) while the completion rate of six-time drug use in half-dose group was significantly higher (P < 0.05). As a postoperative adjuvant, half-dose depot

  16. 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.

  17. Daily CT measurement of needle applicator displacement during multifractionated high-dose-rate interstitial brachytherapy for postoperative recurrent uterine cancer.

    PubMed

    Yoshida, Ken; Ueda, Mari; Takenaka, Tadashi; Yamazaki, Hideya; Kotsuma, Tadayuki; Aramoto, Kazumasa; Miyake, Shunsuke; Koretsune, Yukihiro; Ban, Chiaki; Tanaka, Eiichi

    2012-01-01

    We investigated daily needle applicator displacement during multifractionated high-dose-rate interstitial brachytherapy (HDR-ISBT) for postoperative recurrent uterine cancer. Eight patients with postoperative recurrent uterine cancer received HDR-ISBT with or without external beam radiotherapy using our unique ambulatory technique. To analyze displacement, we obtained daily computed tomography (CT) images for 122 flexible needle applicators at 21, 45, 69, and 93 hours after implantation. Displacement was defined as the length between the center of gravity of titanium markers and the needle applicator tips along the daily CT axis. For cases in which displacement was not corrected, we also calculated the dose that covered 90% of the clinical target volume (D90(CTV)) using a dose-volume histogram (DVH). Median caudal needle applicator displacement at 21, 45, 69, and 93 hours was 3, 2, 4, and 5 mm, respectively. More than 15 mm displacement was observed for 2% (2 of 122) and 17% (10 of 60) of needle applicators at 21 and 93 hours, respectively. Cases in which dwell positions were not changed to correct the treatment plan, 2 of 8 patients showed more than 10% reduction in D90(CTV) values compared with the initial treatment plan. Correction of dwell positions of the treatment source improves treatment DVH for multifractionated HDR-ISBT.

  18. Fast analytical approach of application specific dose efficient spectrum selection for diagnostic CT imaging and PET attenuation correction

    NASA Astrophysics Data System (ADS)

    Rui, Xue; Jin, Yannan; FitzGerald, Paul F.; Wu, Mingye; Alessio, Adam M.; Kinahan, Paul E.; De Man, Bruno

    2016-11-01

    Computed tomography (CT) has been used for a variety of applications, two of which include diagnostic imaging and attenuation correction for PET or SPECT imaging. Ideally, the x-ray tube spectrum should be optimized for the specific application to minimize the patient radiation dose while still providing the necessary information. In this study, we proposed a projection-based analytic approach for the analysis of contrast, noise, and bias. Dose normalized contrast to noise ratio (CNRD), inverse noise normalized by dose (IND) and bias are used as evaluation metrics to determine the optimal x-ray spectrum. Our simulation investigated the dose efficiency of the x-ray spectrum ranging from 40 kVp to 200 kVp. Water cylinders with diameters of 15 cm, 24 cm, and 35 cm were used in the simulation to cover a variety of patient sizes. The effects of electronic noise and pre-patient copper filtration were also evaluated. A customized 24 cm CTDI-like phantom with 13 mm diameter inserts filled with iodine (10 mg ml-1), tantalum (10 mg ml-1), water, and PMMA was measured with both standard (1.5 mGy) and ultra-low (0.2 mGy) dose to verify the simulation results at tube voltages of 80, 100, 120, and 140 kVp. For contrast-enhanced diagnostic imaging, the simulation results indicated that for high dose without filtration, the optimal kVp for water contrast is approximately 100 kVp for a 15 cm water cylinder. However, the 60 kVp spectrum produces the highest CNRD for bone and iodine. The optimal kVp for tantalum has two selections: approximately 50 and 100 kVp. The kVp that maximizes CNRD increases when the object size increases. The trend in the CTDI phantom measurements agrees with the simulation results, which also agrees with previous studies. Copper filtration improved the dose efficiency for water and tantalum, but reduced the iodine and bone dose efficiency in a clinically-relevant range (70-140 kVp). Our study also shows that for CT-based attenuation

  19. Estimation of doses to personnel and patients during endovascular brachytherapy applications.

    PubMed

    Kirisits, Christian; Hefner, Alfred; Wexberg, Paul; Pokrajac, Boris; Glogar, Dietmar; Pötter, Richard; Georg, Dietmar

    2004-01-01

    In the last few years coronary endovascular brachytherapy using gamma- and beta-emitting radionuclides has been established as a standard treatment procedure to prevent restenosis after percutaneous coronary interventions. Direct measurements and calculations were made to determine personnel doses and organ doses of patients due to gamma rays of 192Ir and beta rays of 90Sr/90Y and 32P sources. In general, our results show that the dose levels are low compared with the X-ray exposure from angiography. The dose rate from bremsstrahlung at 1 m distance from a device containing a 90Sr/90Y source of 2.3 GBq is 4 micro Sv h(-1). The skin dose from beta rays during source transfer into and from the patient was estimated with the directional dose equivalent H'(0.07) of 10 micro Sv at 1 m distance from the catheter. By maintaining safe distances, the dose levels can be kept well within annual dose limits.

  20. Risk estimators for radiation-induced bone marrow syndrome lethality in humans

    SciTech Connect

    Scott, B.R.; Hahn, F.F.; McClellan, R.O.; Seiler, F.A.

    1988-09-01

    This manuscript provides risk estimators for acute lethality from radiation-induced injury to the bone marrow of humans after uniform total-body exposure to low linear energy transfer (LET) radiation. The risk estimators are needed for nuclear disaster risk assessment. The approach used is based on the dose X, in units of D50 (i.e., the dose required for 50% lethality). Using animal data, it is demonstrated that the use of dose in units of D50 eliminates most of the variability associated with mammalian species, type of low-LET radiation, and low-LET dose rate. Animal data are used to determine the shape of the dose-effect curve for marrow-syndrome lethality in man and to develop a functional relationship for the dependence of the D50 on dose rate. The functional relationship is used, along with the Weibull model, to develop acute lethality risk estimators for complex temporal patterns of continuous exposure to low-LET radiation. Animal data are used to test model predictions.

  1. Application of Low Dose Radiation Adaptive Response to Control Aging-Related Disease

    SciTech Connect

    Doss, Mohan

    2013-11-01

    Oxidative damage has been implicated in the pathogenesis of most aging-related diseases including neurodegenerative diseases. Antioxidant supplementation has been found to be ineffective in reducing such diseases, but increased endogenous production of antioxidants from the adaptive response due to physical and cognitive exercises (which increase oxidative metabolism and oxidative stress) has been effective in reducing some of the diseases. Low dose radiation (LDR), which increases oxidative stress and results in adaptive response of increased antioxidants, may provide an alternative method of controlling the aging-related diseases. We have studied the effect of LDR on the induction of adaptive response in rat brains and the effectiveness of the LDR in reducing the oxidative damage caused by subsequent high dose radiation. We have also investigated the effect of LDR on apomorphine-induced rotations in the 6-hydroxydopamine (6-OHDA) unilaterally-lesioned rat model of Parkinson?s disease (PD). LDR was observed to initiate an adaptive response in the brain, and reduce the oxidative damage from subsequent high dose radiation exposure, confirming the effectiveness of LDR adaptive response in reducing the oxidative damage from the free radicals due to high dose radiation. LDR resulted in a slight improvement in Tyrosine hydroxylase expression on the lesioned side of substantia nigra (indicative of its protective effect on the dopaminergic neurons), and reduced the behavioral symptoms in the 6-OHDA rat model of PD. Translation of this concept to humans, if found to be applicable, may be a possible approach for controlling the progression of PD and other neurodegenerative diseases. Since any translation of the concept to humans would be hindered by the currently prevalent carcinogenic concerns regarding LDR based on the linear no-threshold (LNT) model, we have also studied the justifications for the use of the LNT model. One of the shortcomings of the LNT model is that it

  2. No-threshold dose-response curves for nongenotoxic chemicals: Findings and applications for risk assessment

    SciTech Connect

    Sheehan, Daniel M. . E-mail: dansheeh@swbell.net

    2006-01-15

    We tested the hypothesis that no threshold exists when estradiol acts through the same mechanism as an active endogenous estrogen. A Michaelis-Menten (MM) equation accounting for response saturation, background effects, and endogenous estrogen level fit a turtle sex-reversal data set with no threshold and estimated the endogenous dose. Additionally, 31 diverse literature dose-response data sets were analyzed by adding a term for nonhormonal background; good fits were obtained but endogenous dose estimations were not significant due to low resolving power. No thresholds were observed. Data sets were plotted using a normalized MM equation; all 178 data points were accommodated on a single graph. Response rates from {approx}1% to >95% were well fit. The findings contradict the threshold assumption and low-dose safety. Calculating risk and assuming additivity of effects from multiple chemicals acting through the same mechanism rather than assuming a safe dose for nonthresholded curves is appropriate.

  3. Dosimetric Comparison of 3-Dimensional Planning Techniques Using an Intravaginal Multichannel Balloon Applicator for High-Dose-Rate Gynecologic Brachytherapy

    SciTech Connect

    Park, Sang-June Chung, Melody; Demanes, D. Jeffrey; Banerjee, Robyn; Steinberg, Michael; Kamrava, Mitchell

    2013-11-15

    Purpose: To study the dosimetric differences of various channel combinations of the Capri vaginal applicator. Methods and Materials: The Capri consists of a single central channel (R1), an inner array of 6 channels (R2), and an outer array of 6 channels (R3). Three-dimensional plans were simulated for 6 channel arrangements (R1, R2, R12, R13, R23, and R123). Treatment plans were optimized to the applicator surface or 5-mm depth while minimizing dose to organs at risk (OARs: bladder, rectum, sigmoid, and urethra). The clinical target volume (CTV) was defined as a 5-mm circumferential shell extending 4 cm in length around the applicator. Clinical target volume coverage (D{sub mean}, D{sub 90}, V{sub 100}, and V{sub 150}) and OAR doses (D{sub 0.1} {sub cm{sup 3}}, D{sub 1} {sub cm{sup 3}}, D{sub 2} {sub cm{sup 3}}, and D{sub mean}) were compared. A comparison between the Capri (R123) and a conventional single-channel applicator was also done. Statistical significance (P value <.05) was evaluated with a 2-tailed t test. Results: When prescribing to 5-mm depth, CTV coverage using all 13 channels (R123) versus a single channel (R1) was similar; however, when prescribing to the surface there were differences (P<.0001) in all CTV metrics except for the V{sub 150}. The R1 plans had higher doses to all OARs compared with R123 plans (P<.007). Doses to OARs were not significantly different between R23 and R123 plans (P=.05-.95), and CTV coverage differences were on the order of 1%. Capri R123 plans provided slightly lower CTV D{sub 90} and D{sub mean} but equivalent OAR doses with smaller standard deviations compared with conventional cylinder plans for both prescriptions. Conclusions: The Capri multichannel applicator provides equivalent target coverage at 5-mm depth, with significantly reduced dose to OARs relative to using a single channel. Optimal plans can be achieved using R12 (lowest V{sub 150}) or R123 or R23 (lowest OAR doses)

  4. Patient-specific radiation dose and cancer risk estimation in CT: Part II. Application to patients

    SciTech Connect

    Li Xiang; Samei, Ehsan; Segars, W. Paul; Sturgeon, Gregory M.; Colsher, James G.; Toncheva, Greta; Yoshizumi, Terry T.; Frush, Donald P.

    2011-01-15

    Purpose: Current methods for estimating and reporting radiation dose from CT examinations are largely patient-generic; the body size and hence dose variation from patient to patient is not reflected. Furthermore, the current protocol designs rely on dose as a surrogate for the risk of cancer incidence, neglecting the strong dependence of risk on age and gender. The purpose of this study was to develop a method for estimating patient-specific radiation dose and cancer risk from CT examinations. Methods: The study included two patients (a 5-week-old female patient and a 12-year-old male patient), who underwent 64-slice CT examinations (LightSpeed VCT, GE Healthcare) of the chest, abdomen, and pelvis at our institution in 2006. For each patient, a nonuniform rational B-spine (NURBS) based full-body computer model was created based on the patient's clinical CT data. Large organs and structures inside the image volume were individually segmented and modeled. Other organs were created by transforming an existing adult male or female full-body computer model (developed from visible human data) to match the framework defined by the segmented organs, referencing the organ volume and anthropometry data in ICRP Publication 89. A Monte Carlo program previously developed and validated for dose simulation on the LightSpeed VCT scanner was used to estimate patient-specific organ dose, from which effective dose and risks of cancer incidence were derived. Patient-specific organ dose and effective dose were compared with patient-generic CT dose quantities in current clinical use: the volume-weighted CT dose index (CTDI{sub vol}) and the effective dose derived from the dose-length product (DLP). Results: The effective dose for the CT examination of the newborn patient (5.7 mSv) was higher but comparable to that for the CT examination of the teenager patient (4.9 mSv) due to the size-based clinical CT protocols at our institution, which employ lower scan techniques for smaller

  5. Patient-specific radiation dose and cancer risk estimation in CT: Part II. Application to patients

    PubMed Central

    Li, Xiang; Samei, Ehsan; Segars, W. Paul; Sturgeon, Gregory M.; Colsher, James G.; Toncheva, Greta; Yoshizumi, Terry T.; Frush, Donald P.

    2011-01-01

    Purpose: Current methods for estimating and reporting radiation dose from CT examinations are largely patient-generic; the body size and hence dose variation from patient to patient is not reflected. Furthermore, the current protocol designs rely on dose as a surrogate for the risk of cancer incidence, neglecting the strong dependence of risk on age and gender. The purpose of this study was to develop a method for estimating patient-specific radiation dose and cancer risk from CT examinations. Methods: The study included two patients (a 5-week-old female patient and a 12-year-old male patient), who underwent 64-slice CT examinations (LightSpeed VCT, GE Healthcare) of the chest, abdomen, and pelvis at our institution in 2006. For each patient, a nonuniform rational B-spine (NURBS) based full-body computer model was created based on the patient’s clinical CT data. Large organs and structures inside the image volume were individually segmented and modeled. Other organs were created by transforming an existing adult male or female full-body computer model (developed from visible human data) to match the framework defined by the segmented organs, referencing the organ volume and anthropometry data in ICRP Publication 89. A Monte Carlo program previously developed and validated for dose simulation on the LightSpeed VCT scanner was used to estimate patient-specific organ dose, from which effective dose and risks of cancer incidence were derived. Patient-specific organ dose and effective dose were compared with patient-generic CT dose quantities in current clinical use: the volume-weighted CT dose index (CTDIvol) and the effective dose derived from the dose-length product (DLP). Results: The effective dose for the CT examination of the newborn patient (5.7 mSv) was higher but comparable to that for the CT examination of the teenager patient (4.9 mSv) due to the size-based clinical CT protocols at our institution, which employ lower scan techniques for smaller patients

  6. Recovery of microorganisms from potentially lethal radiation damage

    NASA Astrophysics Data System (ADS)

    Borsa, Joseph; Lucht, Lisa; Blank, Greg

    1995-02-01

    Dose response curves for inactivation of microorganisms are central in the design of any process intending to use irradiation for the improvement of the microbiological quality of any treated materials, be it food or medical supplies. Under some conditions a fraction of irradiated microorganisms is able to recover from a potentially lethal dose. This recovery phenomenon must be considered in determining the efficacy of irradiation in microbial inactivation. In this work the recovery phenomenon was examined in eleven species of microorganisms. Variables examined included dose, radiation type, post-irradiation holding temperature, and nutritient medium used to culture the organism. Kinetics of damage repair and fixation were also examined. Results indicate that, for certain species of microorganisms, recovery can significantly lower the killing efficacy of irradiation.

  7. Potentiation by caffeine of potentially lethal fast-neutron damage in cultured human cells

    SciTech Connect

    Schroy, C.B.; Furcinitti, P.S.; Todd, P.; Kukulinsky, N.E.

    1980-11-01

    Caffeine was found to potentiate single-dose fast-neutron-induced killing of human T-1 cells when present at 2 mM for 60 hr or more after (and 10 hr before) irradiation. Analyses of survival curves of cells treated with neutrons or X rays with and without caffeine indicate that only the linear, low-dose portion of survival curves is modified. Potentiation of lethality by caffeine is attributed mainly to its effects on single-hit potentially lethal lesions, possibly certain DNA double-strand breaks.

  8. Histopathological effects of anthrax lethal factor on rat liver.

    PubMed

    Altunkaynak, Berrin Zuhal; Ozbek, Elvan

    2015-01-01

    Bacillus anthracis, the causative agent of anthrax, has become an increasingly important scientific topic due to its potential role in bioterrorism. The lethal toxin (LT) of B. anthracis consists of lethal factor (LF) and a protective antigen (PA). This study investigated whether only lethal factor was efficient as a hepatotoxin in the absence of the PA. To achieve this aim, LF (100 µg/kg body weight, dissolved in sterile distilled water) or distilled water vehicle were intraperitoneally injected once into adult rats. At 24 h post-injection, the hosts were euthanized and their livers removed and tissue samples examined under light and electron microscopes. As a result of LF application, hepatic injury - including cytoplasmic and nuclear damage in hepatocytes, sinusoidal dilatation, and hepatocellular lysis - became apparent. Further, light microscopic analyses of liver sections from the LF-injected rats revealed ballooning degeneration and cytoplasmic loss within hepatocytes, as well as peri-sinusoidal inflammation. Additionally, an increase in the numbers of Kupffer cells was evident. Common vascular injuries were also found in the liver samples; these injuries caused hypoxia and pathological changes. In addition, some cytoplasmic and nuclear changes were detected within the liver ultrastructure. The results of these studies allow one to suggest that LF could be an effective toxicant alone and that PA might act in situ to modify the effect of this agent (or the reverse situation wherein LF modifies effects of PA) such that lethality results.

  9. Alcohol Consumption and Nearly Lethal Suicide Attempts.

    ERIC Educational Resources Information Center

    Powell, Kenneth E.; Kresnow, Marcie-jo; Mercy, James A.; Potter, Lloyd B.; Swann, Alan C.; Frankowski, Ralph F.; Lee, Roberta K.; Bayer, Timothy L.

    2002-01-01

    Presents a case-control study of the association between nearly lethal suicide attempts and facets of alcohol consumption; namely, drinking frequency, drinking quantity, binge drinking, alcoholism, drinking within 3 hours of suicide attempt, and age began drinking. In bivariate analyses, all measures were associated with nearly lethal suicide…

  10. Alcohol Consumption and Nearly Lethal Suicide Attempts.

    ERIC Educational Resources Information Center

    Powell, Kenneth E.; Kresnow, Marcie-jo; Mercy, James A.; Potter, Lloyd B.; Swann, Alan C.; Frankowski, Ralph F.; Lee, Roberta K.; Bayer, Timothy L.

    2002-01-01

    Presents a case-control study of the association between nearly lethal suicide attempts and facets of alcohol consumption; namely, drinking frequency, drinking quantity, binge drinking, alcoholism, drinking within 3 hours of suicide attempt, and age began drinking. In bivariate analyses, all measures were associated with nearly lethal suicide…

  11. Fast dose kernel interpolation using Fourier transform with application to permanent prostate brachytherapy dosimetry

    SciTech Connect

    Liu, Derek Sloboda, Ron S.

    2014-05-15

    Purpose: Boyer and Mok proposed a fast calculation method employing the Fourier transform (FT), for which calculation time is independent of the number of seeds but seed placement is restricted to calculation grid points. Here an interpolation method is described enabling unrestricted seed placement while preserving the computational efficiency of the original method. Methods: The Iodine-125 seed dose kernel was sampled and selected values were modified to optimize interpolation accuracy for clinically relevant doses. For each seed, the kernel was shifted to the nearest grid point via convolution with a unit impulse, implemented in the Fourier domain. The remaining fractional shift was performed using a piecewise third-order Lagrange filter. Results: Implementation of the interpolation method greatly improved FT-based dose calculation accuracy. The dose distribution was accurate to within 2% beyond 3 mm from each seed. Isodose contours were indistinguishable from explicit TG-43 calculation. Dose-volume metric errors were negligible. Computation time for the FT interpolation method was essentially the same as Boyer's method. Conclusions: A FT interpolation method for permanent prostate brachytherapy TG-43 dose calculation was developed which expands upon Boyer's original method and enables unrestricted seed placement. The proposed method substantially improves the clinically relevant dose accuracy with negligible additional computation cost, preserving the efficiency of the original method.

  12. 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

  13. Small-molecule inhibitors of lethal factor protease activity protect against anthrax infection.

    PubMed

    Moayeri, Mahtab; Crown, Devorah; Jiao, Guan-Sheng; Kim, Seongjin; Johnson, Alan; Leysath, Clinton; Leppla, Stephen H

    2013-09-01

    Bacillus anthracis, the causative agent of anthrax, manifests its pathogenesis through the action of two secreted toxins. The bipartite lethal and edema toxins, a combination of lethal factor or edema factor with the protein protective antigen, are important virulence factors for this bacterium. We previously developed small-molecule inhibitors of lethal factor proteolytic activity (LFIs) and demonstrated their in vivo efficacy in a rat lethal toxin challenge model. In this work, we show that these LFIs protect against lethality caused by anthrax infection in mice when combined with subprotective doses of either antibiotics or neutralizing monoclonal antibodies that target edema factor. Significantly, these inhibitors provided protection against lethal infection when administered as a monotherapy. As little as two doses (10 mg/kg) administered at 2 h and 8 h after spore infection was sufficient to provide a significant survival benefit in infected mice. Administration of LFIs early in the infection was found to inhibit dissemination of vegetative bacteria to the organs in the first 32 h following infection. In addition, neutralizing antibodies against edema factor also inhibited bacterial dissemination with similar efficacy. Together, our findings confirm the important roles that both anthrax toxins play in establishing anthrax infection and demonstrate the potential for small-molecule therapeutics targeting these proteins.

  14. Tumour response following high-dose intratumoural application of Viscum album on a patient with adenoid cystic carcinoma

    PubMed Central

    Werthmann, Paul Georg; Helling, Dieter; Heusser, Peter; Kienle, Gunver Sophia

    2014-01-01

    Adenoid cystic carcinoma (ACC) is a rare type of cancer that typically originates in the salivary glands. Surgical removal can lead to functional loss and psychological distress. Viscum album extract (VAE) is a herbal remedy with dose-dependent cytotoxic, apoptogenic and immunological effects. In some case reports, tumour regression has been observed following high-dose local applications of VAE. An active 88-year-old man with fast-growing ACC of the hard palate refused surgical removal and received high-dose intratumoural injections of VAE (alone) over a 10-month period. The tumour decreased in size, softened and loosened from its surroundings. A biopsy during the course showed inflammation. The patient remained well and without functional limitations during the therapy and follow-up period (5 months). VAE produced no reported side effects. This aged patient exemplifies a satisfying course of ACC under VAE resulting in good quality of life and partial tumour regression. PMID:25082867

  15. Locomotion Inhibition of Cimex lectularius L. Following Topical, Sublethal Dose Application of the Chitin Synthesis Inhibitor Lufenuron

    PubMed Central

    Campbell, Brittany; Baldwin, Rebecca; Koehler, Philip

    2017-01-01

    To date, few studies have evaluated chitin synthesis inhibitors against bed bugs, although they would provide an alternative mode of action to circumvent insecticide resistance. Acute and sublethal effects of lufenuron were evaluated against two strains of the common bed bug. Combined acute and sublethal effects were used to calculate effective doses. The dose that was effective against 50% of Harlan strain bed bugs was 0.0081% (w/v), and was much higher against Bradenton strain bed bugs (1.11% w/v). Sublethal doses were chosen to determine the effect that leg abnormalities had on pulling force. Both Harlan and Bradenton strain bed bugs had significantly lower locomotion ability (p < 0.0001) following topical application of lufenuron. The observed sublethal effects that limit locomotion could prevent bed bugs from moving within a domicile and taking a blood meal, subsequently reducing a bed bug population over time. PMID:28862646

  16. Locomotion Inhibition of Cimex lectularius L. Following Topical, Sublethal Dose Application of the Chitin Synthesis Inhibitor Lufenuron.

    PubMed

    Campbell, Brittany; Baldwin, Rebecca; Koehler, Philip

    2017-09-01

    To date, few studies have evaluated chitin synthesis inhibitors against bed bugs, although they would provide an alternative mode of action to circumvent insecticide resistance. Acute and sublethal effects of lufenuron were evaluated against two strains of the common bed bug. Combined acute and sublethal effects were used to calculate effective doses. The dose that was effective against 50% of Harlan strain bed bugs was 0.0081% (w/v), and was much higher against Bradenton strain bed bugs (1.11% w/v). Sublethal doses were chosen to determine the effect that leg abnormalities had on pulling force. Both Harlan and Bradenton strain bed bugs had significantly lower locomotion ability (p < 0.0001) following topical application of lufenuron. The observed sublethal effects that limit locomotion could prevent bed bugs from moving within a domicile and taking a blood meal, subsequently reducing a bed bug population over time.

  17. Applicability f the Damage Dose Concept to Ground Evaluation of Trijunction Solar Cells

    NASA Astrophysics Data System (ADS)

    David, J.-P.; Chanterault, C.; Rapp, E.; Inguimbert, C.

    2005-05-01

    The degradation of trijunction solar cells and subcells from the same technology is characterised. The parametric and physical degradations are presented versus damage dose deposited by electrons of different energies and protons. It appears that the physical degradation of GaInP junctions depends relatively closely on the damage dose but this is not the case for the open circuit voltage degradation. Concerning GaAs junctions, the correlation is shown on a very wide range of NIEL values but with large deviations. More work is needed to confirm these results but the damage dose concept appears to be interesting even if not sufficient for accurate ground end-of-live evaluation.

  18. [Lethal effects of scopoletin and bisdemethoxycurcumin against Tetranychus cinnabarinus Boisd. (Acari: Tetranychidae): a simulation study].

    PubMed

    Yang, Zhen-Guo; Zhang, Yong-Qiang; Ding, Wei; Luo, Jin-Xiang

    2013-01-01

    By using slide-dip bioassay method under laboratory condition, an investigation was made on the lethal effects of scopoletin, bisdemethoxycurcumin (BDMC), and their combination at an optimal mass ratio (7:6) of scopoletin to BDMC against the adult females of Tetranychus cinnabarinus Boisd. A time-dose mortality model (TDM) was established, which passed the Hosmer-Lemeshow test. The sensitivity of the adult females to the concentration change of the acaricides was in the sequence of scopoletin > optimal mass ratio of scopoletin to BDMC > BDMC. The peak mortality of the female adults was found at 32, 28 and 32 h after treated with BDMC, scopoletin, and their combination at the optimal mass ratio, respectively. The values of the LC50 and LC90 at 48 h after treated with BDMC, scopoletin, and their combination at the optimal mass ratio were 0.3324, 0.2035 and 0.2195 mg x mL(-1), and 2.1198, 0.9521 and 1.1617 mg x mL(-1), and the median lethal time (LT50) of BDMC, scopoletin, and their combination at the optimal mass ratio was 7.4, 6.0 and 6.1 h at the concentration 1.0 mg x mL(-1), and 6.4, 4.8 and 5.0 h at the concentration 2.0 mg x mL(-1), respectively. The acaricidal activity and time-dose response of the optimal combination of scopoletin and BDMC were closer to those of scopoletin, suggesting a synergistic acaricidal activity of the combination of scopoletin and BDMC, which was worthy to be developed for application.

  19. 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

  20. Development of an objective dose distribution analysis method for OSL dating and pilot studies for planetary applications

    NASA Astrophysics Data System (ADS)

    Lepper, Kenneth Errol

    Scope and method of study. Part I: In its simplest expression a luminescence age is the natural absorbed radiation dose (De) divided by the in-situ dose rate. The experimental techniques of Optically Stimulated Luminescence (OSL) dating have evolved to the point were hundreds of Des, and therefore depositional ages can be quickly and conveniently determined for a single sediment sample. The first major objective of this research was to develop an objective analysis method for analyzing dose distribution data and selecting an age-representative dose (Dp). The analytical method was developed based on dose data sets collected from 3 eolian and 3 fluvial sediment samples from Central Oklahoma. Findings and conclusions. Part I: An objective method of presenting the dose distribution data, and a mathematically rigorous means of determining the Dp, as well as a statistically meaningful definition of the uncertainty in Dp have been proposed. The concept of experimental error deconvolution was introduced. In addition a set of distribution shape parameters to facilitate comparison among samples have been defined. These analytical techniques hold the potential to greatly enhance the accuracy and utility of OSL dating for young fluvial sediments. Scope and method of study. Part II: The second major objective of this research was to propose the application of luminescence dating to sediments on Mars. A set of fundamental luminescence dating properties was evaluated for a martian surface materials analog and a polar deposit contextual analog. Findings and conclusions. Part II: The luminescence signals measured from the analogs were found to have a wide dynamic dose response range with no unusual or prohibitive short-term instabilities and were readily reset by exposure to sunlight. These properties form a stable base for continued investigations toward the development of luminescence dating instruments and procedures for Mars.

  1. Cancer Dose-Response Assessment for Polychlorinated Biphenyls (PCBs) and Application to Environmental Mixtures

    EPA Pesticide Factsheets

    This report updates the cancer dose-response assessment for PCBs and shows how information on toxicity, disposition, and environmental processes can be considered together to evaluate health risks from PCB mixtures in the environment.

  2. Dosimetry in steep dose-rate gradient radiation fields: A challenge in clinical applications

    SciTech Connect

    Massillon-JL, G.

    2010-12-07

    The fundamental goal of radiotherapy is to reduce the damage to normal tissue and optimize the dose to the tumor with an associated high probability of cure. Because of this, an accurate and precise knowledge of the radiation dose distribution delivered around the tumor volume during radiotherapy treatments such as stereotactic radiosurgery, intensity modulated radiotherapy or brachytherapy with low-energy X-ray and beta particle sources is of great importance. However, in each of these radiation fields, there exists a steep dose-rate gradient which makes it very difficult to perform accurate dose measurements. In this work, the physics phenomena involved in the energy absorption for each of these situations are discussed, and a brief revision of what the Medical Physics community is doing is presented.

  3. Dosimetry in steep dose-rate gradient radiation fields: A challenge in clinical applications

    NASA Astrophysics Data System (ADS)

    Massillon-JL, G.

    2010-12-01

    The fundamental goal of radiotherapy is to reduce the damage to normal tissue and optimize the dose to the tumor with an associated high probability of cure. Because of this, an accurate and precise knowledge of the radiation dose distribution delivered around the tumor volume during radiotherapy treatments such as stereotactic radiosurgery, intensity modulated radiotherapy or brachytherapy with low-energy X-ray and beta particle sources is of great importance. However, in each of these radiation fields, there exists a steep dose-rate gradient which makes it very difficult to perform accurate dose measurements. In this work, the physics phenomena involved in the energy absorption for each of these situations are discussed, and a brief revision of what the Medical Physics community is doing is presented.

  4. Study on GEANT4 code applications to dose calculation using imaging data

    NASA Astrophysics Data System (ADS)

    Lee, Jeong Ok; Kang, Jeong Ku; Kim, Jhin Kee; Kwon, Hyeong Cheol; Kim, Jung Soo; Kim, Bu Gil; Jeong, Dong Hyeok

    2015-07-01

    The use of the GEANT4 code has increased in the medical field. Various studies have calculated the patient dose distributions by users the GEANT4 code with imaging data. In present study, Monte Carlo simulations based on DICOM data were performed to calculate the dose absorb in the patient's body. Various visualization tools are installed in the GEANT4 code to display the detector construction; however, the display of DICOM images is limited. In addition, to displaying the dose distributions on the imaging data of the patient is difficult. Recently, the gMocren code, a volume visualization tool for GEANT4 simulation, was developed and has been used in volume visualization of image files. In this study, the imaging based on the dose distributions absorbed in the patients was performed by using the gMocren code. Dosimetric evaluations with were carried out by using thermo luminescent dosimeter and film dosimetry to verify the calculated results.

  5. ESTIMATING CONTAMINANT DOSE FOR INTERMITTENT DERMAL CONTACT: MODEL DEVELOPMENT, TESTING, AND APPLICATION

    EPA Science Inventory

    Assessments of aggregate exposure to pesticides and other surface contamination in residential environments are often driven by assumptions about dermal contacts. Accurately predicting cumulative doses from realistic skin contact scenarios requires characterization of exposure sc...

  6. ESTIMATING CONTAMINANT DOSE FOR INTERMITTENT DERMAL CONTACT: MODEL DEVELOPMENT, TESTING, AND APPLICATION

    EPA Science Inventory

    Assessments of aggregate exposure to pesticides and other surface contamination in residential environments are often driven by assumptions about dermal contacts. Accurately predicting cumulative doses from realistic skin contact scenarios requires characterization of exposure sc...

  7. Development and application of a complex numerical model and software for the computation of dose conversion factors for radon progenies.

    PubMed

    Farkas, Árpád; Balásházy, Imre

    2015-04-01

    A more exact determination of dose conversion factors associated with radon progeny inhalation was possible due to the advancements in epidemiological health risk estimates in the last years. The enhancement of computational power and the development of numerical techniques allow computing dose conversion factors with increasing reliability. The objective of this study was to develop an integrated model and software based on a self-developed airway deposition code, an own bronchial dosimetry model and the computational methods accepted by International Commission on Radiological Protection (ICRP) to calculate dose conversion coefficients for different exposure conditions. The model was tested by its application for exposure and breathing conditions characteristic of mines and homes. The dose conversion factors were 8 and 16 mSv WLM(-1) for homes and mines when applying a stochastic deposition model combined with the ICRP dosimetry model (named PM-A model), and 9 and 17 mSv WLM(-1) when applying the same deposition model combined with authors' bronchial dosimetry model and the ICRP bronchiolar and alveolar-interstitial dosimetry model (called PM-B model). User friendly software for the computation of dose conversion factors has also been developed. The software allows one to compute conversion factors for a large range of exposure and breathing parameters and to perform sensitivity analyses.

  8. Angular dependence correction of MatriXX and its application to composite dose verification.

    PubMed

    Shimohigashi, Yoshinobu; Araki, Fujio; Tominaga, Hirofumi; Sakata, Junichi; Kawasaki, Keiichi; Kanetake, Nagisa; Iwashita, Yuki; Yoshimura, Saori; Kawakami, Tamami; Ishihara, Terunobu; Okuda, Tomoko; Kogo, Kasei

    2012-09-06

    We measured the angular dependence of central and off-axis detectors in a 2D ionization chamber array, MatriXX, and applied correction factors (CFs) to improve the accuracy of composite dose verification of IMRT and VMAT. The MatriXX doses were measured with a 10° step for gantry angles (θ) of 0°-180°, and a 1° step for lateral angles of 90°-110° in a phantom, with a 30 × 10 cm2 field for 6 MV and 10 MV photons. The MatriXX doses were also calculated under the same conditions by the Monte Carlo (MC) algorithm. The CFs for the angular dependence of MatriXX were obtained as a function of θ from the ratios of MatriXX-measured doses to MC-calculated doses, and normalized at θ = 0°. The corrected MatriXX were validated with different fields, various simple plans, and clinical treatment plans. The dose distributions were compared with those of MC calculations and film. The absolute doses were also compared with ionization chamber and MC-calculated doses. The angular dependence of MatriXX showed over-responses of up to 6% and 4% at θ = 90° and under-responses of up to 15% and 11% at 92°, and 8% and 5% at 180° for 6 MV and 10 MV photons, respectively. At 92°, the CFs for the off-axis detectors were larger by up to 7% and 6% than those for the central detectors for 6 MV and 10 MV photons, respectively, and were within 2.5% at other gantry angles. For simple plans, MatriXX doses with angular correction were within 2% of those measured with the ionization chamber at the central axis and off-axis. For clinical treatment plans, MatriXX with angular correction agreed well with dose distributions calculated by the treatment planning system (TPS) for gamma evaluation at 3% and 3 mm. The angular dependence corrections of MatriXX were useful in improving the measurement accuracy of composite dose verification of IMRT and VMAT.

  9. X-ray dose response of calcite-A comprehensive analysis for optimal application in TL dosimetry

    NASA Astrophysics Data System (ADS)

    Kalita, J. M.; Wary, G.

    2016-09-01

    The effect of various annealing treatments on dosimetric characteristics of orange calcite (CaCO3) mineral has been studied in detail. Quantitative analysis on the dose response shows that the 573 K annealed sample showed sublinear dose response from 10 mGy to 1 Gy. The fading and reproducibility of this sample are also good enough for dosimetric application. However, a specific annealing treatment after irradiation shows some significant improvements in the dosimetric characteristics of the sample. The 773 K pre-annealed sample, after X-ray irradiation post-annealing at 340 K for 6 min provides linear dose response from 10 mGy to 3.60 Gy, very less fading and good reproducibility. Moreover, this sample after post-annealing at 380 K for 6 min shows linear dose response from 10 mGy to 5.40 Gy when analyzed from the ∼408 K thermoluminescence (TL) glow peak. Analysis of TL glow curves confirmed that the 1.30 eV trap center in calcite crystal is the most effective trapping site for dosimetric application.

  10. Comparison of multi-stage dose-response mixture models, with applications.

    PubMed

    Ortega, Eva María; Alonso, José

    2014-07-01

    This article concerns the analysis of a stochastic model that we propose for the population that generates a response (response measure) to the dose with the multi-stage model. The parameter uncertainty is dealt with via random dose and random size of the population at risk. The response measure is modeled by a random sum of mixed Bernoulli random variables with arbitrary distribution for the mixing parameters. Some extensions of the model are defined by functionals of the infection probability, fulfilling some convexity properties. We analyze the response by stochastic comparisons under different stochastic relations on the random dosages and the random sizes of the population at risk; or on the random infection rates. We provide stochastic exact bounds of the mixture model for the response, using inequalities and the positive quadrant dependence. Numerical bounds of the response by a dose having a scalar value or having an exponential or uniform distributions are obtained. Some conclusions are derived: the lower estimation of the response measure in the increasing convex order sense by replacing the dosages by their means; effects of the variation of the dose on the magnitude of the probability distribution of the response; effects of parameter correlation on the degree of variability of the response to any random dose; the low-dose region assessment; and also, the classical multi-stage model is compared versus the mixture model featuring independence and versus that with positive quadrant dependence. Copyright © 2014. Published by Elsevier Inc.

  11. Anticancer Dose Adjustment for Patients with Renal and Hepatic Dysfunction: From Scientific Evidence to Clinical Application.

    PubMed

    Hendrayana, Tomi; Wilmer, André; Kurth, Verena; Schmidt-Wolf, Ingo Gh; Jaehde, Ulrich

    2017-02-27

    Most anticancer agents exhibit a narrow therapeutic index, i.e., a small change in plasma concentrations can lead to a less efficacious treatment or an unacceptable degree of toxicity. This study aimed at providing health professionals with a feasible and time-saving tool to adapt the dose of anticancer agents for patients with renal or hepatic dysfunction. A guideline for anticancer agents was developed based on a literature search. An algorithm was generated to enhance the efficiency of the dose adaptation process. Finally, the dosing guideline was converted into an easy-to-use Excel(TM) tool. The concept was applied to a total of 105 adult patients at the Centre for Integrated Oncology, Bonn, Germany. In total, 392 recommendations for dose adaptation were made and 320 (81.6%) recommendations were responded to by the oncologists. 98.4% of the recommendations were accepted. The algorithm simplifies the decision and screening process for high-risk patients. Moreover, it provides the possibility to quickly decide which laboratory tests are required and whether a dose adjustment for a particular anticancer drug is needed. The Excel(TM) tool provides a recommended individual dose for patients with renal or hepatic dysfunction. The effectiveness of this strategy to reduce toxicity should be investigated in further studies before being adopted for routine use.

  12. Lethal photosensitization of Helicobacter species

    NASA Astrophysics Data System (ADS)

    Millson, Charles E.; Wilson, Michael; MacRobert, Alexander J.; Thurrell, Wendy; Mlkvy, Peter; Davies, Claire; Bown, Stephen G.

    1995-01-01

    Helicobacter pylori (H. pylori) is associated with a large number of gastroduodenal disorders. Clearance of the bacteria has been shown to benefit patients with duodenal ulcers, gastric ulcers, and certain rare types of gastric tumors. Broad-spectrum antibiotics are the mainstay of current treatment strategies but side-effects, poor compliance, and drug resistance limit their usefulness. We sensitized H. pylori with toluidine blue, haematoporphyrin derivative, aluminum disulphonated phthalocyanine, methylene blue or protoporphyrin IX prior to exposure to low-power laser light from either a gallium aluminum arsenide laser or a helium neon gas laser. All 5 sensitizers caused reductions of greater than 1000-fold in the number of viable bacteria. Light alone had no effect and only HpD caused a significant decrease in bacterial numbers without laser light. Next, we sensitized H. mustelae on explanted ferret gastric mucosa (ex vivo) with the same sensitizers and exposed them to light from a copper vapor pumped dye laser tuned appropriately. MB caused significant reductions in bacterial counts. Successful lethal photosensitization of Helicobacter pylori both in vitro and ex vivo raises the possibility of a local method for eradicating the bacteria, especially as the bacteria are only found in those parts of the upper gastrointestinal tract that are accessible to the endoscope.

  13. Lethal entanglement in baleen whales.

    PubMed

    Cassoff, Rachel M; Moore, Kathleen M; McLellan, William A; Barco, Susan G; Rotsteins, David S; Moore, Michael J

    2011-10-06

    Understanding the scenarios whereby fishing gear entanglement of large whales induces mortality is important for the development of mitigation strategies. Here we present a series of 21 cases involving 4 species of baleen whales in the NW Atlantic, describing the available sighting history, necropsy observations, and subsequent data analyses that enabled the compilation of the manners in which entanglement can be lethal. The single acute cause of entanglement mortality identified was drowning from entanglement involving multiple body parts, with the animal's inability to surface. More protracted causes of death included impaired foraging during entanglement, resulting in starvation after many months; systemic infection arising from open, unresolved entanglement wounds; and hemorrhage or debilitation due to severe gear-related damage to tissues. Serious gear-induced injury can include laceration of large vessels, occlusion of the nares, embedding of line in growing bone, and massive periosteal proliferation of new bone in an attempt to wall off constricting, encircling lines. These data show that baleen whale entanglement is not only a major issue for the conservation of some baleen whale populations, but is also a major concern for the welfare of each affected individual.

  14. APPLICATION OF THE EXPOSURE DOSE ESTIMATING MODEL (ERDEM) TO ASSESSMENT OF DERMAL EXPOSURE IN THE RAT TO MALATHION

    EPA Science Inventory

    APPLICATION OF THE EXPOSURE DOSE ESTIMATING MODEL (ERDEM) TO ASSESSMENT OF DERMAL EXPOSURE IN THE RAT TO MALATHION.
    Evans, M.V1., Power, F.W2., Dary, C.C2., Tornero-Velez, R2., and Blancato, J.N2.
    1 NHEERL, US EPA, ORD, ETD, RTP, NC; 2 NERL, US EPA, ORD, EDRB, LV, NV
    Re...

  15. APPLICATION OF THE EXPOSURE DOSE ESTIMATING MODEL (ERDEM) TO ASSESSMENT OF DERMAL EXPOSURE IN THE RAT TO MALATHION

    EPA Science Inventory

    APPLICATION OF THE EXPOSURE DOSE ESTIMATING MODEL (ERDEM) TO ASSESSMENT OF DERMAL EXPOSURE IN THE RAT TO MALATHION.
    Evans, M.V1., Power, F.W2., Dary, C.C2., Tornero-Velez, R2., and Blancato, J.N2.
    1 NHEERL, US EPA, ORD, ETD, RTP, NC; 2 NERL, US EPA, ORD, EDRB, LV, NV
    Re...

  16. 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.

  17. Applicator reconstruction in MRI 3D image-based dose planning of brachytherapy for cervical cancer.

    PubMed

    Haack, Søren; Nielsen, Søren Kynde; Lindegaard, Jacob Christian; Gelineck, John; Tanderup, Kari

    2009-05-01

    To elaborate a method for applicator reconstruction for MRI-based brachytherapy for cervical cancer. Custom-made plastic catheters with a copper sulphate solution were made for insertion in the source channels of MR-CT compatible applicators: plastic and titanium tandem ring applicators, and titanium needles. The applicators were CT and MR scanned in a phantom for accurate 3D assessment of applicator visibility and geometry. A reconstruction method was developed and evaluated in 19 patient MR examinations with ring applicator (plastic: 14, titanium: 5). MR applicator reconstruction uncertainties related to inter-observer variation were evaluated. The catheters were visible in the plastic applicator on T1-weighted images in phantom and in 14/14 clinical applications. On T2-weighted images, the catheters appeared weaker but still visible in phantom and in 13/14 MR clinical applications. In the titanium applicator, the catheters could not be separated from the artifacts from the applicator itself. However, these artifacts could be used to localize both titanium ring applicator (5/5 clinical applications) and needles (6/6 clinical applications). Standard deviations of inter-observer differences were below 2 mm in all directions. 3D applicator reconstruction based on MR imaging could be performed for plastic and titanium applicators. Plastic applicators proved well to be suited for MRI-based reconstruction. For improved practicability of titanium applicator reconstruction, development of MR applicator markers is essential. Reconstruction of titanium applicator and needles at 1.5 T MR requires geometric evaluations in phantoms before using the applicator in patients.

  18. Dosimetric evaluation of multilumen intracavitary balloon applicator rotation in high-dose-rate brachytherapy for breast cancer.

    PubMed

    Kim, Yongbok; Trombetta, Mark G

    2014-01-06

    The objective of this work is to evaluate dosimetric impact of multilumen balloon applicator rotation in high-dose-rate (HDR) brachytherapy for breast cancer. Highly asymmetrical dose distribution was generated for patients A and B, depending upon applicator proximity to skin and rib. Both skin and rib spacing was ≤ 0.7 cm for A; only rib spacing was ≤ 0.7 cm for B. Thirty-five rotation scenarios were simulated for each patient by rotating outer lumens every 10° over ± 180° range with respect to central lumen using mathematically calculated rotational matrix. Thirty-five rotated plans were compared with three plans: 1) original multidwell multilumen (MDML) plan, 2) multidwell single-lumen (MDSL) plan, and 3) single-dwell single-lumen (SDSL) plan. For plan comparison, planning target volume for evaluation (PTV_EVAL) coverage (dose to 95% and 90% volume of PTV_EVAL) (D95 and D90), skin and rib maximal dose (Dmax), and normal breast tissue volume receiving 150% (V150) and 200% (V200) of prescribed dose (PD) were evaluated. Dose variation due to device rotation ranged from -5.6% to 0.8% (A) and -6.5% to 0.2% (B) for PTV_EVAL D95; -5.2% to 0.4% (A) and -4.1% to 0.7% (B) for PTV_EVAL D90; -2.0 to 18.4% (A) and -7.8 to 17.5% (B) for skin Dmax; -11.1 to 22.8% (A) and -4.7 to 55.1% (B) of PD for rib Dmax, respectively. Normal breast tissue V150 and V200 variation was < 1.0 cc, except for -0.1 to 2.5cc (B) of V200. Furthermore, 30° device rotation increased rib Dmax over 145% of PD: 152.9% (A) by clockwise 30° rotation and 152.5% (B) by counterclockwise 30° rotation. For a highly asymmetric dose distribution, device rotation can outweigh the potential benefit of improved dose shaping capability afforded by multilumen and make dosimetric data worse than single-lumen plans unless it is properly corrected.

  19. Parametrization and application of scatter kernels for modelling scanned proton beam collimator scatter dose.

    PubMed

    Kimstrand, Peter; Traneus, Erik; Ahnesjö, Anders; Tilly, Nina

    2008-07-07

    Collimators are routinely used in proton radiotherapy to laterally confine the field and improve the penumbra. Collimator scatter contributes up to 15% of the local dose and is therefore important to include in treatment planning dose calculation. We present a method for reconstruction of the collimator scatter phase space based on the parametrization of pre-calculated scatter kernels. Collimator scatter distributions, generated by the Monte Carlo (MC) package GEANT4.8.2, were scored differential in direction and energy. The distributions were then parametrized so as to enable a fast reconstruction by sampling. MC calculated dose distributions in water based on the parametrized phase space were compared to full MC simulations that included the collimator in the simulation geometry, as well as to experimental data. The experiments were performed at the scanned proton beam line at the The Svedberg Laboratory (TSL) in Uppsala, Sweden. Dose calculations using the parametrization of this work and the full MC for isolated typical cases of collimator scatter were compared by means of the gamma index. The result showed that in total 96.7% (99.3%) of the voxels fulfilled the gamma 2.0%/2.0 mm (3.0%/3.0 mm) criterion. The dose distribution for a collimated field was calculated based on the phase space created by the collimator scatter model incorporated into the generation of the phase space of a scanned proton beam. Comparing these dose distributions to full MC simulations, including particle transport in the MLC, yielded that in total for 18 different collimated fields, 99.1% of the voxels satisfied the gamma 1.0%/1.0 mm criterion and no voxel exceeded the gamma 2.6%/2.6 mm criterion. The dose contribution of collimator scatter along the central axis as predicted by the model showed good agreement with experimental data.

  20. Parametrization and application of scatter kernels for modelling scanned proton beam collimator scatter dose

    NASA Astrophysics Data System (ADS)

    Kimstrand, Peter; Traneus, Erik; Ahnesjö, Anders; Tilly, Nina

    2008-07-01

    Collimators are routinely used in proton radiotherapy to laterally confine the field and improve the penumbra. Collimator scatter contributes up to 15% of the local dose and is therefore important to include in treatment planning dose calculation. We present a method for reconstruction of the collimator scatter phase space based on the parametrization of pre-calculated scatter kernels. Collimator scatter distributions, generated by the Monte Carlo (MC) package GEANT4.8.2, were scored differential in direction and energy. The distributions were then parametrized so as to enable a fast reconstruction by sampling. MC calculated dose distributions in water based on the parametrized phase space were compared to full MC simulations that included the collimator in the simulation geometry, as well as to experimental data. The experiments were performed at the scanned proton beam line at the The Svedberg Laboratory (TSL) in Uppsala, Sweden. Dose calculations using the parametrization of this work and the full MC for isolated typical cases of collimator scatter were compared by means of the gamma index. The result showed that in total 96.7% (99.3%) of the voxels fulfilled the gamma 2.0%/2.0 mm (3.0%/3.0 mm) criterion. The dose distribution for a collimated field was calculated based on the phase space created by the collimator scatter model incorporated into the generation of the phase space of a scanned proton beam. Comparing these dose distributions to full MC simulations, including particle transport in the MLC, yielded that in total for 18 different collimated fields, 99.1% of the voxels satisfied the gamma 1.0%/1.0 mm criterion and no voxel exceeded the gamma 2.6%/2.6 mm criterion. The dose contribution of collimator scatter along the central axis as predicted by the model showed good agreement with experimental data.

  1. Lipopolysaccharide-induced lethality and cytokine production in aged mice.

    PubMed Central

    Tateda, K; Matsumoto, T; Miyazaki, S; Yamaguchi, K

    1996-01-01

    This study was designed to define the lipopolysaccharide (LPS) sensitivity of aged mice in terms of lethality and cytokine production and to determine down-regulating responses of corticosterone and interleukin 10 (IL-10). The 50% lethal doses of LPS in young (6- to 7-week-old) and aged (98- to 102-week-old) mice were 601 and 93 microg per mouse (25.6 and 1.6 mg per kg of body weight), respectively. Aged mice were approximately 6.5-fold more sensitive to the lethal toxicity of LPS in micrograms per mouse (16-fold more sensitive in milligrams per kilogram) than young mice. Levels in sera of tumor necrosis factor-alpha (TNF-alpha) IL-1alpha, and IL-6 after intraperitoneal injection of 100 microg of LPS peaked at 1.5, 3, and 3 h, respectively, and declined thereafter in both groups of mice. However, the peak values of these cytokines were significantly higher in aged than in young mice (P < 0.05). Gamma interferon (IFN-gamma) was detectable at 3 h, and sustained high levels were still detected after 12 h in both age groups. Although there were no significant differences in levels of IFN-gamma in sera from both groups, aged mice showed higher IFN-gamma levels throughout the 3- to 12-h study period. Administration of increasing doses of LPS revealed that aged mice had a lower threshold to IL-1alpha production than young mice. In addition, aged mice were approximately 4-fold more sensitive to the lethal toxicity of exogenous TNF in units per mouse (10-fold more sensitive in units per kilogram) than young mice. With regard to down-regulating factors, corticosterone amounts were similar at basal levels and no differences in kinetics after the LPS challenge were observed, whereas IL-10 levels in sera were significantly higher in aged mice at 1.5 and 3 h than in young mice (P < 0.01). These results indicate that aged mice are more sensitive to the lethal toxicities of LPS and TNF than young mice. We conclude that a relatively activated, or primed, state for LPS

  2. Enhanced inactivation of Escherichia coli and Listeria monocytogenes by exposure to 405 nm light under sub-lethal temperature, salt and acid stress conditions.

    PubMed

    McKenzie, Karen; Maclean, Michelle; Timoshkin, Igor V; MacGregor, Scott J; Anderson, John G

    2014-01-17

    The antimicrobial effects of 405 nm light have generated interest in its use as an emerging disinfection technology with potential food-related applications. The aim of this study was to assess the bactericidal efficacy of 405 nm light for inactivation of Escherichia coli and Listeria monocytogenes under sub-lethally stressed environmental conditions. Bacteria were exposed to 405 nm light from a light emitting diode (LED) array under various temperature, salt (NaCl) and acid conditions to determine if bacterial susceptibility to 405 nm light inactivation is affected when exposed under these conditions. Non-stressed bacterial populations (10(5) CFU/mL) were exposed to increasing doses of 405 nm light (~70 mW/cm(2)) and the inactivation results were compared with those generated under stress conditions. Bacteria were held at various temperatures (4°C, 22°C and 45°C), acid concentrations (pH3, 3.5 and 7) and salt concentrations (0%, 0.8%, 10% and 15% NaCl), and simultaneously exposed to 405 nm light. Enhanced inactivation of both E. coli and L. monocytogenes was achieved when light exposure was combined with each of the sub-lethal stresses, with significantly increased inactivation rates compared to non-stressed populations (P≤0.05). One exception was with L. monocytogenes when light-exposed in the presence of 15% salt, as this combination reduced bacterial inactivation. The greatest enhancement of 405 nm light inactivation for both bacterial species was achieved when light exposure was combined with sub-lethal acid stress conditions at pH3. This was demonstrated by a 5-log10 reduction of E. coli following a 405 nm light dose of 84 J/cm(2) compared to 378 J/cm(2) for non-stressed populations (77% reduction in dose) and by a 5-log10 reduction of L. monocytogenes achieved with a dose of 42 J/cm(2) which corresponded to 50% of the dose required for the equivalent reduction of non-stressed populations. This acid-enhanced 405 nm light inactivation effect was

  3. Clinical application of Chamomilla recutita in phlebitis: dose response curve study.

    PubMed

    Reis, Paula Elaine Diniz Dos; Carvalho, Emilia Campos de; Bueno, Paula Carolina Pires; Bastos, Jairo Kenupp

    2011-01-01

    This experimental and dose-response curve study aimed to carry out the quality control of the Chamomilla recutita sample, as well as to estimate the ideal dose, for anti-inflammatory effect, of the extract of its capitula, in patients with phlebitis due to peripheral intravenous infusion of antineoplastic chemotherapy and to evaluate the toxicity of this extract in human beings. The therapeutic efficacy, concerning the anti-inflammatory potential, of different doses of Chamomilla recutita extract were analyzed and compared in 25 patients. The time of regression of phlebitis was shorter for groups with 2.5% concentration (mean=29.2h, standard deviation = 8.98) and 5% concentration (mean = 38.8h, standard deviation = 17.47). Local toxicity was almost not observed. This research contributes to the innovation of the nursing clinical practice, since it suggests an alternative for the treatment of phlebitis through the clinical use of phytotherapeutic drugs.

  4. Novel radiochromic dosimeters based on Calcein dye for high dose applications

    NASA Astrophysics Data System (ADS)

    Aldweri, Feras M.; Rabaeh, Khalid A.; Al-Ahmad, Kefaia N.

    2017-10-01

    New compositions of radio-chromic solutions and polyvinyl alcohol (PVA) films containing different concentrations of Calcein dye have been introduced as high dose dosimeter. The dosimeters were irradiated with gamma rays from 60C o source at doses from 5 to 30 kGy for film and from 0.25 to 1 kGy for solution. UV/vis spectrophotometry was used to investigate the absorbance (optical density) of unirradiated and irradiated films and solutions in terms of absorbance at 493 nm for film and 496 nm for solution. The effects of scan temperature, relative humidity and stability of the response of films and solutions after irradiation were investigated. The results show that these films could be used as dosimeter in industrial radiation processing. The useful dose range of developed Calcein-PVA film and solution dosimeters is in the range of 5-20 kGy and 0.25-1 kGy respectively

  5. Applicability of convex hull in multiple detector response space for neutron dose measurements.

    PubMed

    Hashimoto, Makoto; Iimoto, Takeshi; Kosako, Toshiso

    2009-08-01

    A novel neutron dose measurement method that flexibly responds to variations in the neutron field is being developed by Japan Atomic Energy Agency. This is an implementation of the multi-detector method (first introduced in 1960s) for neutron dose evaluation using a convex hull in the response space defined for multiple detectors. The convex hull provides a range of possible neutron dose corresponding to the incident neutron spectrum. Feasibility of the method was studied using a simulated response of mixed gas proportional counter. Monochromatic neutrons are shown to be fundamentally suitable for mapping the convex. The convex hull can be further reduced taking into consideration a priori information about physically possible incident neutron spectra, for example, theoretically derived moderated neutron spectra originated from a fission neutron source.

  6. Induction of lethal shock and tolerance by Porphyromonas gingivalis lipopolysaccharide in D-galactosamine-sensitized C3H/HeJ mice.

    PubMed

    Tanamoto, K

    1999-07-01

    Lipopolysaccharide (LPS) obtained from Porphyromonas gingivalis was found to exhibit marked lethal toxicity in galactosamine-sensitized C3H/HeJ mice. Although no lethality was observed in mice intraperitoneally challenged with 1 mg of P. gingivalis LPS without galactosamine, when they were sensitized with 30 mg of galactosamine, challenge with 1 and 10 micrograms of LPS resulted in 67 and 100% lethality, respectively. The lethal dose of LPS was almost the same in LPS-responsive C57BL/6 mice and non-LPS-responsive C3H/HeJ mice. Furthermore, when 1 microgram of P. gingivalis LPS was administered to each mouse 90 min before the challenge with the same LPS with galactosamine, tolerance to the lethal action of LPS was induced, and the mice were completely protected from death, even at a dose 100-fold greater than the lethal dose of LPS. Neither a lethal effect nor induction of tolerance to the lethality of P. gingivalis LPS was exhibited by Salmonella LPS in galactosamine-sensitized C3H/HeJ mice. A protein-LPS complex derived from Pseudomonas aeruginosa, which exhibited strong lethality and induced tolerance to a subsequent challenge with a lethal dose of LPS in galactosamine-sensitized LPS-responsive mice, did not exhibit lethal toxicity in galactosamine-sensitized C3H/HeJ mice and failed to induce tolerance in these mice to the lethality of P. gingivalis LPS. These results indicate that P. gingivalis LPS plays the central role in the activation of non-LPS-responsive C3H/HeJ mice.

  7. 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.

  8. A model of CT dose profiles in Banach space; with applications to CT dosimetry

    NASA Astrophysics Data System (ADS)

    Weir, Victor J.

    2016-07-01

    In this paper the scatter component of computed tomography dose profiles is modeled using the solution to a nonlinear ordinary differential equation. This scatter function is summed with a modeled primary function of approximate trapezoidal shape. The primary dose profile is modeled to include the analytic continuation of the Heaviside step function. A mathematical theory is developed in a Banach space. The modeled function is used to accurately fit data from a 256-slice GE Revolution scanner. A 60 cm long body phantom is assembled and used for data collection with both a pencil chamber and a Farmer-type chamber.

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

    SciTech Connect

    Cifter, F; Dhou, S; Lewis, J; Cormack, R; Altundal, Y; Sajo, E

    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 was 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.

  10. Application of PK/PD modeling and simulation to dosing regimen optimization of high-dose human regular U-500 insulin.

    PubMed

    de la Peña, Amparo; Ma, Xiaosu; Reddy, Shobha; Ovalle, Fernando; Bergenstal, Richard M; Jackson, Jeffrey A

    2014-07-01

    Pharmacokinetic/pharmacodynamic (PK/PD) studies of human regular U-500 insulin (U-500R) at high doses commonly used in clinical practice (>100 units) have not been performed. The current analysis applied PK/PD modeling/simulation to fit the data and simulate single-dose and steady-state PK/PD of U-500R high-dose regimens. Data from 3 single-dose euglycemic clamp studies in healthy obese and normal-weight patients, and normal-weight patients with type 1 diabetes were used to build the model. The model was sequential (PK inputs fed into PD component). PK was described using a 1-compartment model with first-order absorption and elimination. The model estimated separate absorption rate constants for U-500R and human regular U-100 insulin. The PD component used an effect compartment model, parameterized in terms of maximum pharmacologic effect (E(max)) and concentration to achieve 50% of E(max). The model described the data well. Steady-state PK for once-daily (QD), twice-daily (BID), or thrice-daily (TID) administration appeared to be reached 24 hours after the first dose. At steady-state, QD dosing showed the greatest fluctuations in PK/PD. BID dosing showed a gradual increase in insulin action with each dose and a fairly stable basal insulin effect. For TID dosing, activity was maintained throughout the dosing interval. PK/PD modeling/simulation of high U-500R doses supports BID or TID administration with an extended duration of activity relative to QD. TID dosing may provide slightly better full-day insulin effect. Additional PK/PD studies and randomized controlled trials of U-500R are needed to validate model predictions in patients with insulin-resistant diabetes requiring high-dose insulin.

  11. The Key Events Dose-Response Framework: Its Potential for Application to Foodborne Pathogenic Microorganisms

    PubMed Central

    BUCHANAN, ROBERT L.; HAVELAAR, ARIE H.; SMITH, MARY ALICE; WHITING, RICHARD C.; JULIEN, ELIZABETH

    2009-01-01

    The Key Events Dose-Response Framework (KEDRF) is an analytical approach that facilitates the use of currently available data to gain insight regarding dose-response relationships. The use of the KEDRF also helps identify critical knowledge gaps that once filled, will reduce reliance on assumptions. The present study considers how the KEDRF might be applied to pathogenic microorganisms, using fetal listeriosis resulting from maternal ingestion of food contaminated with L. monocytogenes as an initial example. Major biological events along the pathway between food ingestion and the endpoint of concern are systematically considered with regard to dose (i.e., number of organisms), pathogen factors (e.g., virulence), and protective host mechanisms (e.g., immune response or other homeostatic mechanisms). It is concluded that the KEDRF provides a useful structure for systematically evaluating the complex array of host and pathogen factors that influence the dose-response relationship. In particular, the KEDRF supports efforts to specify and quantify the sources of variability, a prerequisite to strengthening the scientific basis for food safety decision making. PMID:19690997

  12. Potentiation of the anaphylatoxins in vivo using an inhibitor of serum carboxypeptidase N (SCPN). I. Lethality and pathologic effects on pulmonary tissue.

    PubMed Central

    Huey, R.; Bloor, C. M.; Kawahara, M. S.; Hugli, T. E.

    1983-01-01

    Carboxypeptidase N (EC 3.4.12.7) (SCPN) is a plasma enzyme that efficiently inactivates the anaphylatoxins C3a and C4a and significantly reduces C5a spasmogenic activity by removing the C-terminal arginyl residue from each of these factors. The arginine analog DL-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid (SCPN-INH) is a potent competitive inhibitor of SCPN with a Ki for this carboxypeptidase in serum of 2 x 10(-9) M. Therefore, we have used the SCPN inhibitor to potentiate biologic activity of the anaphylatoxins in vivo. Infusion via the carotid artery of about 40 mg of SCPN-INH into each of 8 adult guinea pigs inactivated the SCPN for at least 3 hours and caused no measurable toxic effects. When cobra venom factor (CVF) is infused into guinea pigs, it activates the alternative pathway of complement, thereby generating the anaphylatoxins C3a and C5a. Ordinarily, infusion of CVF is nonlethal, because the generated anaphylatoxins are rapidly converted to C3a des Arg and C5a des Arg by SCPN. However, CVF (200 micrograms) plus SCPN-INH delivered intravenously in 5 animals induced a lethal reaction in less than 5 minutes. The authors conclude that the lethal effect is due largely to the anaphylatoxins. Histologic sections of the lungs from treated animals show dramatic structural changes consistent with peripheral small airway constriction, bronchial constriction, and vasoconstriction of small muscular arteries. Also, cell aggregates are present in blood vessels. Other histologic changes include severe congestion, pulmonary edema, and an interstitial infiltrate of mononuclear cells. Large doses of chlorpheniramine prevent this lethal reaction. Lethality is apparently attributable to asphyxia and is dependent on the level of CVF administered: eg, 100 micrograms CVF was not lethal in 4 animals given SCPN inhibitor, although signs of respiratory distress were observed. On histologic examination of lungs from guinea pigs given CVF and SCPN-INH, the features are

  13. Applications of nonlocal means algorithm in low-dose X-ray CT image processing and reconstruction: A review.

    PubMed

    Zhang, Hao; Zeng, Dong; Zhang, Hua; Wang, Jing; Liang, Zhengrong; Ma, Jianhua

    2017-03-01

    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.

  14. Non-Lethal Weapons (NLW) Reference Book

    DTIC Science & Technology

    2012-01-01

    v Section A COUNTER-PERSONNEL (CP) FIELDED NLW Non-Lethal Capability Sets ( NLCS ) 1 Escalation of Force-Mission Modules (EoF-MM) 1...Weapons, 27 September 1999. Policy References Section A CP Fielded NLW 1 Non-Lethal Capability Sets ( NLCS ). A versatile package of commercial...and government off-the-shelf mission enhancing equipment and munitions. NLCS provide the warfighter with a variety of acoustic, optical distraction

  15. Lethality and Autonomous Robots: An Ethical Stance

    DTIC Science & Technology

    2007-01-01

    Lethality and Autonomous Robots : An Ethical Stance Ronald C. Arkin and Lilia Moshkina College of Computing Georgia Institute of Technology Atlanta... autonomous robots that maintain an ethical infrastructure to govern their behavior will be referred to as humane-oids. 2. Understanding the Ethical...2007 4. TITLE AND SUBTITLE Lethality and Autonomous Robots : An Ethical Stance 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER

  16. Non-Lethal Unmanned Aerial Vehicles (UAVs)

    DTIC Science & Technology

    1993-06-15

    ELEMENT NO. NO. NO. ACCESSION N.- Same as Item Yb 11. TITLE (Include Security Clasiiicotion) "Non- Lethal Unmanned Aerial Vehicles (UAVs)" (U) 12. PERSONAL...NOTATION Non- Lethal Unmanned Aerial Vehicle (UAV) reflects current terminolcgy. Remotely Piloted Vehicle (RPV) and Drone Aircraft are outdated terms...1?. COSAT CODES tS SUBJECT T-RMS (Cont,’we on reverfe if necesary and identi•y by block number) FIELD GROUP SUB-GROUP UAVs Flight Terminal I

  17. Non-Lethal Unmanned Aerial Vehicles (UVs)

    DTIC Science & Technology

    1993-06-15

    Security Classification) "Non- Lethal Unmanned Aerial Vehicles (UAVs)" (U) ERSONAL AUTHOR(S) 13a. TYPE OF REPORT 13b. TIME COVERED 14. DATE OF REPORT (Year...Month,,Oay) 15. PAGE COUNT Final FROM TO 1 1993 June 15 39 16. SUPPLEMENTARY NOTATION Non- Lethal Unmanned Aerial Vehicle (UAV) reflects current...identify by 3lock number) FIELD GROUP SUB-GROUP UAVs Flight Terminal Payload FLIR Infrared 19. ABSTRACT (Continue on reverse if necessary and

  18. Models for pulmonary lethality and morbidity after irradiation from internal and external sources

    SciTech Connect

    Scott, B.R.; Filipy, R.E.; Hahn, E.F.

    1989-05-01

    This report provides a hazard-function model for estimating the risk of death from radiation pneumonitis and/or pulmonary fibrosis following a light-water nuclear power accident. A similar model is also provided for estimating the prevalence of respiratory functional morbidity among those that survive death from acute effects. Hazard-function models for lethality and for morbidity were constructed using the cumulative hazard estimator H, which is related to the risk estimator R through the equation R = 1-exp(-H). The estimator H can be calculated using information provided in the report. The method of calculation depends on the exposure scenario. In general, the total normalized dose X for lethality or for morbidity is calculated. For lethality, X = 1 corresponds to a median lethal dose (LD/sub 50/); for morbidity, X = 1 corresponds to a median effective dose (ED/sub 50/). H is related to X by the equation H = 1n(2)X/sup V/, where V depends on the type of radiation (or radiations) involved. Contributions to X can arise from each of two main modes of exposure: (1) brief exposure of the lung, at a relatively high dose rate, to mainly external gammas, followed by (2) chronic internal alpha, and/or beta, and/or gamma irradiation of the lung. Equations are provided for calculating the contributions to X from both modes of exposure. 73 refs., 16 figs., 2 tabs.

  19. 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

  20. Assessment of daily needle applicator displacement during high-dose-rate interstitial brachytherapy for prostate cancer using daily CT examinations.

    PubMed

    Takenaka, Tadashi; Yoshida, Ken; Ueda, Mari; Yamazaki, Hideya; Miyake, Shunsuke; Tanaka, Eiichi; Yoshida, Mineo; Yoshimura, Yasushi; Oka, Toshitsugu; Honda, Kazuya

    2012-01-01

    To improve treatment conformity for prostate cancer, we investigated daily applicator displacement during high-dose-rate interstitial brachytherapy (HDR-ISBT). Thirty patients treated with HDR-ISBT as monotherapy were examined. All patients received a treatment dosage of 49 Gy per 7 fractions over 4 days. For dose administration, we examined 376 flexible applicators (1128 points) using our unique ambulatory implant technique. Using CT images with a 3-mm slice thickness, we calculated the relative coordinates of the titanium markers and the tips of the applicators. We calculated the distance between the center of gravity of the markers and the tips of the catheters, and compared the distances measured on the day of implantation and the second, third, and fourth treatment days. The mean displacement distance for all applicators was 4.3 ± 3.4 mm, 4.6 ± 4.1 mm, and 5.8 ± 4.5 mm at 21, 45, and 69 hours after initial planning CT. We used a 15-mm margin for needle displacement and only 2 points of 2 patients (16 mm and 18 mm at 69 hours, 2/1128 = 0.2%) exceeded this range. Almost patients (87%) showed the largest displacement within the first 21 hours. The relative doses that covered 100% of CTV (D100(CTV)) values compared with the initial treatment plan were reduced to 0.96 ± 0.08, 0.96 ± 0.08 and 0.94 ± 0.1 at 21, 45 and 69 hours. However, the relative D90(CTV) values kept acceptable levels (1.01 ± 0.02, 1.01 ± 0.03 and 1.01 ± 0.03). Cranial margin of 15 mm seems to be effective to keep D90(CTV) level if we do not do corrective action.

  1. SU-E-T-232: Custom High-Dose-Rate Brachytherapy Surface Mold Applicators: The Importance Source to Skin Distance

    SciTech Connect

    Park, S; Demanes, J; Kamrava, M

    2015-06-15

    Purpose: Surface mold applicators can be customized to fit irregular skin surfaces that are difficult to treat with other radiation therapy techniques. Optimal design of customized HDR skin brachytherapy is not well-established. We evaluated the impact of applicator thickness (source to skin distance) on target dosimetry. Methods: 27 patients had 34 treated sites: scalp 4, face 13, extremity 13, and torso 4. Custom applicators were constructed from 5–15 mm thick thermoplastic bolus molded over the skin lesion. A planar array of plastic brachytherapy catheters spaced 5–10 mm apart was affixed to the bolus. CT simulation was used to contour the target volume and to determine the prescription depth. Inverse planning simulated annealing followed by graphical optimization was used to plan and deliver 40–56 Gy in 8–16 fractions. Target coverage parameters (D90, Dmean, and V100) and dose uniformity (V110–200, D0.1cc, D1cc, and D2cc) were studied according to target depth (<5mm vs. ≥5mm) and applicator thickness (5–10mm vs. ≥10mm). Results: The average prescription depth was 4.2±1.5mm. The average bolus thickness was 9.2±2.4mm. The median CTV volume was 10.0 cc (0.2–212.4 cc). Similar target coverage was achieved with prescription depths of <5mm and ≥5mm (Dmean = 113.8% vs. 112.4% and D90 = 100.2% vs. 98.3%). The <5mm prescription depth plans were more uniform (D0.1cc = 131.8% vs. 151.8%). Bolus thickness <10mm vs. ≥10mm plans also had similar target coverage (Dmean = 118.2% vs. 110.7% and D90 = 100.1% vs. 99.0%). Applicators ≥10mm thick, however, provide more uniform target dosimetry (D0.1cc = 146.9% vs. 139.5%). Conclusion: Prescription depth is based upon the thickness of the lesion and upon the clinical needs of the patient. Applicators ≥10mm thick provide more dose uniformity than 5–10mm thick applicators. Applicator thickness is an important variable that should be considered during treatment planning to achieve optimal dose uniformity.

  2. Theory of lethal mutagenesis for viruses.

    PubMed

    Bull, J J; Sanjuán, R; Wilke, C O

    2007-03-01

    Mutation is the basis of adaptation. Yet, most mutations are detrimental, and elevating mutation rates will impair a population's fitness in the short term. The latter realization has led to the concept of lethal mutagenesis for curing viral infections, and work with drugs such as ribavirin has supported this perspective. As yet, there is no formal theory of lethal mutagenesis, although reference is commonly made to Eigen's error catastrophe theory. Here, we propose a theory of lethal mutagenesis. With an obvious parallel to the epidemiological threshold for eradication of a disease, a sufficient condition for lethal mutagenesis is that each viral genotype produces, on average, less than one progeny virus that goes on to infect a new cell. The extinction threshold involves an evolutionary component based on the mutation rate, but it also includes an ecological component, so the threshold cannot be calculated from the mutation rate alone. The genetic evolution of a large population undergoing mutagenesis is independent of whether the population is declining or stable, so there is no runaway accumulation of mutations or genetic signature for lethal mutagenesis that distinguishes it from a level of mutagenesis under which the population is maintained. To detect lethal mutagenesis, accurate measurements of the genome-wide mutation rate and the number of progeny per infected cell that go on to infect new cells are needed. We discuss three methods for estimating the former. Estimating the latter is more challenging, but broad limits to this estimate may be feasible.

  3. Efficient implementation of the 3D-DDA ray traversal algorithm on GPU and its application in radiation dose calculation.

    PubMed

    Xiao, Kai; Chen, Danny Z; Hu, X Sharon; Zhou, Bo

    2012-12-01

    The three-dimensional digital differential analyzer (3D-DDA) algorithm is a widely used ray traversal method, which is also at the core of many convolution∕superposition (C∕S) dose calculation approaches. However, porting existing C∕S dose calculation methods onto graphics processing unit (GPU) has brought challenges to retaining the efficiency of this algorithm. In particular, straightforward implementation of the original 3D-DDA algorithm inflicts a lot of branch divergence which conflicts with the GPU programming model and leads to suboptimal performance. In this paper, an efficient GPU implementation of the 3D-DDA algorithm is proposed, which effectively reduces such branch divergence and improves performance of the C∕S dose calculation programs running on GPU. The main idea of the proposed method is to convert a number of conditional statements in the original 3D-DDA algorithm into a set of simple operations (e.g., arithmetic, comparison, and logic) which are better supported by the GPU architecture. To verify and demonstrate the performance improvement, this ray traversal method was integrated into a GPU-based collapsed cone convolution∕superposition (CCCS) dose calculation program. The proposed method has been tested using a water phantom and various clinical cases on an NVIDIA GTX570 GPU. The CCCS dose calculation program based on the efficient 3D-DDA ray traversal implementation runs 1.42 ∼ 2.67× faster than the one based on the original 3D-DDA implementation, without losing any accuracy. The results show that the proposed method can effectively reduce branch divergence in the original 3D-DDA ray traversal algorithm and improve the performance of the CCCS program running on GPU. Considering the wide utilization of the 3D-DDA algorithm, various applications can benefit from this implementation method.

  4. Effect of application sites and multiple doses on nicotine pharmacokinetics in healthy male Japanese smokers following application of the transdermal nicotine patch.

    PubMed

    Sobue, Satoshi; Sekiguchi, Kaneo; Kikkawa, Hironori; Irie, Shin

    2005-12-01

    The transdermal nicotine patch, which contains 25 mg nicotine per 30 cm(2), is designed to deliver approximately 15 mg nicotine to the blood circulation in 16 hours of application for the treatment of smoking cessation. It was applied to 3 different skin sites (upper arm, abdomen, and back) to examine regional variations in percutaneous nicotine absorption in a single-dose, 3-period, crossover study involving 9 healthy male Japanese smokers. Nicotine pharmacokinetics during once-daily application of the transdermal nicotine patch for 5 days was also investigated in 10 healthy smokers. There were statistically significant effects of application sites on percutaneous nicotine absorption. The ratios (90% confidence intervals) of AUC and C(max) for comparison to the upper arm were 102% (88, 117%) and 106% (95, 119%) for the back and 75% (65, 87%) and 75% (66, 84%) for the abdomen, respectively. These suggest that systemic exposure after application to the upper arm was greater compared with the abdomen but equivalent to the back. Following multiple doses, linear pharmacokinetics and no significant accumulation of nicotine concentrations were observed, and steady state was reached by day 2. Only mild itching and erythema were observed at the application sites. The transdermal nicotine patch was well tolerated in both studies.

  5. Connectivity Homology Enables Inter-Species Network Models of Synthetic Lethality

    PubMed Central

    Jacunski, Alexandra; Dixon, Scott J.; Tatonetti, Nicholas P.

    2015-01-01

    Synthetic lethality is a genetic interaction wherein two otherwise nonessential genes cause cellular inviability when knocked out simultaneously. Drugs can mimic genetic knock-out effects; therefore, our understanding of promiscuous drugs, polypharmacology-related adverse drug reactions, and multi-drug therapies, especially cancer combination therapy, may be informed by a deeper understanding of synthetic lethality. However, the colossal experimental burden in humans necessitates in silico methods to guide the identification of synthetic lethal pairs. Here, we present SINaTRA (Species-INdependent TRAnslation), a network-based methodology that discovers genome-wide synthetic lethality in translation between species. SINaTRA uses connectivity homology, defined as biological connectivity patterns that persist across species, to identify synthetic lethal pairs. Importantly, our approach does not rely on genetic homology or structural and functional similarity, and it significantly outperforms models utilizing these data. We validate SINaTRA by predicting synthetic lethality in S. pombe using S. cerevisiae data, then identify over one million putative human synthetic lethal pairs to guide experimental approaches. We highlight the translational applications of our algorithm for drug discovery by identifying clusters of genes significantly enriched for single- and multi-drug cancer therapies. PMID:26451775

  6. Cosmic-ray-induced radiation environment and dose to man for low-orbit space applications

    SciTech Connect

    Sandmeier, H.A.; Hansen, G.E.; Battat, M.E.; O'Brien, K.

    1981-09-01

    Neutrons and photons resulting from the interaction of galactic cosmic rays with the material of an orbiting satellite or an orbiting space station at an altitude of some few hundreds of kilometers, and below the level of the radiation belts, have been calculated as a function of geomagnetic latitude and solar activity level. The photon and neutron leakage currents from the top of the atmosphere have been computed. The radiation dose-equivalent rate to an unshielded astronaut has also been calculated. The maximum dose-equivalent rate, near the magnetic poles, was 2 mrem/h. In deep space this would amount to 18 rem/y, indicating that for a prolonged stay in space, shielding would be needed.

  7. Radiation dose response estimation with emphasis on low dose range using restricted cubic splines: application to all solid cancer mortality data, 1950-2003, in atomic bomb survivors.

    PubMed

    Nakashima, Eiji

    2015-07-01

    Using the all solid cancer mortality data set of the Life Span Study (LSS) cohort from 1950 to 2003 (LSS Report 14) data among atomic bomb survivors, excess relative risk (ERR) statistical analyses were performed using the second degree polynomial and the threshold and restricted cubic spline (RCS) dose response models. For the RCS models with 3 to 7 knots of equally spaced percentiles with margins in the dose range greater than 50 mGy, the dose response was assumed to be linear at less than 70 to 90 mGy. Due to the skewed dose distribution of atomic bomb survivors, the current knot system for the RCS analysis results in a detailed depiction of the dose response as less than approximately 0.5 Gy. The 6 knot RCS models for the all-solid cancer mortality dose response of the whole dose or less than 2 Gy were selected with the AIC model selection criterion and fit significantly better (p < 0.05) than the linear (L) model. The usual RCS includes the L-global model but not the quadratic (Q) nor linear-quadratic (LQ) global models. The authors extended the RCS to include L or LQ global models by putting L or LQ constraints on the cubic spline in the lower and upper tails, and the best RCS model selected with AIC criterion was the usual RCS with L-constraints in both the lower and upper tails. The selected RCS had a linear dose-response model in the lower dose range (i.e., < 0.2-0.3 Gy) and was compatible with the linear no-threshold (LNT) model in this dose range. The proposed method is also useful in describing the dose response of a specific cancer or non-cancer disease incidence/mortality.

  8. [Study on the application of benchmark dose and biological monitoring indexes of fluorides in drinking water].

    PubMed

    Xiang, Quan-Yong; Liang, You-Xin; Chen, Bing-Heng; Wang, Cai-Sheng; Zhen, Shi-Qi; Chen, Lian-Sheng; Zhou, Ming-Sheng; Li, Jie-Fei

    2004-07-01

    By using Benchmark Dose (BMD) approach to explore the relations among drinking water fluoride, urine fluoride, serum fluoride and dental fluorosis; and to evaluate the significance of urine fluoride and serum fluoride in control and prevention of endemic fluorosis. 512 children (290 in Xinhuai Village, 222 in Wamiao Village) aged 8-13 years were recruited in the study. Epidemiological methods were used to investigate the prevalence of dental fluorosis, and the levels of urine fluoride, serum fluoride, and drinking water fluoride in superficial well. The children were divided into six subgroups by the concentration of fluoride in drinking water: < 0.5 mg/L, 0.5-mg/L, 1.0-mg/L, 2.0-mg/L, 3.0-mg/L and > or = 4.0 mg/L. There was significant dose-response relationship between the drinking water fluoride and the prevalence of dental fluorosis or the prevalence of defect dental fluorosis. The BMDLs (Benchmark Dose Lower Bound) were 1.01 and 1.30 mg/L, respectively. Urine fluoride and serum fluoride also had significant dose-response relationship to the prevalence of dental fluorosis or defect dental fluorosis. The correlation coefficient between drinking water fluoride and urine fluoride was 0.717, and it was 0.855 between drinking water fluoride and serum fluoride, and 0.617 between urine fluoride and serum fluoride. The currently national standard of fluoride in drinking water in China is safe and reasonable. As a biological monitoring index, the levels of fluoride in serum may be more useful than that in urine in the control and prevention of endemic fluorosis.

  9. Preliminary Assessment of ICRP Dose Conversion Factor Recommendations for Accident Analysis Applications

    SciTech Connect

    Vincent, A.M.

    2002-03-13

    Accident analysis for U.S. Department of Energy (DOE) nuclear facilities is an integral part of the overall safety basis developed by the contractor to demonstrate facility operation can be conducted safely. An appropriate documented safety analysis for a facility discusses accident phenomenology, quantifies source terms arising from postulated process upset conditions, and applies a standardized, internationally-recognized database of dose conversion factors (DCFs) to evaluate radiological conditions to offsite receptors.

  10. Dominant lethal mutations of topoisomerase II inhibitors etoposide and merbarone in male mice: a mechanistic study.

    PubMed

    Attia, Sabry M

    2012-05-01

    Two topoisomerase II inhibitors, etoposide and merbarone, were tested for the induction of dominant lethal mutations in male mice. Etoposide was administered at a dosage of 30 or 60 mg/kg. Merbarone was administered at a dosage of 40 or 80 mg/kg. These males were mated at weekly intervals to virgin females for 6 weeks. In the present experiments, regardless of the agent, spermatids appeared to be the most sensitive germ-cell stage to dominant lethal induction. Etoposide and merbarone clearly induced dominant lethal mutations in the early spermatid stage only with the highest tested doses. The mutagenic effects were also directly correlated with reactive oxygen species accumulation as an obvious increase in 2',7'-dichlorofluorescein fluorescence level was noted in the sperm of animals treated with higher doses of etoposide and merbarone. Treatment of male mice with N-acetylcysteine significantly protected mice from etoposide- and merbarone-induced dominant lethality. Moreover, N-acetylcysteine treatment had no antagonizing effect on etoposide- and merbarone-induced topoisomerase II inhibition. Overall, this study provides for the first time that etoposide and merbarone induce dominant lethal mutations in the early spermatid stage through a mechanism that involves increases in oxidative stress. The demonstrated mutagenicity profile of etoposide and merbarone may support further development of effective chemotherapy with less mutagenicity.

  11. Application of the Key Events Dose-response Framework to Folate Metabolism.

    PubMed

    Hu, Jing; Wang, Bing; Sahyoun, Nadine R

    2016-06-10

    Folate is a vitamin that plays a role as a cofactor and coenzyme in many essential reactions. These reactions are interrelated and any change in folate homeostasis could affect other reactions. With food fortified with folic acid, and use of multivitamin, unmetabolized folic acid (UMFA) has been detected in blood circulation, particularly among older adults. This has raised concern about the potential harmful effect of high folic acid intake and UMFA on health conditions such as cognitive dysfunction and cancer. To examine what is known about folate metabolism and the release of circulating UMFA, the Key Events Dose-Response Framework (KEDRF) was used to review each of the major key events, dose-response characteristics and homeostatic mechanisms of folate metabolism. The intestine, liver and kidneys each play essential roles in regulating body folate homeostasis. But the determining event in folate metabolism leading to the release of UMFA in circulation appears to be the saturation of dihydrofolate reductase in the liver. However, at each of the key events in folate metabolism, limited information is available on threshold, homeostatic regulation and intracellular effects of folic acid. More studies are needed to fill in the knowledge gaps for quantitatively characterizing the dose-effect relationship especially in light of the call for extending folate fortification to other foods.

  12. What is desirable and feasible in dose reconstruction for application in epidemiological studies?

    SciTech Connect

    Bouville, A.; Beebe, G.W.; Anspaugh, L.

    1996-02-01

    Epidemiological studies of populations are of two general forms, monitoring or formal, and serve several possible purposes. Monitoring studies inform members of potentially affected population groups of the nature and magnitude of the risks that might have been imposed on them. Formal epidemiological studies can increase scientific knowledge about the quantitative risk that attends exposure. Risks of human health due to radiation exposure are most appropriately estimated by means of formal epidemiological studies. Dosimetric data are essential for any epidemiological study, but the detail and accuracy needed depend on the purposes to be served. If the need is for a monitoring study, then general information about doses will suffice. However, a formal study that is expected to contribute to scientific information about quantitative radiation risk requires careful individual dose estimation. This paper is devoted to the discussion of dosimetric data needed for formal epidemiological studies of populations exposed as a result of nuclear power operations. The recommendations made by the National Research Council have largely been followed. The examples used in this paper are relevant to the Chernobyl accident, which caused a large number of people to be exposed at relatively high doses and provided an opportunity for formal epidemiological studies to be initiated. The studies that are singled out are those of thyroid cancer among children who resided in Belarus and in Ukraine at the time of the accident, and those of leukemia among workers involved in the mitigation of the accident and in clean-up operations.

  13. Application of thermoluminescence measurements to detect low dose gamma-irradiated table grapes

    NASA Astrophysics Data System (ADS)

    Sillano, O.; Román, A.; Deza, A.; Rubio, T.; Espinoza, J.

    1994-06-01

    A major factor hampering the introduction of ionizing radiation as an alternative quarantine treatment to chemical fumigation for fruit and vegetables is the lack of reliable, simple and inexpensive post-treatment methods to confirm this low dose irradiation treatment. Considering this purpose, thermoluminescence (TL) measurements of the wind blown dust naturally adhered to the surface of table grapes, was surveyed. Two doses, 0.5 and 1.0 kGy, were studied, applied to the main Chilean table grape export varieties: Thompson Seedless and Flame Seedless. TL measurements were carried out over 78 days for Thompson Seedless and 62 days for Flame Seedless varieties, both stored at 1 ± 1°C (usual handling of this fruit). TL response fading of dust samples stored at room temperature was also followed over 125 days. The TL response values obtained from the irradiated samples exceeded at least 3 times the highest ones obtained from the unirradiated counterparts. The treatment, even for the lower γ-radiation dose applied, could be properly detected well above the shipping and marketing time for this Chilean export fruit (2-8 weeks). This method also has the advantage of using relatively inexpensive equipment.

  14. Detector photon response and absorbed dose and their applications to rapid triage techniques

    NASA Astrophysics Data System (ADS)

    Voss, Shannon Prentice

    As radiation specialists, one of our primary objectives in the Navy is protecting people and the environment from the effects of ionizing and non-ionizing radiation. Focusing on radiological dispersal devices (RDD) will provide increased personnel protection as well as optimize emergency response assets for the general public. An attack involving an RDD has been of particular concern because it is intended to spread contamination over a wide area and cause massive panic within the general population. A rapid method of triage will be necessary to segregate the unexposed and slightly exposed from those needing immediate medical treatment. Because of the aerosol dispersal of the radioactive material, inhalation of the radioactive material may be the primary exposure route. The primary radionuclides likely to be used in a RDD attack are Co-60, Cs-137, Ir-192, Sr-90 and Am-241. Through the use of a MAX phantom along with a few Simulink MATLAB programs, a good anthropomorphic phantom was created for use in MCNPX simulations that would provide organ doses from internally deposited radionuclides. Ludlum model 44-9 and 44-2 detectors were used to verify the simulated dose from the MCNPX code. Based on the results, acute dose rate limits were developed for emergency response personnel that would assist in patient triage.

  15. Application of a radiophotoluminescent glass dosimeter to nonreference condition dosimetry in the postal dose audit system

    SciTech Connect

    Mizuno, Hideyuki Fukumura, Akifumi; Fukahori, Mai; Sakata, Suoh; Yamashita, Wataru; Takase, Nobuhiro; Yajima, Kaori; Katayose, Tetsurou; Abe-Sakama, Kyoko; Kanai, Tatsuaki; Kusano, Yohsuke; Shimbo, Munefumi

    2014-11-01

    Purpose: The purpose of this study was to obtain a set of correction factors of the radiophotoluminescent glass dosimeter (RGD) output for field size changes and wedge insertions. Methods: Several linear accelerators were used for irradiation of the RGDs. The field sizes were changed from 5 × 5 cm to 25 × 25 cm for 4, 6, 10, and 15 MV x-ray beams. The wedge angles were 15°, 30°, 45°, and 60°. In addition to physical wedge irradiation, nonphysical (dynamic/virtual) wedge irradiations were performed. Results: The obtained data were fitted with a single line for each energy, and correction factors were determined. Compared with ionization chamber outputs, the RGD outputs gradually increased with increasing field size, because of the higher RGD response to scattered low-energy photons. The output increase was about 1% per 10 cm increase in field size, with a slight difference dependent on the beam energy. For both physical and nonphysical wedged beam irradiation, there were no systematic trends in the RGD outputs, such as monotonic increase or decrease depending on the wedge angle change if the authors consider the uncertainty, which is approximately 0.6% for each set of measured points. Therefore, no correction factor was needed for all inserted wedges. Based on this work, postal dose audits using RGDs for the nonreference condition were initiated in 2010. The postal dose audit results between 2010 and 2012 were analyzed. The mean difference between the measured and stated doses was within 0.5% for all fields with field sizes between 5 × 5 cm and 25 × 25 cm and with wedge angles from 15° to 60°. The standard deviations (SDs) of the difference distribution were within the estimated uncertainty (1SD) except for the 25 × 25 cm field size data, which were not reliable because of poor statistics (n = 16). Conclusions: A set of RGD output correction factors was determined for field size changes and wedge insertions. The results obtained from recent postal dose

  16. Pulse-dose application of chelated copper to a river for Didymosphenia geminata control: effects on macroinvertebrates and fish.

    PubMed

    Clearwater, Susan J; Jellyman, Phillip G; Biggs, Barry J F; Hickey, Christopher W; Blair, Neil; Clayton, John S

    2011-01-01

    A 1-h pulse-dose of a chelated Cu formulation (Gemex™; New Zealand) was applied to a river to test efficacy against the invasive mat-forming diatom Didymosphenia geminata (didymo) and to provide information on nontarget species effects that could not be adequately predicted from laboratory and experimental mesocosm studies. Intensive sampling allowed characterization of doses achieved at multiple downstream locations, and concurrent application of rhodamine dye allowed quantification of dispersion, adsorption, and dilution processes. The target dose of 10 to 20 mg Cu/L for 60 min was achieved at least 0.9 km downstream at sites with contrasting levels of didymo mat development. Adsorptive losses of Gemex were 12%/km where didymo was mostly nonvisible and approximately 36%/km where substantial didymo mats were present. At 0.9 km downstream, Cu concentrations peaked at 12 mg/L, and didymo was <5% viable (down from 65-72%) for ≥21 d posttreatment. Viability data indicate that elimination of nonvisible infestations is possible and that suppression of early-stage infestations (≤40% cover, ≤4.5 mm thick) could be achieved after repeated applications. After a single Gemex application, no significant accumulation of Cu was noted in the sediments six weeks posttreatment, but Cu concentrations remained high in algal mats (109-367 mg/kg dry wt). Long-term effects on the nontarget algal, invertebrate, or fish communities were minimal, although significant localized trout mortalities, not predicted by prior laboratory exposures, occurred on the treatment day. Extended Gemex exposure in low-hardness waters might have caused the mortalities, although changes in chelated Cu speciation also possibly contributed. The present study integrates effects on resident biota with dosage data, including changes in pH, in a natural waterway. © 2010 SETAC.

  17. Dose uniformity of scored and unscored tablets: Application of the FDA Tablet Scoring Guidance for Industry.

    PubMed

    Ciavarella, Anthony; Khan, Mansoor; Gupta, Abhay; Faustino, Patrick

    2016-06-20

    This FDA laboratory study examines the impact of tablet splitting, the effect of tablet splitters, and the presence of a tablet score on the dose uniformity of two model drugs. Whole tablets were purchased from five manufacturers for amlodipine and six for gabapentin. Two splitters were used for each drug product and the gabapentin tablets were also split by hand. Whole and split amlodipine tablets were tested for content uniformity following the general chapter of the United States Pharmacopeia (USP) Uniformity of Dosage Units <905>, which is a requirement of the new FDA Guidance for Industry on tablet scoring. The USP weight variation method was used for gabapentin split tablets based on the recommendation of the guidance. All whole tablets met the USP acceptance criteria for the Uniformity of Dosage Units. Variation in whole tablet content ranged from 0.5-2.1 standard deviation (SD) of the % label claim. Splitting the unscored amlodipine tablets resulted in a significant increase in dose variability of 6.5-25.4 SD when compared to whole tablets. Split tablets from all amlodipine drug products did not meet the USP acceptance criteria for content uniformity. Variation in the weight for gabapentin split tablets was greater than the whole tablets, ranging from 1.3-9.3 SD. All fully scored gabapentin products met the USP acceptance criteria for weight variation. Size, shape, and the presence or absence of a tablet score can affect the content uniformity and weight variation of amlodipine and gabapentin tablets. Tablet splitting produced higher variability. Differences in dose variability and fragmentation were observed between tablet splitters and hand splitting. These results are consistent with the FDA's concerns that tablet splitting "can affect how much drug is present in the split tablet and available for absorption" as stated in the guidance (1). Copyright © 2016, Parenteral Drug Association.

  18. Radiation dose reduction with application of non-linear adaptive filters for abdominal CT

    PubMed Central

    Singh, Sarabjeet; Kalra, Mannudeep K; Sung, Mi Kim; Back, Anni; Blake, Michael A

    2012-01-01

    AIM: To evaluate the effect of non-linear adaptive filters (NLAF) on abdominal computed tomography (CT) images acquired at different radiation dose levels. METHODS: Nineteen patients (mean age 61.6 ± 7.9 years, M:F = 8:11) gave informed consent for an Institutional Review Board approved prospective study involving acquisition of 4 additional image series (200, 150, 100, 50 mAs and 120 kVp) on a 64 slice multidetector row CT scanner over an identical 10 cm length in the abdomen. The CT images acquired at 150, 100 and 50 mAs were processed with the NLAF. Two radiologists reviewed unprocessed and processed images for image quality in a blinded randomized manner. CT dose index volume, dose length product, patient weight, transverse diameters, objective noise and CT numbers were recorded. Data were analyzed using Analysis of Variance and Wilcoxon signed rank test. RESULTS: Of the 31 lesions detected in abdominal CT images, 28 lesions were less than 1 cm in size. Subjective image noise was graded as unacceptable in unprocessed images at 50 and 100 mAs, and in NLAF processed images at 50 mAs only. In NLAF processed images, objective image noise was decreased by 21% (14.4 ± 4/18.2 ± 4.9) at 150 mAs, 28.3% (15.7 ± 5.6/21.9 ± 4) at 100 mAs and by 39.4% (18.8 ± 9/30.4 ± 9.2) at 50 mAs compared to unprocessed images acquired at respective radiation dose levels. At 100 mAs the visibility of smaller structures improved from suboptimal in unprocessed images to excellent in NLAF processed images, whereas diagnostic confidence was respectively improved from probably confident to fully confident. CONCLUSION: NLAF lowers image noise, improves the visibility of small structures and maintains lesion conspicuity at down to 100 mAs for abdominal CT. PMID:22328968

  19. [Convulsion due to application of low dose meperidine: a case report].

    PubMed

    Ozkaya, Halit; Akcan, Abdullah Barış; Aydemir, Gökhan; Akbaş, Mert

    2012-01-01

    Meperidine is an opiod analgesic used in a variety of clinical situations. The active metabolite, normeperidine, is a central nervous system excitatory agent and has the ability to cause irritability, hyperreflexia, tremor, myoclonus and seizures. Previously identified risk factors for the development of meperidine-related seizures include renal failure, high meperidine dosages, and co-adminestration of hepatic enzyme inducing medications or phenothiazines which decreases seizure treshold. Patients with normal renal function rarely manifest seizure activity when given meperidine. Here we report a 10 year old boy with a femur fraction who had normal renal function. We used low dose meperidine due to post operative pains.

  20. Pharmacokinetics of difloxacin in pigs and broilers following intravenous, intramuscular, and oral single-dose applications.

    PubMed

    Ding, H Z; Yang, G X; Huang, X H; Chen, Z L; Zeng, Z L

    2008-06-01

    Pharmacokinetics of difloxacin, a fluoroquinolone antibiotic, was determined in pigs and broilers after intravenous (i.v.), intramuscular (i.m.), or oral (p.o.) administration at a single dose of five (pigs) or 10 mg/kg (broilers). Plasma concentration profiles were analyzed by a compartmental pharmacokinetic method. Following i.v., i.m. and p.o. doses, the elimination half-lives (t(1/2beta)) were 17.14 +/- 4.14, 25.79 +/- 8.10, 16.67 +/- 4.04 (pigs) and 6.11 +/- 1.50, 5.64 +/- 0.74, 8.20 +/- 3.12 h (broilers), respectively. After single i.m. and p.o. administration, difloxacin was rapidly absorbed, with peak plasma concentrations (C(max)) of 1.77 +/- 0.66, 2.29 +/- 0.85 (pigs) and 2.51 +/- 0.36, 1.00 +/- 0.21 microg/mL (broilers) attained at t(max) of 1.29 +/- 0.26, 1.41 +/- 0.88 (pigs) and 0.86 +/- 0.4, 4.34 +/- 2.40 h (broilers), respectively. Bioavailabilities (F) were (95.3 +/- 28.9)% and (105.7 +/- 37.1)% (pigs) and (77.0 +/- 11.8)% and (54.2 +/- 12.6)% (broilers) after i.m. and p.o. doses, respectively. Apparent distribution volumes(V(d(area))) of 4.91 +/- 1.88 and 3.10 +/- 0.67 L/kg and total body clearances(Cl(B)) of 0.20 +/- 0.06 and 0.37 +/- 0.10 L/kg/h were determined in pigs and broilers, respectively. Areas under the curve (AUC), the half-lives of both absorption and distribution(t(1/2ka), t(1/2alpha)) were also determined. Based on the single-dose pharmacokinetic parameters determined, multiple dosage regimens were recommended as: a dosage of 5 mg/kg given intramuscularly every 24 h in pigs, or administered orally every 24 h at the dosage of 10 mg/kg in broilers, can maintain effective plasma concentrations with bacteria infections, in which MIC(90) are <0.25 microg/mL and <0.1 microg/mL respectively.

  1. Development of the voxel computational phantoms of pediatric patients and their application to organ dose assessment

    NASA Astrophysics Data System (ADS)

    Lee, Choonik

    A series of realistic voxel computational phantoms of pediatric patients were developed and then used for the radiation risk assessment for various exposure scenarios. The high-resolution computed tomographic images of live patients were utilized for the development of the five voxel phantoms of pediatric patients, 9-month male, 4-year female, 8-year female, 11-year male, and 14-year male. The phantoms were first developed as head and torso phantoms and then extended into whole body phantoms by utilizing computed tomographic images of a healthy adult volunteer. The whole body phantom series was modified to have the same anthropometrics with the most recent reference data reported by the international commission on radiological protection. The phantoms, named as the University of Florida series B, are the first complete set of the pediatric voxel phantoms having reference organ masses and total heights. As part of the dosimetry study, the investigation on skeletal tissue dosimetry methods was performed for better understanding of the radiation dose to the active bone marrow and bone endosteum. All of the currently available methodologies were inter-compared and benchmarked with the paired-image radiation transport model. The dosimetric characteristics of the phantoms were investigated by using Monte Carlo simulation of the broad parallel beams of external phantom in anterior-posterior, posterior-anterior, left lateral, right lateral, rotational, and isotropic angles. Organ dose conversion coefficients were calculated for extensive photon energies and compared with the conventional stylized pediatric phantoms of Oak Ridge National Laboratory. The multi-slice helical computed tomography exams were simulated using Monte Carlo simulation code for various exams protocols, head, chest, abdomen, pelvis, and chest-abdomen-pelvis studies. Results have found realistic estimates of the effective doses for frequently used protocols in pediatric radiology. The results were very

  2. 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

    2017-02-08

    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

  3. 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

  4. CD4+ T cells provide protection against acute lethal encephalitis caused by Venezuelan equine encephalitis virus.

    PubMed

    Yun, Nadezhda E; Peng, Bi-Hung; Bertke, Andrea S; Borisevich, Viktoriya; Smith, Jennifer K; Smith, Jeanon N; Poussard, Allison L; Salazar, Milagros; Judy, Barbara M; Zacks, Michele A; Estes, D Mark; Paessler, Slobodan

    2009-06-19

    Studying the mechanisms of host survival resulting from viral encephalitis is critical to the development of vaccines. Here we have shown in several independent studies that high dose treatment with neutralizing antibody prior to intranasal infection with Venezuelan equine encephalitis virus had an antiviral effect in the visceral organs and prolonged survival time of infected mice, even in the absence of alphabeta T cells. Nevertheless, antibody treatment did not prevent the development of lethal encephalitis. On the contrary, the adoptive transfer of primed CD4(+) T cells was necessary to prevent lethal encephalitis in mice lacking alphabeta T cell receptor.

  5. Human Health Risk Assessment: A case study application of principles in dose response assessment

    EPA Science Inventory

    This case study application workshop will build on fundamental concepts and techniques in risk assessment presented and archived at previous TRAC meeting workshops. Practical examples from publicly available, peer reviewed risk assessments will be used as teaching aids. Course ...

  6. Study on application of high doses plasmodium berghei in cell culture

    NASA Astrophysics Data System (ADS)

    Spencer, L. M.; De Santis, M.; Davila, J.; Foinquinos, A.; Salcedo, E.; Sajo-Bohus, L.

    2012-02-01

    Malaria, one of the most important infection disease problems in the world, is caused by protozoan parasites of the genus Plasmodium. This disease is responsible for hundreds of the millions of clinical cases and more than one million deaths per year, for this reason, malaria is a priority and the WHO estimates that half of the world population is at risk. In this work we study how the absorbed dose inactivates the parasite (Plasmodium berghei) in rodent model (BALB/c mice), by applying X-ray irradiation. The dose was increased from 10 to 50 Gy in parasitized red blood cells (PRBC) with merozoite stage using in vitro short cultures. Also the reduction of the irradiation effect was determined by intra-peritoneal inoculations of irradiated parasites. Afterwards, the parasitaemia was assessed daily on smears made from tail blood and stained with Giemsa's reagent. Besides, the effect of irradiation was evaluated using an immunological test as indirect immunofluorescence assay (IFA). The results of this study showed that the most effective radiation for inactivation of parasites is about 50 Gy and the immunofluorescence pattern showed a different distribution of the fluorescence on parasites. These results showed direct correlation between the effect of irradiated parasites and parasitaemia in the group of mice infected with RBC after 50 Gy irradiation. Our results indicated that the threshold is between 30 to 50 Gy to inactivate the parasites.

  7. Application of Machine-Learning Models to Predict Tacrolimus Stable Dose in Renal Transplant Recipients

    NASA Astrophysics Data System (ADS)

    Tang, Jie; Liu, Rong; Zhang, Yue-Li; Liu, Mou-Ze; Hu, Yong-Fang; Shao, Ming-Jie; Zhu, Li-Jun; Xin, Hua-Wen; Feng, Gui-Wen; Shang, Wen-Jun; Meng, Xiang-Guang; Zhang, Li-Rong; Ming, Ying-Zi; Zhang, Wei

    2017-02-01

    Tacrolimus has a narrow therapeutic window and considerable variability in clinical use. Our goal was to compare the performance of multiple linear regression (MLR) and eight machine learning techniques in pharmacogenetic algorithm-based prediction of tacrolimus stable dose (TSD) in a large Chinese cohort. A total of 1,045 renal transplant patients were recruited, 80% of which were randomly selected as the “derivation cohort” to develop dose-prediction algorithm, while the remaining 20% constituted the “validation cohort” to test the final selected algorithm. MLR, artificial neural network (ANN), regression tree (RT), multivariate adaptive regression splines (MARS), boosted regression tree (BRT), support vector regression (SVR), random forest regression (RFR), lasso regression (LAR) and Bayesian additive regression trees (BART) were applied and their performances were compared in this work. Among all the machine learning models, RT performed best in both derivation [0.71 (0.67-0.76)] and validation cohorts [0.73 (0.63-0.82)]. In addition, the ideal rate of RT was 4% higher than that of MLR. To our knowledge, this is the first study to use machine learning models to predict TSD, which will further facilitate personalized medicine in tacrolimus administration in the future.

  8. Open-source hardware and software and web application for gamma dose rate network operation.

    PubMed

    Luff, R; Zähringer, M; Harms, W; Bleher, M; Prommer, B; Stöhlker, U

    2014-08-01

    The German Federal Office for Radiation Protection operates a network of about 1800 gamma dose rate stations as a part of the national emergency preparedness plan. Each of the six network centres is capable of operating the network alone. Most of the used hardware and software have been developed in-house under open-source license. Short development cycles and close cooperation between developers and users ensure robustness, transparency and fast maintenance procedures, thus avoiding unnecessary complex solutions. This also reduces the overall costs of the network operation. An easy-to-expand web interface has been developed to make the complete system available to other interested network operators in order to increase cooperation between different countries. The interface is also regularly in use for education during scholarships of trainees supported, e.g. by the 'International Atomic Energy Agency' to operate a local area dose rate monitoring test network. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  9. Application of the International Life Sciences Institute Key Events Dose-Response Framework to food contaminants.

    PubMed

    Fenner-Crisp, Penelope A

    2012-12-01

    Contaminants are undesirable constituents in food. They may be formed during production of a processed food, present as a component in a source material, deliberately added to substitute for the proper substance, or the consequence of poor food-handling practices. Contaminants may be chemicals or pathogens. Chemicals generally degrade over time and become of less concern as a health threat. Pathogens have the ability to multiply, potentially resulting in an increased threat level. Formal structures have been lacking for systematically generating and evaluating hazard and exposure data for bioactive agents when problem situations arise. We need to know what the potential risk may be to determine whether intervention to reduce or eliminate contact with the contaminant is warranted. We need tools to aid us in assembling and assessing all available relevant information in an expeditious and scientifically sound manner. One such tool is the International Life Sciences Institute (ILSI) Key Events Dose-Response Framework (KEDRF). Developed as an extension of the WHO's International Program on Chemical Safety/ILSI mode of action/human relevance framework, it allows risk assessors to understand not only how a contaminant exerts its toxicity but also the dose response(s) for each key event and the ultimate outcome, including whether a threshold exists. This presentation will illustrate use of the KEDRF with case studies included in its development (chloroform and Listeriaonocytogenes) after its publication in the peer-reviewed scientific literature (chromium VI) and in a work in progress (3-monochloro-1, 2-propanediol).

  10. Application of Machine-Learning Models to Predict Tacrolimus Stable Dose in Renal Transplant Recipients

    PubMed Central

    Tang, Jie; Liu, Rong; Zhang, Yue-Li; Liu, Mou-Ze; Hu, Yong-Fang; Shao, Ming-Jie; Zhu, Li-Jun; Xin, Hua-Wen; Feng, Gui-Wen; Shang, Wen-Jun; Meng, Xiang-Guang; Zhang, Li-Rong; Ming, Ying-Zi; Zhang, Wei

    2017-01-01

    Tacrolimus has a narrow therapeutic window and considerable variability in clinical use. Our goal was to compare the performance of multiple linear regression (MLR) and eight machine learning techniques in pharmacogenetic algorithm-based prediction of tacrolimus stable dose (TSD) in a large Chinese cohort. A total of 1,045 renal transplant patients were recruited, 80% of which were randomly selected as the “derivation cohort” to develop dose-prediction algorithm, while the remaining 20% constituted the “validation cohort” to test the final selected algorithm. MLR, artificial neural network (ANN), regression tree (RT), multivariate adaptive regression splines (MARS), boosted regression tree (BRT), support vector regression (SVR), random forest regression (RFR), lasso regression (LAR) and Bayesian additive regression trees (BART) were applied and their performances were compared in this work. Among all the machine learning models, RT performed best in both derivation [0.71 (0.67–0.76)] and validation cohorts [0.73 (0.63–0.82)]. In addition, the ideal rate of RT was 4% higher than that of MLR. To our knowledge, this is the first study to use machine learning models to predict TSD, which will further facilitate personalized medicine in tacrolimus administration in the future. PMID:28176850

  11. Application of Machine-Learning Models to Predict Tacrolimus Stable Dose in Renal Transplant Recipients.

    PubMed

    Tang, Jie; Liu, Rong; Zhang, Yue-Li; Liu, Mou-Ze; Hu, Yong-Fang; Shao, Ming-Jie; Zhu, Li-Jun; Xin, Hua-Wen; Feng, Gui-Wen; Shang, Wen-Jun; Meng, Xiang-Guang; Zhang, Li-Rong; Ming, Ying-Zi; Zhang, Wei

    2017-02-08

    Tacrolimus has a narrow therapeutic window and considerable variability in clinical use. Our goal was to compare the performance of multiple linear regression (MLR) and eight machine learning techniques in pharmacogenetic algorithm-based prediction of tacrolimus stable dose (TSD) in a large Chinese cohort. A total of 1,045 renal transplant patients were recruited, 80% of which were randomly selected as the "derivation cohort" to develop dose-prediction algorithm, while the remaining 20% constituted the "validation cohort" to test the final selected algorithm. MLR, artificial neural network (ANN), regression tree (RT), multivariate adaptive regression splines (MARS), boosted regression tree (BRT), support vector regression (SVR), random forest regression (RFR), lasso regression (LAR) and Bayesian additive regression trees (BART) were applied and their performances were compared in this work. Among all the machine learning models, RT performed best in both derivation [0.71 (0.67-0.76)] and validation cohorts [0.73 (0.63-0.82)]. In addition, the ideal rate of RT was 4% higher than that of MLR. To our knowledge, this is the first study to use machine learning models to predict TSD, which will further facilitate personalized medicine in tacrolimus administration in the future.

  12. Application of melt granulation technology to enhance tabletting properties of poorly compactible high-dose drugs.

    PubMed

    Lakshman, Jay P; Kowalski, James; Vasanthavada, Madhav; Tong, Wei-Qin; Joshi, Yatindra M; Serajuddin, Abu T M

    2011-04-01

    Using metformin HCl as the model drug and hydroxypropylcellulose (HPC) as the polymeric excipient, a melt granulation (MG) process that employs a twin-screw extruder has been developed to enhance compactibility of poorly compactible high-dose drug substances. A high (90%) drug-load tablet formulation, containing 1025 mg of active pharmaceutical ingredients and 109 mg of excipients, was produced. Drug-polymer-powder mixtures were melt granulated at a temperature above glass transition of HPC (130°C) but below melting point of metformin HCl (224°C). MG was compared with modified wet granulation (WG) and solvent granulation (SG) processes. Under identical compression force, the hardness of tablets produced was MG>SG>WG and the friability was MGdose drugs and combination products by decreasing the need for relatively large amounts of excipients generally used to overcome physicochemical limitations of drug substances. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:1553-1565, 2011.

  13. The development of early pediatric models and their application to radiation absorbed dose calculations

    SciTech Connect

    Poston, J.W.

    1989-01-01

    This presentation will review and describe the development of pediatric phantoms for use in radiation dose calculations . The development of pediatric models for dose calculations essentially paralleled that of the adult. In fact, Snyder and Fisher at the Oak Ridge National Laboratory reported on a series of phantoms for such calculations in 1966 about two years before the first MIRD publication on the adult human phantom. These phantoms, for a newborn, one-, five-, ten-, and fifteen-year old, were derived from the adult phantom. The pediatric'' models were obtained through a series of transformations applied to the major dimensions of the adult, which were specified in a Cartesian coordinate system. These phantoms suffered from the fact that no real consideration was given to the influence of these mathematical transformations on the actual organ sizes in the other models nor to the relation of the resulting organ masses to those in humans of the particular age. Later, an extensive effort was invested in designing individual'' pediatric phantoms for each age based upon a careful review of the literature. Unfortunately, the phantoms had limited use and only a small number of calculations were made available to the user community. Examples of the phantoms, their typical dimensions, common weaknesses, etc. will be discussed.

  14. The development of early pediatric models and their application to radiation absorbed dose calculations

    SciTech Connect

    Poston, J.W.

    1989-12-31

    This presentation will review and describe the development of pediatric phantoms for use in radiation dose calculations . The development of pediatric models for dose calculations essentially paralleled that of the adult. In fact, Snyder and Fisher at the Oak Ridge National Laboratory reported on a series of phantoms for such calculations in 1966 about two years before the first MIRD publication on the adult human phantom. These phantoms, for a newborn, one-, five-, ten-, and fifteen-year old, were derived from the adult phantom. The ``pediatric`` models were obtained through a series of transformations applied to the major dimensions of the adult, which were specified in a Cartesian coordinate system. These phantoms suffered from the fact that no real consideration was given to the influence of these mathematical transformations on the actual organ sizes in the other models nor to the relation of the resulting organ masses to those in humans of the particular age. Later, an extensive effort was invested in designing ``individual`` pediatric phantoms for each age based upon a careful review of the literature. Unfortunately, the phantoms had limited use and only a small number of calculations were made available to the user community. Examples of the phantoms, their typical dimensions, common weaknesses, etc. will be discussed.

  15. Dose Uniformity of Scored and Unscored Tablets: Application of the FDA Tablet Scoring Guidance for Industry.

    PubMed

    Ciavarella, Anthony B; Khan, Mansoor A; Gupta, Abhay; Faustino, Patrick J

    This U.S. Food and Drug Administration (FDA) laboratory study examines the impact of tablet splitting, the effect of tablet splitters, and the presence of a tablet score on the dose uniformity of two model drugs. Whole tablets were purchased from five manufacturers for amlodipine and six for gabapentin. Two splitters were used for each drug product, and the gabapentin tablets were also split by hand. Whole and split amlodipine tablets were tested for content uniformity following the general chapter of the United States Pharmacopeia (USP) Uniformity of Dosage Units <905>, which is a requirement of the new FDA Guidance for Industry on tablet scoring. The USP weight variation method was used for gabapentin split tablets based on the recommendation of the guidance. All whole tablets met the USP acceptance criteria for the Uniformity of Dosage Units. Variation in whole tablet content ranged from 0.5 to 2.1 standard deviation (SD) of the percent label claim. Splitting the unscored amlodipine tablets resulted in a significant increase in dose variability of 6.5-25.4 SD when compared to whole tablets. Split tablets from all amlodipine drug products did not meet the USP acceptance criteria for content uniformity. Variation in the weight for gabapentin split tablets was greater than the whole tablets, ranging from 1.3 to 9.3 SD. All fully scored gabapentin products met the USP acceptance criteria for weight variation. Size, shape, and the presence or absence of a tablet score can affect the content uniformity and weight variation of amlodipine and gabapentin tablets. Tablet splitting produced higher variability. Differences in dose variability and fragmentation were observed between tablet splitters and hand splitting. These results are consistent with the FDA's concerns that tablet splitting can have an effect on the amount of drug present in a split tablet and available for absorption. Tablet splitting has become a very common practice in the United States and throughout

  16. Modeling and simulation in pediatric drug therapy: Application of pharmacometrics to define the right dose for children.

    PubMed

    Vinks, A A; Emoto, C; Fukuda, T

    2015-09-01

    During the past decades significant progress has been made in our understanding of the importance of age-appropriate development of new drug therapies in children. Importantly, several regulatory initiatives in Europe and the US have provided a framework for a rationale. In the US, most notably the enactment of the Best Pharmaceuticals for Children Act (BPCA) and Product Research and Equity Act (PREA) has facilitated the studying of on-patent and off-patent drugs in children. The biggest challenge in pediatric studies is defining a safe and effective dose or dose range in a patient population that can span from premature neonates to adolescents. From a mechanism-based perspective, advances in the science of quantitative pharmacology and pharmacometrics have resulted in the development of model-based approaches to better describe and understand important age-related factors influencing drug disposition and response in pediatric patients. The application of modeling and simulation has been shown to result in better estimates of pediatric doses as evidenced by several studies, although the optimal approach is still being debated. The extrapolation of efficacy findings from adults to the pediatric population has streamlined the development process especially for studies in older children. However, a focus on developmental changes in neonates and infants as well as further developing a paradigm for conducting pharmacodynamic studies in neonates, infants, and children remain important unmet needs. In this overview we will review current approaches for age-appropriate dose selection and highlight ongoing efforts to define exposure-response and clinical outcome relationships across the pediatric age spectrum. © 2015 American Society for Clinical Pharmacology and Therapeutics.

  17. Applications of tissue heterogeneity corrections and biologically effective dose volume histograms in assessing the doses for accelerated partial breast irradiation using an electronic brachytherapy source.

    PubMed

    Shi, Chengyu; Guo, Bingqi; Cheng, Chih-Yao; Eng, Tony; Papanikolaou, Nikos

    2010-09-21

    A low-energy electronic brachytherapy source (EBS), the model S700 Axxent x-ray device developed by Xoft Inc., has been used in high dose rate (HDR) intracavitary accelerated partial breast irradiation (APBI) as an alternative to an Ir-192 source. The prescription dose and delivery schema of the electronic brachytherapy APBI plan are the same as the Ir-192 plan. However, due to its lower mean energy than the Ir-192 source, an EBS plan has dosimetric and biological features different from an Ir-192 source plan. Current brachytherapy treatment planning methods may have large errors in treatment outcome prediction for an EBS plan. Two main factors contribute to the errors: the dosimetric influence of tissue heterogeneities and the enhancement of relative biological effectiveness (RBE) of electronic brachytherapy. This study quantified the effects of these two factors and revisited the plan quality of electronic brachytherapy APBI. The influence of tissue heterogeneities is studied by a Monte Carlo method and heterogeneous 'virtual patient' phantoms created from CT images and structure contours; the effect of RBE enhancement in the treatment outcome was estimated by biologically effective dose (BED) distribution. Ten electronic brachytherapy APBI cases were studied. The results showed that, for electronic brachytherapy cases, tissue heterogeneities and patient boundary effect decreased dose to the target and skin but increased dose to the bones. On average, the target dose coverage PTV V(100) reduced from 95.0% in water phantoms (planned) to only 66.7% in virtual patient phantoms (actual). The actual maximum dose to the ribs is 3.3 times higher than the planned dose; the actual mean dose to the ipsilateral breast and maximum dose to the skin were reduced by 22% and 17%, respectively. Combining the effect of tissue heterogeneities and RBE enhancement, BED coverage of the target was 89.9% in virtual patient phantoms with RBE enhancement (actual BED) as compared to 95

  18. High-Dose-Rate Rotte 'Y' Applicator Brachytherapy for Definitive Treatment of Medically Inoperable Endometrial Cancer: 10-Year Results

    SciTech Connect

    Coon, Devin; Beriwal, Sushil Heron, Dwight E.; Kelley, Joseph L.; Edwards, Robert P.; Sukumvanich, Paniti; Zorn, Kristin K.; Krivak, Thomas C.

    2008-07-01

    Purpose: To assess the intermediate clinical outcomes of medically inoperable patients with endometrial cancer treated with definitive Rotte 'Y' applicator high-dose-rate brachytherapy (HDRB) over a 10-year period. Methods and Materials: Forty-nine inoperable patients were treated with HDRB from 1997 to 2007. Forty three (84%) were markedly obese (body mass index >35 kg/m{sup 2}). Thirty-one patients (63.3%) underwent two-dimensional treatment planning, whereas 18 patients (36.7%) underwent three-dimensional treatment planning. Thirty five of the patients (71.4%) were first treated with external beam radiotherapy (EBRT). For patients receiving EBRT in addition to HDRB, the median Y-applicator dose was 20 Gy in 5 fractions; for patients receiving HDRB alone it was 35 Gy in 5 fractions. All patients received two Y-applicator treatments per day. Results: Median follow-up time for all patients was 33 months. Acute HDRB toxicities were limited to Grade 1 and 2 occurring in 5 patients. One patient had a myocardial infarction. Four patients had late Grade 2 or 3 toxicity. Three patients had local recurrence (median time to recurrence, 16 months). The 3- and 5-year actuarial cause-specific survival rates were 93% and 87%, respectively; the overall survival rate was 83% and 42%, respectively, at 3 and 5 years. Conclusions: Twice-daily HDRB using a Y-applicator is a well-tolerated and efficacious regimen for the definitive treatment of medically inoperable patients with early-stage endometrial cancer. The recent incorporation of three-dimensional treatment planning has the potential to further decrease treatment morbidities.

  19. Impacts of nitrogen addition on plant biodiversity in mountain grasslands depend on dose, application duration and climate: a systematic review.

    PubMed

    Humbert, Jean-Yves; Dwyer, John M; Andrey, Aline; Arlettaz, Raphaël

    2016-01-01

    Although the influence of nitrogen (N) addition on grassland plant communities has been widely studied, it is still unclear whether observed patterns and underlying mechanisms are constant across biomes. In this systematic review, we use meta-analysis and metaregression to investigate the influence of N addition (here referring mostly to fertilization) upon the biodiversity of temperate mountain grasslands (including montane, subalpine and alpine zones). Forty-two studies met our criteria of inclusion, resulting in 134 measures of effect size. The main general responses of mountain grasslands to N addition were increases in phytomass and reductions in plant species richness, as observed in lowland grasslands. More specifically, the analysis reveals that negative effects on species richness were exacerbated by dose (ha(-1) year(-1) ) and duration of N application (years) in an additive manner. Thus, sustained application of low to moderate levels of N over time had effects similar to short-term application of high N doses. The climatic context also played an important role: the overall effects of N addition on plant species richness and diversity (Shannon index) were less pronounced in mountain grasslands experiencing cool rather than warm summers. Furthermore, the relative negative effect of N addition on species richness was more pronounced in managed communities and was strongly negatively related to N-induced increases in phytomass, that is the greater the phytomass response to N addition, the greater the decline in richness. Altogether, this review not only establishes that plant biodiversity of mountain grasslands is negatively affected by N addition, but also demonstrates that several local management and abiotic factors interact with N addition to drive plant community changes. This synthesis yields essential information for a more sustainable management of mountain grasslands, emphasizing the importance of preserving and restoring grasslands with both low

  20. The receptors that mediate the direct lethality of anthrax toxin.

    PubMed

    Liu, Shihui; Zhang, Yi; Hoover, Benjamin; Leppla, Stephen H

    2012-12-27

    Tumor endothelium marker-8 (TEM8) and capillary morphogenesis protein-2 (CMG2) are the two well-characterized anthrax toxin receptors, each containing a von Willebrand factor A (vWA) domain responsible for anthrax protective antigen (PA) binding. Recently, a cell-based analysis was used to implicate another vWA domain-containing protein, integrin β1 as a third anthrax toxin receptor. To explore whether proteins other than TEM8 and CMG2 function as anthrax toxin receptors in vivo, we challenged mice lacking TEM8 and/or CMG2. Specifically, we used as an effector protein the fusion protein FP59, a fusion between the PA-binding domain of anthrax lethal factor (LF) and the catalytic domain of Pseudomonas aeruginosa exotoxin A. FP59 is at least 50-fold more potent than LF in the presence of PA, with 2 μg PA + 2 μg FP59 being sufficient to kill a mouse. While TEM8(-/-) and wild type control mice succumbed to a 5 μg PA + 5 μg FP59 challenge, CMG2(-/-) mice were completely resistant to this dose, confirming that CMG2 is the major anthrax toxin receptor in vivo. To detect whether any toxic effects are mediated by TEM8 or other putative receptors such as integrin β1, CMG2(-/-)/TEM8(-/-) mice were challenged with as many as five doses of 50 μg PA + 50 μg FP59. Strikingly, the CMG2(-/-)/TEM8(-/-) mice were completely resistant to the 5-dose challenge. These results strongly suggest that TEM8 is the only minor anthrax toxin receptor mediating direct lethality in vivo and that other proteins implicated as receptors do not play this role.

  1. Long-term sub-lethal effects of low concentration commercial herbicide (glyphosate/pelargonic acid) formulation in Bryophyllum pinnatum.

    PubMed

    Pokhrel, Lok R; Karsai, Istvan

    2015-12-15

    Potential long-term (~7months) sub-lethal impacts of soil-applied low levels of Roundup herbicide formulation were investigated in a greenhouse environment using the vegetative clones of succulent non-crop plant model, Bryophyllum pinnatum (Lam.) Oken. An eleven day LC50 (concentration that killed 50% of the plants) was found to be 6.25% (~1.25mg glyphosate/mL and 1.25mg pelargonic acid/mL combined), and complete mortality occurred at 12.5%, of the field application rate (i.e., ~20mg glyphosate/mL and 20mg pelargonic acid/mL as active ingredients). While sub-lethal Roundup (1-5%) exposures led to hormesis-characterized by a significant increase in biomass and vegetative reproduction, higher concentrations (≥6.25%) were toxic. A significant interaction between Roundup concentrations and leaf biomass was found to influence the F1 plantlets' biomass. Biomass asymmetry generally increased with increasing Roundup concentrations, indicating that plants were more stressed at higher Roundup treatments but within the low-dose regime (≤5% of the as-supplied formulation). While leaf apex region demonstrated higher reproduction with lower biomass increase, leaf basal area showed lower reproduction with greater biomass increase, in plantlets. The results suggest long-term exposures to drifted low levels of Roundup in soil may promote biomass and reproduction in B. pinnatum. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Identification of lethal toxin with the thermostable direct hemolysin produced by Vibrio parahaemolyticus, and some physicochemical properties of the purified toxin.

    PubMed Central

    Honda, T; Taga, S; Takeda, T; Hasibuan, M A; Takeda, Y; Miwatani, T

    1976-01-01

    Lethal toxin was purified extensively from the culture filtrate of a Kanagawa phenomenon-positive strain of Vibrio parahaemolyticus. The purified toxin was a protein, and its homogeneity was demonstrated by sodium dodecyl sulfate-polyacrylamide gel disc electrophoresis and analytical ultracentrifugation. It was demonstrated that the thermostable direct hemolysin was identical to the lethal toxin and that it was the main, if not only, lethal toxin in the culture filtrate. The purified toxin had a lethal effect when injected into mice either intravenously or intraperitoneally. Its lethal effect was very rapid, a dose of 5 mug of toxin per mouse killing the animals within 1 min. The lethal activity was inhibited by a ganglioside mixture. Some physicochemical properties of the purified toxin are reported. Images PMID:1248866

  3. SU-E-T-29: A Web Application for GPU-Based Monte Carlo IMRT/VMAT QA with Delivered Dose Verification

    SciTech Connect

    Folkerts, M; Graves, Y; Tian, Z; Gu, X; Jia, X; Jiang, S

    2014-06-01

    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 able 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.

  4. Highly variable recessive lethal or nearly lethal mutation rates during germ-line development of male Drosophila melanogaster.

    PubMed

    Gao, Jian-Jun; Pan, Xue-Rong; Hu, Jing; Ma, Li; Wu, Jian-Min; Shao, Ye-Lin; Barton, Sara A; Woodruff, Ronny C; Zhang, Ya-Ping; Fu, Yun-Xin

    2011-09-20

    Each cell of higher organism adults is derived from a fertilized egg through a series of divisions, during which mutations can occur. Both the rate and timing of mutations can have profound impacts on both the individual and the population, because mutations that occur at early cell divisions will affect more tissues and are more likely to be transferred to the next generation. Using large-scale multigeneration screening experiments for recessive lethal or nearly lethal mutations of Drosophila melanogaster and recently developed statistical analysis, we show for male D. melanogaster that (i) mutation rates (for recessive lethal or nearly lethal) are highly variable during germ cell development; (ii) first cell cleavage has the highest mutation rate, which drops substantially in the second cleavage or the next few cleavages; (iii) the intermediate stages, after a few cleavages to right before spermatogenesis, have at least an order of magnitude smaller mutation rate; and (iv) spermatogenesis also harbors a fairly high mutation rate. Because germ-line lineage shares some (early) cell divisions with somatic cell lineage, the first conclusion is readily extended to a somatic cell lineage. It is conceivable that the first conclusion is true for most (if not all) higher organisms, whereas the other three conclusions are widely applicable, although the extent may differ from species to species. Therefore, conclusions or analyses that are based on equal mutation rates during development should be taken with caution. Furthermore, the statistical approach developed can be adopted for studying other organisms, including the human germ-line or somatic mutational patterns.

  5. Inadequate anaesthesia in lethal injection for execution.

    PubMed

    Koniaris, Leonidas G; Zimmers, Teresa A; Lubarsky, David A; Sheldon, Jonathan P

    Anaesthesia during lethal injection is essential to minimise suffering and to maintain public acceptance of the practice. Lethal injection is usually done by sequential administration of thiopental, pancuronium, and potassium chloride. Protocol information from Texas and Virginia showed that executioners had no anaesthesia training, drugs were administered remotely with no monitoring for anaesthesia, data were not recorded and no peer-review was done. Toxicology reports from Arizona, Georgia, North Carolina, and South Carolina showed that post-mortem concentrations of thiopental in the blood were lower than that required for surgery in 43 of 49 executed inmates (88%); 21 (43%) inmates had concentrations consistent with awareness. Methods of lethal injection anaesthesia are flawed and some inmates might experience awareness and suffering during execution.

  6. Extra lethal damage due to residual incompletely repaired sublethal damage in hyperfractionated and continuous radiation treatment

    SciTech Connect

    Chen, J.; van de Geijn, J.; Goffman, T. )

    1991-05-01

    In the conventional linear--quadratic model of single-dose response, the {alpha} and {beta} terms reflect lethal damage created {ital during} the delivery of a dose, from two different presumed molecular processes, one linear with dose, the other quadratic. With the conventional one-fraction-per-day (or less) regimens, the sublethal damage (SLD), presumably repairing exponentially over time, is essentially completely fixed by the time of the next dose of radiation. If this assumption is true, the effects of subsequent fractions of radiation should be independent, that is, there should be little, if any, reversible damage left from previous fractions, at the time of the next dose. For multiple daily fractions, or for the limiting case, continuous radiation, this simplification may overlook damaged cells that have had insufficient time for repair. A generalized method is presented for accounting for extra lethal damage (ELD) arising from such residual SLD for hyperfractionation and continuous irradiation schemes. It may help to predict differences in toxicity and tumor control, if any, obtained with unconventional'' treatment regimens. A key element in the present model is the finite size and the dynamic character of the pool of sublethal damage. Besides creating the usual linear and quadratic components of lethal damage, each new fraction converts a certain fraction of the existing SLD into ELD, and creates some new SLD.

  7. Radiation dose reduction in the evaluation of scoliosis: an application of digital radiography

    SciTech Connect

    Kushner, D.C.; Cleveland, R.H.; Herman, T.E.; Zaleske, D.J.; Ehrlich, M.G.; Correia, J.A.

    1986-10-01

    This report documents the clinical testing of scanning beam digital radiography as an imaging method in patients with scoliosis. This type of digital imaging requires a skin exposure of only 2.4 mR (0.619 microC/kg) per image, compared with the lowest possible posteroanterior screen-film exposure of 10 mR (2.58 microC/kg) at the chest and 60 mR (15.48 microC/kg) at the lumbar spine. Digital radiographic and screen-film images were obtained on multiple test objects and 273 patients. Scoliosis measurements using screen-film radiographs and digital radiographs were comparable to within a mean difference of 1 degrees at many different degrees of severity. The low-dose digital images were found to be useful and accurate for the detection and measurement of scoliosis after the first screen-film radiographs have excluded tumors and structural abnormalities.

  8. Calculation of electron Dose Point Kernel in water with GEANT4 for medical application

    SciTech Connect

    Guimaraes, C. C.; Sene, F. F.; Martinelli, J. R.

    2009-06-03

    The rapid insertion of new technologies in medical physics in the last years, especially in nuclear medicine, has been followed by a great development of faster Monte Carlo algorithms. GEANT4 is a Monte Carlo toolkit that contains the tools to simulate the problems of particle transport through matter. In this work, GEANT4 was used to calculate the dose-point-kernel (DPK) for monoenergetic electrons in water, which is an important reference medium for nuclear medicine. The three different physical models of electromagnetic interactions provided by GEANT4 - Low Energy, Penelope and Standard - were employed. To verify the adequacy of these models, the results were compared with references from the literature. For all energies and physical models, the agreement between calculated DPKs and reported values is satisfactory.

  9. 3D-printed surface mould applicator for high-dose-rate brachytherapy

    NASA Astrophysics Data System (ADS)

    Schumacher, Mark; Lasso, Andras; Cumming, Ian; Rankin, Adam; Falkson, Conrad B.; Schreiner, L. John; Joshi, Chandra; Fichtinger, Gabor

    2015-03-01

    In contemporary high-dose-rate brachytherapy treatment of superficial tumors, catheters are placed in a wax mould. The creation of current wax models is a difficult and time consuming proces.The irradiation plan can only be computed post-construction and requires a second CT scan. In case no satisfactory dose plan can be created, the mould is discarded and the process is repeated. The objective of this work was to develop an automated method to replace suboptimal wax moulding. We developed a method to design and manufacture moulds that guarantee to yield satisfactory dosimetry. A 3D-printed mould with channels for the catheters designed from the patient's CT and mounted on a patient-specific thermoplastic mesh mask. The mould planner was implemented as an open-source module in the 3D Slicer platform. Series of test moulds were created to accommodate standard brachytherapy catheters of 1.70mm diameter. A calibration object was used to conclude that tunnels with a diameter of 2.25mm, minimum 12mm radius of curvature, and 1.0mm open channel gave the best fit for this printer/catheter combination. Moulds were created from the CT scan of thermoplastic mesh masks of actual patients. The patient-specific moulds have been visually verified to fit on the thermoplastic meshes. The masks were visually shown to fit onto the thermoplastic meshes, next the resulting dosimetry will have to be compared with treatment plans and dosimetry achieved with conventional wax moulds in order to validate our 3D printed moulds.

  10. 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

  11. Radiation dose affected by mammographic composition and breast size: first application of a radiation dose management system for full-field digital mammography in Korean women.

    PubMed

    Baek, Ji Eun; Kang, Bong Joo; Kim, Sung Hun; Lee, Hyun Sil

    2017-02-02

    Relative to Western women, Korean women show several differences in breast-related characteristics, including higher rates of dense breasts and small breasts. We investigated how mammographic composition and breast size affect the glandular dose during full-field digital mammography (FFDM) in Korean women using a radiation dose management system. From June 1 to June 30, 2015, 2120 FFDM images from 560 patients were acquired and mammographic breast composition and breast size were assessed. We analyzed the correlations of patient age, peak kilovoltage (kVp), current (mAs), compressed breast thickness, compression force, mammographic breast composition, and mammographic breast size with the mean glandular dose (MGD) of the breast using a radiation dose management system. The causes of increased radiation were investigated, among patients with radiation doses above the diagnostic reference level (4th quartile, ≥75%). The MGD per view of 2120 images was 1.81 ± 0.70 mGy. In multivariate linear regression analysis, age was negatively associated with MGD (p < 0.05). The mAs, kVp, compressed breast thickness, and mammographic breast size were positively associated with MGD (p < 0.05). The "dense" group had a significantly higher MGD than the "non-dense" group (p < 0.05). Patients with radiation dose values above the diagnostic reference value had large breasts of dense composition. Among Korean women, patients with large and dense breasts should be more carefully managed to ensure that a constant radiation dose is maintained.

  12. Live deaths online: internet suicide and lethality.

    PubMed

    Klein, Carolina A

    2012-01-01

    The Internet provides an infinite platform for the portrayal of lethal events. Beyond mere display, however, it dispenses information, allows for participation and sharing of content, and constitutes a virtual interactive forum. The Internet may ultimately shape society's approach to perceiving and dealing with death. Thus, psychiatrists may wish to be aware of these matters so that they may be considered in assessments and clinical care. In this article, the author attempts to identify key online locations where lethality is portrayed and how it may affect the individual patient and practitioner and the population at large.

  13. Crystallographic Studies of the Anthrax Lethal Toxin.

    DTIC Science & Technology

    1997-01-01

    Singh, K. R. Klimpel, C. P. Quinn, Y. K. Chaudhary, J. Biol. Chem. 266, 15493-97 (1991). The carboxyl- terminal end of protective antigen is required for...AD CONTRACT NUMBER DAMD17-94-C-4047 TITLE: Crystallographic Studies of the Anthrax Lethal Toxin PRINCIPAL INVESTIGATOR: Christin A. Frederick, Ph.D...FUNDING NUMBERS Anthrax Lethal Toxin DAMDI7-94-C-4047 6. AUTHOR(S) Christin A. Frederick, Ph.D. 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8

  14. Fetal Skeletal Lethal Dysplasia: Case Report.

    PubMed

    Savoldi, Alexandre Mello; Villar, Maria Auxiliadora Monteiro; Machado, Heloisa Novaes; Llerena Júnior, Juan C

    2017-08-07

    The clinical management and decision-making in pregnancies in which there is suspicion of lethal fetal malformations during the prenatal period, such as lethal skeletal dysplasia (SD), demand a multidisciplinary approach coordinated by an experienced physician. Based on the presentation of a case of osteogenesis imperfecta type IIA, we offer and discuss recommendations with the intention of organizing clinical and laboratory investigations aiming toward the clinical management, prognosis, and etiological diagnosis of these malformations, as well as genetic counselling to patients who wish to become pregnant. Thieme Revinter Publicações Ltda Rio de Janeiro, Brazil.

  15. Infection-Mediated Priming of Phagocytes Protects against Lethal Secondary Aspergillus fumigatus Challenge

    PubMed Central

    Savers, Amélie; Rasid, Orhan; Parlato, Marianna; Brock, Matthias; Jouvion, Gregory; Ryffel, Bernhard; Cavaillon, Jean-Marc; Eberl, Gerard; Ibrahim-Granet, Oumaïma

    2016-01-01

    Phagocytes restrict the germination of Aspergillus fumigatus conidia and prevent the establishment of invasive pulmonary aspergillosis in immunecompetent mice. Here we report that immunecompetent mice recovering from a primary A. fumigatus challenge are protected against a secondary lethal challenge. Using RAGγc knock-out mice we show that this protection is independent of T, B and NK cells. In protected mice, lung phagocytes are recruited more rapidly and are more efficient in conidial phagocytosis and killing. Protection was also associated with an enhanced expression of CXCR2 and Dectin-1 on bone marrow phagocytes. We also show that protective lung cytokine and chemokine responses are induced more rapidly and with enhanced dynamics in protected mice. Our findings support the hypothesis that following a first encounter with a non-lethal dose of A. fumigatus conidia, the innate immune system is primed and can mediate protection against a secondary lethal infection. PMID:27078879

  16. Tests for induction of presumed dominant-lethal effects in female mice

    SciTech Connect

    Generoso, W.M.; Cain, K.T.; Hughes, L.A.; Braden, P.W.

    1985-01-01

    The two carcinogens, benzo(a)pyrene (BP), and 2-acetylaminofluorene (2AAF), and their respective noncarcinogenic analogs, pyrene (PYR) and 4-acetylaminofluorene (4AAF), were tested for induction of presumed dominant-lethal effects in female mice. Each chemical was administered as a single intraperitoneal injection using the maximum dose that could be given as limited either by toxicity or solubility. The study was conducted in at least two stocks of females and the induction of presumed dominant-lethal response was determined in oocytes in maturing follicles. Among the four compounds studied, only BP induced clear-cut presumed dominant-lethal effects. In addition, it had cytotoxic effects on the oocytes resulting in marked reduction in the reproductive performance of treated females. 11 refs., 1 fig., 4 tabs.

  17. 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

  18. An algorithm for kilovoltage x-ray dose calculations with applications in kV-CBCT scans and 2D planar projected radiographs

    NASA Astrophysics Data System (ADS)

    Pawlowski, Jason M.; Ding, George X.

    2014-04-01

    A new model-based dose calculation algorithm is presented for kilovoltage x-rays and is tested for the cases of calculating the radiation dose from kilovoltage cone-beam CT (kV-CBCT) and 2D planar projected radiographs. This algorithm calculates the radiation dose to water-like media as the sum of primary and scattered dose components. The scatter dose is calculated by convolution of a newly introduced, empirically parameterized scatter dose kernel with the primary photon fluence. Several approximations are introduced to increase the scatter dose calculation efficiency: (1) the photon energy spectrum is approximated as monoenergetic; (2) density inhomogeneities are accounted for by implementing a global distance scaling factor in the scatter kernel; (3) kernel tilting is ignored. These approximations allow for efficient calculation of the scatter dose convolution with the fast Fourier transform. Monte Carlo simulations were used to obtain the model parameters. The accuracy of using this model-based algorithm was validated by comparing with the Monte Carlo method for calculating dose distributions for real patients resulting from radiotherapy image guidance procedures including volumetric kV-CBCT scans and 2D planar projected radiographs. For all patients studied, mean dose-to-water errors for kV-CBCT are within 0.3% with a maximum standard deviation error of 4.1%. Using a medium-dependent correction method to account for the effects of photoabsorption in bone on the dose distribution, mean dose-to-medium errors for kV-CBCT are within 3.6% for bone and 2.4% for soft tissues. This algorithm offers acceptable accuracy and has the potential to extend the applicability of model-based dose calculation algorithms from megavoltage to kilovoltage photon beams.

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

    SciTech Connect

    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. - Highlights: • Toxicity and anti

  20. 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.

  1. 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.

  2. Application of a hot-melt granulation process to enhance fenofibrate solid dose manufacturing.

    PubMed

    Chaudhary, Rakesh Singh; Amankwaa, Edward; Kumar, Sandeep; Hu, Tom; Chan, Mohamed; Sanghvi, Pradeep

    2016-01-01

    Evaluation of hot-melt granulation of fenofibrate and croscarmellose sodium and its cooling time for the molten mass in a ratio of 55:45 was conducted to assess the manufacturing process capability to produce an acceptable granulation which flows well on Korsch PH300 tablet compression machine. The formation of the drug-polymer eutectic mixture was investigated by differential scanning calorimetry, scanning electron microscopy and X-ray powder diffraction. The physical properties of the hot-melt was determined by examining the milled blocks after solidification and milling after cooling periods of 10, 20 and 30 d. The milled material was assessed for the effect of hold time of the blend on the solid dose compression characteristics. The impact of cooling on the processing of the blocks was assessed after 10, 20 and 30 d of cooling. The study suggests that after the hot-melt formed the fenofibrate crystallized independently and a solid solution with croscarmellose sodium was not formed. The age of the blocks determined the hardness of the crystals, changing the processing nature of the granules with respect to compression and powder flow characteristics. The blocks processed after 20 d and beyond produced granules with a characteristic suitable for holding the blend for 14 d in the bin with no impact on flow properties and compressibility of the blend. There was no chipping, capping, sticking or picking observed and a higher compression speed was achieved.

  3. A probabilistic model of human variability in physiology for future application to dose reconstruction and QIVIVE.

    PubMed

    McNally, Kevin; Loizou, George D

    2015-01-01

    The risk assessment of environmental chemicals and drugs is undergoing a paradigm shift in approach which seeks the full replacement of animal testing with high throughput, mechanistic, in vitro systems. This new approach will be reliant on the measurement in vitro, of concentration-dependent responses where prolonged excessive perturbations of specific biochemical pathways are likely to lead to adverse health effects in an intact organism. Such an approach requires a framework, into which disparate data generated by in vitro, in silico, and in chemico systems can be integrated and utilized for quantitative in vitro-to-in vivo extrapolation (QIVIVE), ultimately to the human population level. Physiologically based pharmacokinetic (PBPK) models are ideally suited to this and are needed to translate in vitro concentration- response relationships to an exposure or dose, route and duration regime in human populations. Thus, a realistic description of the variation in the physiology of the human population being modeled is critical. Whilst various studies in the past decade have made progress in describing human variability, the algorithms are typically coded in computer programs and as such are unsuitable for reverse dosimetry. In this report we overcome this limitation by developing a hierarchical statistical model using standard probability distributions for the specification of a virtual US and UK human population. The work draws on information from both population databases and cadaver studies.

  4. [Adherence of type 2 diabetes patients on insulin analogues application: missed dose, time imprecision and dose reduction. The results of GAPP2TM(Global Attitudes of Physicians and Patient) survey in the Czech Republic].

    PubMed

    Prázný, Martin

    2014-11-01

    Irregular insulin dose is one of the main problems associated with insulin therapy in patients with type 2 diabetes; its extent is not known precisely. The aim of survey conducted in the Czech Republic in the international project GAPP2 - Global Attitudes of Patients and Physicians was to determine the incidence and the impact of irregular use of basal insulin analogues in patients with type 2 diabetes, to point out the reasons for these irregularities and to focus on how physicians discuss irregular application of insulin with patients. The project GAPP2 is an international cross-sectional study performed on-line via the Internet using a questionnaire filled by diabetic patients treated with insulin analogues and physicians who treat these patients. The survey was conducted in two steps in 17 countries; the first step included 6 countries and was completed in the beginning of 2012, the second step involved 11 other countries including the Czech Republic with termination in 2014. The survey was designed to obtain the views of patients and physicians on certain aspects of insulin treatment and persistent issues in this field in the real daily practice. Special focus was on the incidence and management of hypoglycaemia as well as on irregularities of insulin application. In the part dedicated to adherence to basal insulin application were observed three types of irregular insulin therapy: missed dose, time imprecision of dose (± 2 hours vs. the prescribed time) and dose reduction in all cases in the past 30 days before completing the questionnaire. In addition, it was investigated the attitude and relation of patients to these issues. The results have shown that irregular insulin dose in the Czech Republic is less frequent than in other countries involved in the GAPP2 research. Nevertheless, approximately one fifth of diabetic patients using insulin analogues in basal-bolus or only basal therapy regimen is related to this problem. The last irregular insulin

  5. Practical aspects and applications of the biological effective dose three-dimensional calculation for multi-phase radiotherapy treatment plans

    NASA Astrophysics Data System (ADS)

    Kauweloa, Kevin Ikaika

    was found using the current, clinically accepted dose limits, allowing the BEDT distributions to be calculated, which could be used to determine whether at least 700 cc of the healthy liver did not receive the BEDT limit. Three previously multi-target liver cancer patients were studied. For each case, it was shown that the conventional treatment plans were relatively conservative and that more than 700 cc of the healthy liver received less than the BED T limit. These results show that greater doses can be delivered to the targets without exceeding the BEDT limit to the healthy tissue, which typically causes radiation toxicity. When applying BEDT to gynecological cases, the BEDT can reveal the relative effect each treatment would have individually hence the cumulative BEDT would better inform the physician of the potential results with the patient's treatment. The problem presented for these cases, however, is the method in summing dose distributions together when there is significant motion between treatments and the presence of applicators for the HDR phase. One way to calculate the cumulative BEDT is to use structure guided deformable image registration (SG-DIR) that only focuses on the anatomical contours, to avoid errors introduced by the applicators. Eighteen gynecological patients were studied and VelocityAI was used to perform this SG- DIR. In addition, formalism was developed to assess and characterize the remnant dose-mapping error from this approach, from the shortest distance between contour points (SDBP). The results revealed that warping errors rendered relatively large normal tissue complication probability (NTCP) values which are certainly non negligible and does render this method not clinically viable. However, a more accurate SG-DIR algorithm could improve the accuracy of BEDT distributions in these multi-phase cases.

  6. 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.

  7. 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.

  8. Medical Conditions and Nearly Lethal Suicide Attempts.

    ERIC Educational Resources Information Center

    Ikeda, Robin M.; Kresnow, Marcie-jo; Mercy, James A.; Powell, Kenneth E.; Simon, Thomas R.; Potter, Lloyd B.; Durant, Tonji M.; Swahn, Monica H.

    2002-01-01

    This population-based, case-control study examined physical illness as a risk factor for suicidal behavior. Case patients were more likely than controls to report having any serious medical conditions. Results suggest that young men with medical conditions are at increased risk for nearly lethal suicide attempts. (Contains 33 references and 3…

  9. 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

  10. 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…

  11. Sarcocystis species lethal for domestic pigeons.

    PubMed

    Olias, Philipp; Gruber, Achim D; Kohls, Andrea; Hafez, Hafez M; Heydorn, Alfred Otto; Mehlhorn, Heinz; Lierz, Michael

    2010-03-01

    A large number of Sarcocystis spp. infect birds as intermediate hosts, but pigeons are rarely affected. We identified a novel Sarcocystis sp. that causes lethal neurologic disease in domestic pigeons in Germany. Experimental infections indicated transmission by northern goshawks, and sequence analyses indicated transnational distribution. Worldwide spread is possible.

  12. 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…

  13. Medical Conditions and Nearly Lethal Suicide Attempts.

    ERIC Educational Resources Information Center

    Ikeda, Robin M.; Kresnow, Marcie-jo; Mercy, James A.; Powell, Kenneth E.; Simon, Thomas R.; Potter, Lloyd B.; Durant, Tonji M.; Swahn, Monica H.

    2002-01-01

    This population-based, case-control study examined physical illness as a risk factor for suicidal behavior. Case patients were more likely than controls to report having any serious medical conditions. Results suggest that young men with medical conditions are at increased risk for nearly lethal suicide attempts. (Contains 33 references and 3…

  14. Characteristics and Lethality of a Novel Recombinant Dermonecrotic Venom Phospholipase D from Hemiscorpius lepturus

    PubMed Central

    Torabi, Elham; Behdani, Mahdi; Hosseininejad Chafi, Mohammad; Moazzami, Reza; Sabatier, Jean-Marc; Khalaj, Vahid; Shahbazzadeh, Delavar; Pooshang Bagheri, Kamran

    2017-01-01

    Hemoscorpius lepturus is the most medically important scorpion in Iran. The clinical signs of H. lepturus envenomation are remarkably similar to those reported for brown spiders, including dermonecrosis, hematuria, renal failure and even death. The lethality and toxicity of brown spiders’ venom have been attributed to its phospholipase D activity. This study aims to identify a phospholipase D with possible lethality and dermonecrotic activity in H. lepturus venom. In this study, a cDNA library of the venom glands was generated by Illumina RNA sequencing. Phospholipase D (PLD) from H. lepturus was characterized according to its significant similarity with PLDs from brown spiders. The main chain designated as Hl-RecPLD1 (the first recombinant isoform of H. lepturus PLD) was cloned, expressed and purified. Sphingomyelinase, dermonecrotic and lethal activities were examined. Hl-PLD1 showed remarkable sequence similarity and structural homology with PLDs of brown spiders. The conformation of Hl-PLD1 was predicted as a “TIM beta/alpha-barrel”. The lethal dose 50 (LD50) and dermonecrotic activities of Hl-RecPLD1 were determined as 3.1 µg/mouse and 0.7 cm2 at 1 µg respectively. It is the first report indicating that a similar molecular evolutionary mechanism has occurred in both American brown spiders and this Iranian scorpion. In conclusion, Hl-RecPLD1 is a highly active phospholipase D, which would be considered as the lethal dermonecrotic toxin in H. lepturus venom. PMID:28335389

  15. Linear relationship between lethal mutation yield and intake of ethyl methanesulfonate in Drosophila melanogaster

    SciTech Connect

    Ayaki, T.; Oshima, K.; Yoshikawa, I.

    1985-01-01

    Males of Drosophila melanogaster were fed sucrose solutions containing various concentrations of EMS (from 0.25 to 10mM) for 24 hr. To measure the intake of an EMS solution, /sup 3/H-labeled sucrose was added to the feeding solution, and the /sup 3/H activity inside the flies was used as a measure for the intake volume of EMS solution. The relationship between the estimated absorbed dose and the exposure concentration was almost linear in a low concentration range but became concave with a downward curvature in a high concentration range. The dose-response relationship between the frequency of sex-linked recessive lethals and the estimated absorbed dose showed no deviation from linearity at all the five absorbed doses tested. It may be concluded that the absorbed doses thus estimated were very close to true absorbed doses, indicating the usefulness of the present method for dosimetry of chemicals to be given to files.

  16. Histological dermal changes caused by preparation and application procedures in percutaneous dose toxicity studies in dogs, rabbits and rats

    PubMed Central

    Mitsuishi, Mikio; Oshikata, Takafumi; Kumabe, Shino; Kobayashi, Azusa; Katoku, Koshiro; Kanno, Takeshi; Hamamura, Masao; Tsuchitani, Minoru

    2014-01-01

    We reevaluated histological slides of dorsal skin in control animals from past percutaneous dose toxicity studies using dogs, rabbits and rats to provide background data concerning histological changes related to preparation and application procedures and vehicles or embrocations of every variety. Acanthosis, dermal or perifollicular inflammatory cell infiltration in dogs; hyperkeratosis, acanthosis, dermal inflammatory cell infiltration or hemorrhage in rabbits; and acanthosis, dermal inflammatory cell infiltration, crust or foreign body granuloma in rats were present as procedure-related underlying histological changes in the control animals. Four mechanical acts, (1) rubbing with gauze to remove an administered substance for reapplication, (2) use of a taut bandage to avoid slipping from the application site, (3) peeling a patch off as a preparation procedure for reapplication, and (4) clipping or shaving, were considered to cause injury to the skin. The degree of influence of the various application procedures was found to be as follows: sham, lotion < cream < ointment and tape in dogs; untreated control, sham < lotion < tape and poultice in rabbits; and sham, sodium carboxymethylcellulose < olive oil and lotion < ointment and tape in rats. The degree of ointment influence on rabbits is equivocal. PMID:26023255

  17. Application of flash dual-source CT at low radiation dose and low contrast medium dose in triple-rule-out (tro) examination.

    PubMed

    Chen, Hong-Liang; Chen, Tian-Wu; Qiu, Li-Hua; Diao, Xian-Ming; Zhang, Chao; Chen, Li

    2015-01-01

    To evaluate the clinical imaging capacity of FLASH dual-source CT at low radiation dose and low contrast medium dose in thoracic aorta, pulmonary artery & vein and coronary artery. One hundred and eight patients of thoracalgia were randomly divided into two groups; 60 cases (group A) received dual-source CT scan in flash model at 100 KV and contrast medium dose of 74 ml combined with digital subtraction angiography (DSA) examination; 48 cases (group B) received retrospectively. ECG-triggered high-pitch spiral acquisition at 120 KV and contrast medium dose of 101 ml. Several image reconstruction techniques were adopted for coronary artery, pulmonary artery and aorta. The imaging quality and the diagnostic value of this technique were evaluated. Coronary artery stenosis of group A was compared against the results of DSA examination. The scan time in group A was obviously shorter than that of group B, i.e., t=0.7±0.1 s in group A and t=7.7±1.7 s in group A. The image reconstruction phase of coronary artery was 70.4±15.6% in group A, and the systolic phase accounted for 13.3% of the optimal reconstruction phase. Compared with group B, the radiation dose of group A decreased obviously, i.e. ED=2.7±0.7 mSv for group A and ED=21.6±6.0 mSv for group B. Moreover, less contrast agent was consumed in group A than in group B, which was 74 ml in group A and 101 ml in group B. The image quality of aorta and pulmonary artery & vein was grade 1 for all cases in group A, which was the same as with group B. The coronary artery images of group A had better quality, with score of 2.9±0.1. Of 780 segments, only 2 segments could be effectively diagnosed, showing no statistically significant differences from group B (P>0.05). The coronary artery stenosis revealed by dual-source CT for group A was not significantly different from that by DSA (P>0.05). FLASH dual-source CT scan at reduced radiation dose and reduced contrast medium dose used for triple-rule-out (TRO) examination

  18. Application of flash dual-source CT at low radiation dose and low contrast medium dose in triple-rule-out (tro) examination

    PubMed Central

    Chen, Hong-Liang; Chen, Tian-Wu; Qiu, Li-Hua; Diao, Xian-Ming; Zhang, Chao; Chen, Li

    2015-01-01

    Objective: To evaluate the clinical imaging capacity of FLASH dual-source CT at low radiation dose and low contrast medium dose in thoracic aorta, pulmonary artery & vein and coronary artery. Method: One hundred and eight patients of thoracalgia were randomly divided into two groups; 60 cases (group A) received dual-source CT scan in flash model at 100 KV and contrast medium dose of 74 ml combined with digital subtraction angiography (DSA) examination; 48 cases (group B) received retrospectively. ECG-triggered high-pitch spiral acquisition at 120 KV and contrast medium dose of 101 ml. Several image reconstruction techniques were adopted for coronary artery, pulmonary artery and aorta. The imaging quality and the diagnostic value of this technique were evaluated. Coronary artery stenosis of group A was compared against the results of DSA examination. Results: The scan time in group A was obviously shorter than that of group B, i.e., t=0.7±0.1 s in group A and t=7.7±1.7 s in group A. The image reconstruction phase of coronary artery was 70.4±15.6% in group A, and the systolic phase accounted for 13.3% of the optimal reconstruction phase. Compared with group B, the radiation dose of group A decreased obviously, i.e. ED=2.7±0.7 mSv for group A and ED=21.6±6.0 mSv for group B. Moreover, less contrast agent was consumed in group A than in group B, which was 74 ml in group A and 101 ml in group B. The image quality of aorta and pulmonary artery & vein was grade 1 for all cases in group A, which was the same as with group B. The coronary artery images of group A had better quality, with score of 2.9±0.1. Of 780 segments, only 2 segments could be effectively diagnosed, showing no statistically significant differences from group B (P>0.05). The coronary artery stenosis revealed by dual-source CT for group A was not significantly different from that by DSA (P>0.05). Conclusion: FLASH dual-source CT scan at reduced radiation dose and reduced contrast medium dose used for

  19. On the combination of c- and D-optimal designs: General approaches and applications in dose-response studies.

    PubMed

    Holland-Letz, Tim

    2017-03-01

    Dose-response modeling in areas such as toxicology is often conducted using a parametric approach. While estimation of parameters is usually one of the goals, often the main aim of the study is the estimation of quantities derived from the parameters, such as the ED50 dose. From the view of statistical optimal design theory such an objective corresponds to a c-optimal design criterion. Unfortunately, c-optimal designs often create practical problems, and furthermore commonly do not allow actual estimation of the parameters. It is therefore useful to consider alternative designs which show good c-performance, while still being applicable in practice and allowing reasonably good general parameter estimation. In effect, using optimal design terminology this means that a reasonable performance regarding the D-criterion is expected as well. In this article, we propose several approaches to the task of combining c- and D-efficient designs, such as using mixed information functions or setting minimum requirements regarding either c- or D-efficiency, and show how to algorithmically determine optimal designs in each case. We apply all approaches to a standard situation from toxicology, and obtain a much better balance between c- and D-performance. Next, we investigate how to adapt the designs to different parameter values. Finally, we show that the methodology used here is not just limited to the combination of c- and D-designs, but can also be used to handle more general constraint situations such as limits on the cost of an experiment.

  20. Upgrades of DARWIN, a dose and spectrum monitoring system applicable to various types of radiation over wide energy ranges

    NASA Astrophysics Data System (ADS)

    Sato, Tatsuhiko; Satoh, Daiki; Endo, Akira; Shigyo, Nobuhiro; Watanabe, Fusao; Sakurai, Hiroki; Arai, Yoichi

    2011-05-01

    A dose and spectrum monitoring system applicable to neutrons, photons and muons over wide ranges of energy, designated as DARWIN, has been developed for radiological protection in high-energy accelerator facilities. DARWIN consists of a phoswitch-type scintillation detector, a data-acquisition (DAQ) module for digital waveform analysis, and a personal computer equipped with a graphical-user-interface (GUI) program for controlling the system. The system was recently upgraded by introducing an original DAQ module based on a field programmable gate array, FPGA, and also by adding a function for estimating neutron and photon spectra based on an unfolding technique without requiring any specific scientific background of the user. The performance of the upgraded DARWIN was examined in various radiation fields, including an operational field in J-PARC. The experiments revealed that the dose rates and spectra measured by the upgraded DARWIN are quite reasonable, even in radiation fields with peak structures in terms of both spectrum and time variation. These results clearly demonstrate the usefulness of DARWIN for improving radiation safety in high-energy accelerator facilities.

  1. Application of physiologically-based toxicokinetic modelling in oral-to-dermal extrapolation of threshold doses of cosmetic ingredients.

    PubMed

    Gajewska, M; Worth, A; Urani, C; Briesen, H; Schramm, K-W

    2014-06-16

    The application of physiologically based toxicokinetic (PBTK) modelling in route-to-route (RtR) extrapolation of three cosmetic ingredients: coumarin, hydroquinone and caffeine is shown in this study. In particular, the oral no-observed-adverse-effect-level (NOAEL) doses of these chemicals are extrapolated to their corresponding dermal values by comparing the internal concentrations resulting from oral and dermal exposure scenarios. The PBTK model structure has been constructed to give a good simulation performance of biochemical processes within the human body. The model parameters are calibrated based on oral and dermal experimental data for the Caucasian population available in the literature. Particular attention is given to modelling the absorption stage (skin and gastrointestinal tract) in the form of several sub-compartments. This gives better model prediction results when compared to those of a PBTK model with a simpler structure of the absorption barrier. In addition, the role of quantitative structure-property relationships (QSPRs) in predicting skin penetration is evaluated for the three substances with a view to incorporating QSPR-predicted penetration parameters in the PBTK model when experimental values are lacking. Finally, PBTK modelling is used, first to extrapolate oral NOAEL doses derived from rat studies to humans, and then to simulate internal systemic/liver concentrations - Area Under Curve (AUC) and peak concentration - resulting from specified dermal and oral exposure conditions. Based on these simulations, AUC-based dermal thresholds for the three case study compounds are derived and compared with the experimentally obtained oral threshold (NOAEL) values.

  2. SU-E-T-491: Influence of Applicator Dimensions On Doses to Bladder, Rectum and Sigmoid in HDR Brachytherapy for Cervical Cancer

    SciTech Connect

    Dumane, V; Rhome, R; Yuan, Y; Gupta, V

    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 D2cc 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.

  3. Experimental investigation on electrical characteristics and dose measurement of dielectric barrier discharge plasma device used for therapeutic application

    NASA Astrophysics Data System (ADS)

    Shahbazi Rad, Zahra; Abbasi Davani, Fereydoun

    2017-04-01

    In this research, a Dielectric Barrier Discharge (DBD) plasma device operating in air has been made. The electrical characteristics of this device like instantaneous power, dissipated power, and discharge capacitance have been measured. Also, the effects of applied voltage on the dissipated power and discharge capacitance of the device have been investigated. The determination of electrical parameters is important in DBD plasma device used in living tissue treatment for choosing the proper treatment doses and preventing the destructive effects. The non-thermal atmospheric pressure DBD plasma source was applied for studying the acceleration of blood coagulation time, in vitro and wound healing time, in vivo. The citrated blood drops coagulated within 5 s treatment time by DBD plasma. The effects of plasma temperature and electric field on blood coagulation have been studied as an affirmation of the applicability of the constructed device. Also, the effect of constructed DBD plasma on wound healing acceleration has been investigated.

  4. Calculation of microplanar beam dose profiles in a tissue/lung/tissue phantom.

    PubMed

    Company, F Z; Allen, B J

    1998-09-01

    Recent advances in synchrotron generated x-ray beams with a high fluence rate permit investigation of the application of an array of closely spaced, parallel or converging microplanar beams in radiotherapy. The proposed technique takes advantage of the hypothesized repair mechanism of capillary cells between alternate microbeam zones, which regenerates the lethally irradiated endothelial cells. The lateral and depth doses of 100 keV microplanar beams are investigated for different beam dimensions and spacings in a tissue, lung and tissue/lung/tissue phantom. The EGS4 Monte Carlo code is used to calculate dose profiles at different depths and bundles of beams (up to 20 x 20 cm square cross section). The maximum dose on the beam axis (peak) and the minimum interbeam dose (valley) are compared at different depths, bundles, heights, widths and beam spacings.

  5. Characterization of statistical prior image constrained compressed sensing (PICCS): II. Application to dose reduction.

    PubMed

    Lauzier, Pascal Theriault; Chen, Guang-Hong

    2013-02-01

    The ionizing radiation imparted to patients during computed tomography exams is raising concerns. This paper studies the performance of a scheme called dose reduction using prior image constrained compressed sensing (DR-PICCS). The purpose of this study is to characterize the effects of a statistical model of x-ray detection in the DR-PICCS framework and its impact on spatial resolution. Both numerical simulations with known ground truth and in vivo animal dataset were used in this study. In numerical simulations, a phantom was simulated with Poisson noise and with varying levels of eccentricity. Both the conventional filtered backprojection (FBP) and the PICCS algorithms were used to reconstruct images. In PICCS reconstructions, the prior image was generated using two different denoising methods: a simple Gaussian blur and a more advanced diffusion filter. Due to the lack of shift-invariance in nonlinear image reconstruction such as the one studied in this paper, the concept of local spatial resolution was used to study the sharpness of a reconstructed image. Specifically, a directional metric of image sharpness, the so-called pseudopoint spread function (pseudo-PSF), was employed to investigate local spatial resolution. In the numerical studies, the pseudo-PSF was reduced from twice the voxel width in the prior image down to less than 1.1 times the voxel width in DR-PICCS reconstructions when the statistical model was not included. At the same noise level, when statistical weighting was used, the pseudo-PSF width in DR-PICCS reconstructed images varied between 1.5 and 0.75 times the voxel width depending on the direction along which it was measured. However, this anisotropy was largely eliminated when the prior image was generated using diffusion filtering; the pseudo-PSF width was reduced to below one voxel width in that case. In the in vivo study, a fourfold improvement in CNR was achieved while qualitatively maintaining sharpness; images also had a

  6. Application of a physiologically based pharmacokinetic model for reference dose and reference concentration estimation for acetone.

    PubMed

    Gentry, P Robinan; Covington, Tammie R; Clewell, Harvey J; Anderson, Melvin E

    2003-12-12

    Recent health risk assessments to propose a Reference Dose (RfD) for acetone (Forsyth, 2001; U.S. EPA, 2001) have been based on the results of an oral subchronic study conducted in rats and mice (Dietz et al., 1991; NTP, 1991). These assessments have utilized the traditional concept of establishing the RfD by determining the lowest experimentally determined No-Observed-Adverse-Effect Level (NOAEL) and applying various Uncertainty Factors (UFs) (U.S. EPA, 1988). This article describes a risk assessment for acetone based on the systemic toxicity observed in subchronic and developmental toxicity studies to estimate an RfD and an inhalation reference concentration (RfC) for acetone. Specifically, this approach examined the subchronic study by Dietz et al. (1991), as well as an inhalation developmental toxicity study on acetone (Mast et al., 1988) and several toxicology studies of isopropanol (IPA). This was accomplished by applying a physiologically based pharmacokinetic (PBPK) model developed previously for IPA and its metabolite acetone (Clewell et al., 2001). The incorporation of the PBPK model into the derivation of an RfD and RfC for acetone allowed for a tissue-based approach rather than an external exposure-based approach, making it possible to derive an oral RfD from an inhalation study. In addition, the use of the PBPK model to analyze data from chronic and reproductive/developmental studies conducted with IPA enabled an assessment of the potential for acetone to produce any of the effects observed in the IPA studies. This analysis provided sufficient information to reduce the need for UFs in the adjustment of the NOAEL from the oral subchronic study for the determination of an RfD. Using the PBPK model in the acetone risk assessment supports a composite UF of 60 for the subchronic study, compared to composite factors of 300 to 3000 in the other recent risk assessments. This difference resulted in an RfD of 16 mg/kg/d, compared to the values of 0.3 to 3 that

  7. Characterization of statistical prior image constrained compressed sensing (PICCS): II. Application to dose reduction

    SciTech Connect

    Lauzier, Pascal Theriault; Chen Guanghong

    2013-02-15

    Purpose: The ionizing radiation imparted to patients during computed tomography exams is raising concerns. This paper studies the performance of a scheme called dose reduction using prior image constrained compressed sensing (DR-PICCS). The purpose of this study is to characterize the effects of a statistical model of x-ray detection in the DR-PICCS framework and its impact on spatial resolution. Methods: Both numerical simulations with known ground truth and in vivo animal dataset were used in this study. In numerical simulations, a phantom was simulated with Poisson noise and with varying levels of eccentricity. Both the conventional filtered backprojection (FBP) and the PICCS algorithms were used to reconstruct images. In PICCS reconstructions, the prior image was generated using two different denoising methods: a simple Gaussian blur and a more advanced diffusion filter. Due to the lack of shift-invariance in nonlinear image reconstruction such as the one studied in this paper, the concept of local spatial resolution was used to study the sharpness of a reconstructed image. Specifically, a directional metric of image sharpness, the so-called pseudopoint spread function (pseudo-PSF), was employed to investigate local spatial resolution. Results: In the numerical studies, the pseudo-PSF was reduced from twice the voxel width in the prior image down to less than 1.1 times the voxel width in DR-PICCS reconstructions when the statistical model was not included. At the same noise level, when statistical weighting was used, the pseudo-PSF width in DR-PICCS reconstructed images varied between 1.5 and 0.75 times the voxel width depending on the direction along which it was measured. However, this anisotropy was largely eliminated when the prior image was generated using diffusion filtering; the pseudo-PSF width was reduced to below one voxel width in that case. In the in vivo study, a fourfold improvement in CNR was achieved while qualitatively maintaining sharpness

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

    SciTech Connect

    Grandic, Marjana; Sepcic, Kristina; Turk, Tom; Juntes, Polona; Frangez, Robert

    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. 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/kg) revealed

  9. Development of posture-specific computational phantoms using motion capture technology and application to radiation dose-reconstruction for the 1999 Tokai-Mura nuclear criticality accident

    NASA Astrophysics Data System (ADS)

    Vazquez, Justin A.; Caracappa, Peter F.; Xu, X. George

    2014-09-01

    The majority of existing computational phantoms are designed to represent workers in typical standing anatomical postures with fixed arm and leg positions. However, workers found in accident-related scenarios often assume varied postures. This paper describes the development and application of two phantoms with adjusted postures specified by data acquired from a motion capture system to simulate unique human postures found in a 1999 criticality accident that took place at a JCO facility in Tokai-Mura, Japan. In the course of this accident, two workers were fatally exposed to extremely high levels of radiation. Implementation of the emergent techniques discussed produced more accurate and more detailed dose estimates for the two workers than were reported in previous studies. A total-body dose of 6.43 and 26.38 Gy was estimated for the two workers, who assumed a crouching and a standing posture, respectively. Additionally, organ-specific dose estimates were determined, including a 7.93 Gy dose to the thyroid and 6.11 Gy dose to the stomach for the crouching worker and a 41.71 Gy dose to the liver and a 37.26 Gy dose to the stomach for the standing worker. Implications for the medical prognosis of the workers are discussed, and the results of this study were found to correlate better with the patient outcome than previous estimates, suggesting potential future applications of such methods for improved epidemiological studies involving next-generation computational phantom tools.

  10. Lethality and synthetic lethality in the genome-wide metabolic network of Escherichia coli.

    PubMed

    Ghim, Cheol-Min; Goh, Kwang-Il; Kahng, Byungnam

    2005-12-21

    Recent genomic analyses on the cellular metabolic network show that reaction flux across enzymes are diverse and exhibit power-law behavior in its distribution. While intuition might suggest that the reactions with larger fluxes are more likely to be lethal under the blockade of its catalysing gene products or gene knockouts, we find, by in silico flux analysis, that the lethality rarely has correlations with the flux level owing to the widespread backup pathways innate in the genome-wide metabolism of Escherichia coli. Lethal reactions, of which the deletion generates cascading failure of following reactions up to the biomass reaction, are identified in terms of the Boolean network scheme as well as the flux balance analysis. The avalanche size of a reaction, defined as the number of subsequently blocked reactions after its removal, turns out to be a useful measure of lethality. As a means to elucidate phenotypic robustness to a single deletion, we investigate synthetic lethality in reaction level, where simultaneous deletion of a pair of nonlethal reactions leads to the failure of the biomass reaction. Synthetic lethals identified via flux balance and Boolean scheme are consistently shown to act in parallel pathways, working in such a way that the backup machinery is compromised.

  11. SU-E-T-141: Automated Dose Point Placement for Cervical Cance