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Sample records for lethal doses application

  1. Derivation of Human Lethal Doses

    DTIC Science & Technology

    2006-01-19

    emergency medicine, pharmacology, forensic medicine, and industrial chemical toxicology, in addition to a poison information center. The authors presented...Meditsinskaya Ekspeertiza. Forensic Medical Examination, 26(2), 48, 1983 (as cited in Sax’s). This reference is not available for review. Rat – LD50...mg/kg No LDLo, MLD, or lethal dose for humans Rat – LD50 (Bulletin of the Entomological Society of America, 1969) (as cited in Sax’s). This

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  8. 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

  9. 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

  10. 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

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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

  18. 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

  19. 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.

  20. 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

  1. 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.

  2. 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

  3. 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

  4. 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.

  5. 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.

  6. 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.

  7. 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

  8. 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.

  9. 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.

  10. 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

  11. 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

  12. 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.

  13. [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.

  14. 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.

  15. 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.

  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. 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.

  19. 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

  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. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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

  11. 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

  12. 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.

  13. 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.

  14. 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

  15. 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

  16. 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.

  17. 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

  18. 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.

  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. 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.

  1. 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.

  2. 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

  3. 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

  4. 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.

  5. 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.

  6. 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

  7. 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.

  8. 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

  9. 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.

  10. 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.

  11. Judged Lethality

    DTIC Science & Technology

    1980-12-01

    75 High Blood Pressure 535 89 17 538 76 Drug Abuse 1,020 1,371 19 95 80 Bronchitis 162 19 43 2,111 85 Pregnancy 67 24 13 787 250 Diabetes 487 101 52...Diseases 4 Mumps 3 Dental Problems 1 Always Overestimated High Blood Pressure 9 Alcoholism 6 Influenza 2 Note: Measles (8), tuberculosis (13), auto...statis- tical lethality rate and total number of people killed (cancer, strokes, heart attacks, emphysema, high blood pressure ) were rather accurately

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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

  17. 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.

  18. 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.

  19. 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.

  20. 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

  1. 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

  2. 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

  3. 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

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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

  18. 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.

  19. 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

  20. 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.

  1. 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.

  2. 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.

  3. 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

  4. 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.

  5. 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.

  6. 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

  7. 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.

  8. 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.

  9. 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

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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

  15. 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

  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. 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

  19. 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.

  20. 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.

  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. 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

  3. 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

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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

  14. 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

  15. 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.

  16. 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.

  17. 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

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. Beneficial Effect of Dexamethasone in Decreasing the Lethality of Acute T-2 Toxicosis,

    DTIC Science & Technology

    1986-11-07

    lethality of T-2 toxin. Steroidal agents, assessed at equivalent doses for ant i-inf lammatory activity, were all effective, with dexamethasone being more...effective than either mthylprednisolone or hydrocor- tisone. The doses of dexamethasone producing the highest efficacy were 1.0 mg/kg and 12.5 mg/kg for...Bdte-4 2 The mean time to 4eath, mean survival time, and percent lethality were deter- (A amined for untreated and dexamethasone -treated mice injected

  3. 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.

  4. 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.

  5. 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

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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

  12. 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.

  13. 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.

  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. 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.

  19. 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.

  20. 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

  1. 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

  2. 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

  3. 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

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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

  9. 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.

  10. 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.

  11. 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

  12. 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.

  13. 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.

  14. 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

  15. 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.

  16. 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.

  17. 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.

  18. 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

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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

  6. 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.

  7. 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.

  8. 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).

  9. 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.

  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 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

  12. 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.

  13. 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%.

  14. 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

  15. 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

  16. 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.

  17. 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

  18. 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.

  19. 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.

  20. 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

  1. 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.

  2. 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.

  3. 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.

  4. 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

  5. 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.

  6. 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)

  7. 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

  8. 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.

  9. 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.

  10. 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

  11. 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…

  12. 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.

  13. 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

  14. 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.

  15. 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.

  16. 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.

  17. 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...

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  3. 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.

  4. 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...

  5. 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

  6. 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

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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

  15. 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

  16. 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.

  17. 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.

  18. Two cases of lethal nitrazepam poisoning.

    PubMed

    Brødsgaard, I; Hansen, A C; Vesterby, A

    1995-06-01

    This case report describes two cases of lethal poisoning caused by a combination of advanced chronic disease and an overdose of nitrazepam. In both cases, a relatively small blood concentration of nitrazepam was found postmortem.

  19. 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.

  20. 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

  1. 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

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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

  10. 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

  11. 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.

  12. 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

  13. [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.

  14. 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.

  15. 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

  16. 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.

  17. 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.

  18. 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.

  19. 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

  20. 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.

  1. 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.

  2. 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.

  3. 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.

  4. 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).

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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

  10. 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.

  11. 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.

  12. 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.

  13. 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

  14. 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.

  15. 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

  16. 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.

  17. 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

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. 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

  3. 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.

  4. 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…

  5. 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.

  6. 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…

  7. 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.

  8. 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.

  9. 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.

  10. 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

  11. 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

  12. 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

  13. 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.

  14. Induction of dominant lethal mutations by Ascaris trypsin inhibitor in male mice.

    PubMed

    Blaszkowska, Joanna

    2010-01-01

    Trypsin inhibitor (ATI) isolated from Ascaris suum, a gastrointestinal nematode parasite, was tested for the induction of dominant lethal mutations in male mice. Dominant lethal effects of ATI for the main stages of germ cell development were analyzed by mating at specific time points after dosing. Three groups of adult BALB/c males received 50, 100 or 250mg/kg body weight (bw) single intraperitoneal (ip) injection of ATI in sterile phosphate-buffered saline (PBS). The control group received concurrent injection of PBS. After the administration of ATI or PBS, each male was mated with two untreated females. For fractionated examination with regard to successive germ cell stages (spermatozoa, spermatids, spermatocytes, and spermatogonia), every second week two other untreated virgin females were placed with each male for mating. The uteri of the females were inspected on the 15th day of gestation, and preimplantation loss and postimplantation loss determined from dominant lethal parameters. Exposure of mice germ cells to ATI did not impair mating activity of males. Pregnancy rates were reduced ( approximately 5-10%) by treatment of males with higher doses of ATI, but differences between treatment and control groups were not statistically significant (P>0.05). In the females bred to ATI-treated males, significant increase in preimplantation loss was observed at post-injection week 1 (reflecting exposure to spermatozoa) and 3 (reflecting exposure to mid and early spermatids) for higher doses of the inhibitor (P<0.05 or P<0.01). During mating days 15-21 a statistically significant increase in postimplantation loss and dominant lethal effects were observed for all doses of ATI. At higher doses, dominant lethal effects were restricted to spermatozoa (P<0.01). These data suggest that ATI induces dominant lethal mutations at postmeiotic stages of spermatogenesis, but spermatids are the most sensitive cell stage to the effect of ATI. These preliminary findings show that ATI

  15. The effect of the interval between dose applications on the observed specific-locus mutation rate in the mouse following fractionated treatments of spermatogonia with ethylnitrosourea.

    PubMed

    Favor, J; Neuhäuser-Klaus, A; Ehling, U H; Wulff, A; van Zeeland, A A

    1997-03-21

    Our earlier analyses have suggested an apparent threshold dose-response for ethylnitrosourea-induced specific-locus mutations in treated spermatogonia of the mouse to be due to a saturable repair process. In the current study a series of fractionated-treatment experiments was carried out in which male (102 x C3H)F1 mice were exposed to 4 x 10, 2 x 40. 4 x 20 or 4 x 40 mg ethylnitrosourea per kg body weight with 24 h between applications; 4 x 40 mg ethylnitrosourea per kg body weight with 72 h between dose applications; and 2 x 40, 4 x 20 and 4 x 40 mg ethylnitrosourea per kg body weight with 168 h between dose applications. For all experiments with 24-h intervals between dose applications, there was no effect due to dose fractionation on the observed mutation rates, indicating the time interval between dose applications to be shorter than the recovery time of the repair processes acting on ethylnitrosourea-induced DNA adducts. In contrast, a fractionation interval of 168 h was associated with a significant reduction in the observed mutation rate due to recovery of the repair process. However, although reduced, the observed mutation rates for fractionation intervals of 168 h were higher than the spontaneous specific-locus mutation rate. These observations contradict the expectation for a true threshold dose response. We interpret this discrepancy to be due to the differences in the predictions of a mathematical abstraction of experimental data and the complexities of the biological system being studied. Biologically plausible explanations of the discrepancy are presented.

  16. 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.

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

    PubMed

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

    2015-05-01

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

  18. SU-E-T-141: Automated Dose Point Placement for Cervical Cancer Brachytherapy Using Tandem and Ovoid Applicators

    SciTech Connect

    Kang, H; Padilla, L; Hasan, Y; Al-Hallaq, H

    2015-06-15

    Purpose: To develop a standalone application, which automatically and consistently calculates the coordinates of points A and H based solely on the implanted applicator geometry for cervical cancer HDR brachytherapy. Methods: Manchester point A and ABS point H are both located 2cm lateral from the central tandem plane. While both points are located 2cm above the cervical os, surrogates for the os differ. Point A is defined relative to the anatomical cervical os. Point H is defined relative to the intersection of the tandem with the superior aspects of the ovoids. The application takes an input text file generated by the treatment planning system (TPS, BrachyVision, Varian) that specifies the source geometries. It then outputs the 3D coordinates of points A and H in both the left and right directions. The algorithm was implemented and tested on 34 CT scans of 7 patients treated with HDR brachytherapy delivered using tandem and ovoids. A single experienced user retrospectively and manually placed points A and H on the CT scans, whose coordinates were used as the gold standard for the comparison to the automatically calculated points. Results: The automatically calculated coordinates of points A and H agree within 0.7mm with the gold standard. The averages and standard deviations of the 3D coordinate difference between points placed by the two methods are 0.3±0.1 and 0.4±0.1mm for points A and H, respectively. The maximum difference in 3D magnitude is 0.7mm. Conclusion: The algorithm consistently calculates dose point coordinates independently of the planner for cervical cancer brachytherapy treated with tandem and ovoids. Automated point placement based on the geometry of the implanted applicators agrees in sub-millimeter with careful manual placements by an experienced user. This algorithm expedites the planning process and eliminates dependencies on either user input or TPS visualization tools.

  19. High-throughput automated dissolution method applicable for a wide dose range of controlled release pellets.

    PubMed

    Petruševska, Marija; Horvat, Matej; Peternel, Luka; Kristan, Katja

    2016-01-01

    The aim of the present study was to demonstrate the application of an automated high-throughput (HT) dissolution method as a useful screening tool for characterization of controlled release pellets in the formulation development phase. Five controlled release pellet formulations with drug substances exhibiting high or low solubility were chosen to investigate the correlation of the automated HT dissolution method with the conventional dissolution testing. Overall, excellent correlations (R(2 )>( )0.96) between the HT and the conventional dissolution method were obtained. In one case the initial unsatisfactory correlation (R(2 )=( )0.84) and poor method agreement (SD = 12.5) was improved by optimizing the HT dissolution method with design of experiment approach. Here in comparison to initial experimental HT dissolution settings, increased amount of pellets (25% of the capsule filling mass), lower temperature (22 °C) and no shaking resulted in significantly better correlation (R(2 )=( )0.97) and method agreement (SD = 5.3). These results show that such optimization is valuable for the development of HT dissolution methods. In conclusion, the high correlation of dissolution profiles obtained from the conventional and the automated HT dissolution method combined with low within-sample and measurement system variability, justifies the utilization of the automated HT dissolution method during development phase of controlled release pellets.

  20. Sensitivity and uncertainty investigations for Hiroshima dose estimates and the applicability of the Little Boy mockup measurements

    SciTech Connect

    Bartine, D.E.; Cacuci, D.G.

    1983-09-13

    This paper describes sources of uncertainty in the data used for calculating dose estimates for the Hiroshima explosion and details a methodology for systematically obtaining best estimates and reduced uncertainties for the radiation doses received. (ACR)

  1. Lethal arthrogryposis with anterior horn cell disease.

    PubMed

    Vuopala, K; Ignatius, J; Herva, R

    1995-01-01

    Fifteen infants (11 families) with lethal arthrogryposis and anterior horn motor neuron loss are described. The clinical presentation was the fetal akinesia deformation sequence (FADS) with multiple contractures and facial anomalies. At autopsy neurogenic muscular atrophy was present in all infants. The spinal cord showed a paucity of anterior horn motor neurons in the 12 infants studied. Both male and female infants were affected. Nine cases were sporadic, whereas in two families there were three affected cases. Consanguinity between the parents was reported in one family with one affected child. This and the recurrence of the condition speak for autosomal recessive inheritance. Detailed neuropathological examination and documentation of the clinical features are needed for a better delineation of and genetic counseling for perinatally lethal arthrogryposis.

  2. Henipaviruses-unanswered questions of lethal zoonoses.

    PubMed

    Field, Hume; Kung, Nina

    2011-12-01

    The highly lethal Hendra and Nipah viruses have been described for little more than a decade, yet within that time have been aetiologically associated with major livestock and human health impacts, albeit on a limited scale. Do these emerging pathogens pose a broader threat, or are they inconsequential 'viral chatter'. Given their lethality, and the evident multi-generational human-to-human transmission associated with Nipah virus in Bangladesh, it seems prudent to apply the precautionary principle. While much is known of their clinical, pathogenic and epidemiologic features in livestock species and humans, a number of fundamental questions regarding the relationship between the viruses, their natural fruit-bat host and the environment remain unanswered. In this paper, we pose and probe these questions in context, and offer perspectives based primarily on our experience with Hendra virus in Australia, augmented with Nipah virus parallels.

  3. PARP inhibitors: Synthetic lethality in the clinic.

    PubMed

    Lord, Christopher J; Ashworth, Alan

    2017-03-17

    PARP inhibitors (PARPi), a cancer therapy targeting poly(ADP-ribose) polymerase, are the first clinically approved drugs designed to exploit synthetic lethality, a genetic concept proposed nearly a century ago. Tumors arising in patients who carry germline mutations in either BRCA1 or BRCA2 are sensitive to PARPi because they have a specific type of DNA repair defect. PARPi also show promising activity in more common cancers that share this repair defect. However, as with other targeted therapies, resistance to PARPi arises in advanced disease. In addition, determining the optimal use of PARPi within drug combination approaches has been challenging. Nevertheless, the preclinical discovery of PARPi synthetic lethality and the route to clinical approval provide interesting lessons for the development of other therapies. Here, we discuss current knowledge of PARP inhibitors and potential ways to maximize their clinical effectiveness.

  4. Lethality and Autonomous Systems: The Roboticist Demographic

    DTIC Science & Technology

    2008-01-01

    humanoid (22%), and other (23%); 9) Media Influence: only 18% said that media had a strong or very strong influence on their attitude to robots ...and whether certain emotions would be appropriate in a military robot . The Wars question was worded as follows: To what extent do you think ...Lethality and Autonomous Systems: The Roboticist Demographic Lilia V. Moshkina and Ronald C. Arkin Mobile Robot Laboratory, College of

  5. Lethality Rate Estimation and Testing Procedures

    DTIC Science & Technology

    1989-09-11

    AUTHOR(S) Steven W. Rust, Paul I. Feder, Frederick R. Todt, Ronald L. Joiner Ila. TYPE OF REPORT 13b, IME .OVFRE 8 14. ATE OF PORT (VeerMontl.vay) 15...GD, and VX Administered Topically to Rabbits " (MREF Protocol 21, May 1985) to compare liquid or powder experimental decontaminants against the dual...chemical surety materick (CSM). The standardized screen is based on a lethality endpoint in laboratory albino rabbits . An essential aspect of this testing

  6. GPU-Accelerated Monte Carlo Electron Transport Methods: Development and Application for Radiation Dose Calculations Using Six GPU cards

    NASA Astrophysics Data System (ADS)

    Su, Lin; Du, Xining; Liu, Tianyu; Xu, X. George

    2014-06-01

    An electron-photon coupled Monte Carlo code ARCHER - Accelerated Radiation-transport Computations in Heterogeneous EnviRonments - is being developed at Rensselaer Polytechnic Institute as a software testbed for emerging heterogeneous high performance computers that utilize accelerators such as GPUs. This paper presents the preliminary code development and the testing involving radiation dose related problems. In particular, the paper discusses the electron transport simulations using the class-II condensed history method. The considered electron energy ranges from a few hundreds of keV to 30 MeV. For photon part, photoelectric effect, Compton scattering and pair production were modeled. Voxelized geometry was supported. A serial CPU code was first written in C++. The code was then transplanted to the GPU using the CUDA C 5.0 standards. The hardware involved a desktop PC with an Intel Xeon X5660 CPU and six NVIDIA Tesla™ M2090 GPUs. The code was tested for a case of 20 MeV electron beam incident perpendicularly on a water-aluminum-water phantom. The depth and later dose profiles were found to agree with results obtained from well tested MC codes. Using six GPU cards, 6x106 electron histories were simulated within 2 seconds. In comparison, the same case running the EGSnrc and MCNPX codes required 1645 seconds and 9213 seconds, respectively. On-going work continues to test the code for different medical applications such as radiotherapy and brachytherapy.

  7. Lethal interpersonal violence in the Middle Pleistocene.

    PubMed

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

    2015-01-01

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

  8. Lethal Interpersonal Violence in the Middle Pleistocene

    PubMed Central

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

    2015-01-01

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

  9. Stress-Related Signaling Pathways in Lethal and Non-Lethal Prostate Cancer

    PubMed Central

    Valdimarsdóttir, Unnur; Fang, Fang; Gerke, Travis; Tyekucheva, Svitlana; Fiorentino, Michelangelo; Lambe, Mats; Sesso, Howard D.; Sweeney, Christopher J.; Wilson, Kathryn M.; Giovannucci, Edward L.; Loda, Massimo

    2015-01-01

    Purpose Recent data suggest that neuroendocrine signaling may influence progression in some cancers. We aimed to determine whether genes within the five major stress-related signaling pathways are differentially expressed in tumor tissue when comparing prostate cancer patients with lethal and non-lethal disease. Experimental Design We measured mRNA expression of 51 selected genes involved in predetermined stress-related signaling pathways (adrenergic, glucocorticoid, dopaminergic, serotoninergic, and muscarinic systems) in tumor tissue and normal prostate tissue collected from prostate cancer patients in the Physicians’ Health Study (n=150; n=82 with normal) and the Health Professionals Follow-Up Study (n=254; n=120 with normal). We assessed differences in pathway expression in relation to prostate cancer lethality as the primary outcome, and to biomarkers as secondary outcomes. Results Differential mRNA expression of genes within the adrenergic (p=0.001), glucocorticoid (p<0.0001), serotoninergic (p=0.0019), and muscarinic (p=0.0045) pathways in tumor tissue was associated with the risk of lethality. The adrenergic pathway was also statistically significant (p=0.001) when comparing against differential expression of genes not involved in the pathways. In adjacent normal prostate tissue, none of the pathways was clearly differentially expressed between lethal and non-lethal prostate cancer. The glucocorticoid and adrenergic pathways were associated with cell proliferation, while the glucocorticoid pathway was additionally associated with angiogenesis and perineural invasion. Conclusions Our study suggests that stress-related signaling pathways, particularly the adrenergic and glucocorticoid, may be dysregulated in the tumors of men whose prostate cancer proves to be lethal, and motivates further investigation of these pathways in functional studies. PMID:26490316

  10. Thermally assisted OSL application for equivalent dose estimation; comparison of multiple equivalent dose values as well as saturation levels determined by luminescence and ESR techniques for a sedimentary sample collected from a fault gouge

    NASA Astrophysics Data System (ADS)

    Şahiner, Eren; Meriç, Niyazi; Polymeris, George S.

    2017-02-01

    Equivalent dose estimation (De) constitutes the most important part of either trap-charge dating techniques or dosimetry applications. In the present work, multiple, independent equivalent dose estimation approaches were adopted, using both luminescence and ESR techniques; two different minerals were studied, namely quartz as well as feldspathic polymineral samples. The work is divided into three independent parts, depending on the type of signal employed. Firstly, different De estimation approaches were carried out on both polymineral and contaminated quartz, using single aliquot regenerative dose protocols employing conventional OSL and IRSL signals, acquired at different temperatures. Secondly, ESR equivalent dose estimations using the additive dose procedure both at room temperature and at 90 K were discussed. Lastly, for the first time in the literature, a single aliquot regenerative protocol employing a thermally assisted OSL signal originating from Very Deep Traps was applied for natural minerals. Rejection criteria such as recycling and recovery ratios are also presented. The SAR protocol, whenever applied, provided with compatible De estimations with great accuracy, independent on either the type of mineral or the stimulation temperature. Low temperature ESR signals resulting from Al and Ti centers indicate very large De values due to bleaching in-ability, associated with large uncertainty values. Additionally, dose saturation of different approaches was investigated. For the signal arising from Very Deep Traps in quartz saturation is extended almost by one order of magnitude. It is interesting that most of De values yielded using different luminescence signals agree with each other and ESR Ge center has very large D0 values. The results presented above highly support the argument that the stability and the initial ESR signal of the Ge center is highly sample-dependent, without any instability problems for the cases of quartz resulting from fault gouge.

  11. Use of international data sets to evaluate and validate pathway assessment models applicable to exposure and dose reconstruction at DOE facilities. Progress report, August 1993--January 1994

    SciTech Connect

    Hendrickson, S.M.; Hoffman, F.O.

    1994-03-01

    This project, ``Use of International Data Sets to Evaluate and Validate Pathway Assessment Models Applicable to Exposure and Dose Reconstruction at DOE Facilities,`` grew out of several activities being conducted by the Principal Investigator Dr. F Owen Hoffman. One activity was originally part of the Chernobyl Studies Project and began as Task 7.1D, ``Internal Dose From Direct Contamination of Terrestrial Food Sources.`` The objective of Task 7.1D was to (1) establish a collaborative US USSR effort to improve and validate our methods of forecasting doses and dose commitments from the direct contamination of food sources, and (2) perform experiments and validation studies to improve our ability to predict rapidly and accurately the long-term internal dose from the contamination of agricultural soil. The latter was to include the consideration of remedial measures to block contamination of food grown on contaminated soil. The current objective of this project is to evaluate and validate pathway-assessment models applicable to exposure and dose reconstruction at DOE facilities through use of international data sets. This project incorporates the activity of Task 7.1D into a multinational effort to evaluate data used for the prediction of radionuclide transfer through agricultural and aquatic systems to humans. It also includes participation in two multinational studies, BIOMOVS (BIOspheric MOdel Validation Study) with the Swedish National Institute for Radiation Protection and VAMP (VAlidation of Model Predictions) with the International Atomic Energy Agency, that address testing the performance of models of radionuclide transport through foodchains.

  12. Clinical application of a new warfarin-dosing regimen based on the CYP2C9 and VKORC1 genotypes in atrial fibrillation patients

    PubMed Central

    JIANG, NIAN-XIN; GE, JUN-WEI; XIAN, YU-QIONG; HUANG, SHAO-YING; LI, YAN-SONG

    2016-01-01

    The polymorphisms of cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex 1 (VKORC1) are important genetic factors for warfarin dose determinations. The present study aimed to investigate the contribution of the CYP2C9 and VKORC1 genotypes to warfarin dose requirement in atrial fibrillation (AF) patients, and to evaluate the clinical application of a warfarin-dosing algorithm. A total of 122 AF patients with a target international normalized ratio of 2.0 to 3.0 were included to determine the genotypes of CYP2C9 (rs1057910) and VKORC1 (rs9923231). A warfarin-dosing algorithm was developed based on age, height, and the CYP2C9 and VKORC1 genotypes of AF patients. The results indicated that the mean warfarin daily dose requirement was lower in the CYP2C9*1/*3 genotype compared with those in the homozygous wild-type CYP2C9*1/*1 patients (P<0.05), and was higher in patients with the VKORC1 AG and GG genotypes compared with those with the AA genotype (P<0.05). The multivariate regression model showed that age, height, and the CYP2C9 and VKORC1 genotypes were the best variables for estimating warfarin dose (R2=56.4%). A new warfarin-dosing algorithm was developed and its validity was confirmed in a second cohort of AF patients. During the 50-day follow-up, 63.3% (19/30) of control group patients and 86.7% (26/30) of patients in the experimental group acquired the warfarin maintenance dose. Among all the patients who acquired the warfarin maintenance dose, the mean time elapse from initiation until warfarin maintenance dose was significantly less in the experimental group (25.8±1.7 day) compared to the control group (33.1±1.9 day) (P<0.05). There was significant linear correlation between predicted warfarin maintenance dose and actual dose (r=0.822, P<0.01). In conclusion, a new warfarin-dosing algorithm was developed based on the CYP2C9 and VKORC1 genotypes, and it can shorten the time elapse from initiation until warfarin maintenance dose in AF patients

  13. Engineered female-specific lethality for control of pest Lepidoptera.

    PubMed

    Jin, Li; Walker, Adam S; Fu, Guoliang; Harvey-Samuel, Timothy; Dafa'alla, Tarig; Miles, Andrea; Marubbi, Thea; Granville, Deborah; Humphrey-Jones, Nerys; O'Connell, Sinead; Morrison, Neil I; Alphey, Luke

    2013-03-15

    The sterile insect technique (SIT) is a pest control strategy involving the mass release of radiation-sterilized insects, which reduce the target population through nonviable matings. In Lepidoptera, SIT could be more broadly applicable if the deleterious effects of sterilization by irradiation could be avoided. Moreover, male-only release can improve the efficacy of SIT. Adequate methods of male-only production in Lepidoptera are currently lacking, in contrast to some Diptera. We describe a synthetic genetic system that allows male-only moth production for SIT and also replaces radiation sterilization with inherited female-specific lethality. We sequenced and characterized the doublesex (dsx) gene from the pink bollworm (Pectinophora gossypiella). Sex-alternate splicing from dsx was used to develop a conditional lethal genetic sexing system in two pest moths: the diamondback moth (Plutella xylostella) and pink bollworm. This system shows promise for enhancing existing pink bollworm SIT, as well as broadening SIT-type control to diamondback moth and other Lepidoptera.

  14. Differentiation factor/leukemia inhibitory factor protection against lethal endotoxemia in mice: synergistic effect with interleukin 1 and tumor necrosis factor

    PubMed Central

    1992-01-01

    Differentiation factor (D factor), also called leukemia inhibitory factor (LIF), is a glycoprotein that has been increasingly recognized to possess a wide range of physiological activities. We examined the possibility that the administration of D factor may confer beneficial effects and enhance host resistance against lethal endotoxemia. A single intravenous dose of recombinant human D factor completely protected C57/Bl6 mice from the lethal effect of Escherichia coli endotoxin (lipopolysaccharide [LPS]). The protective effects were dose dependent and observed when administered 2-24 h before LPS. Previous work has shown that interleukin 1 (IL-1) and tumor necrosis factor (TNF) also protect against a subsequent LPS challenge in a dose- dependent manner. When human D factor was combined with sub-protective doses of IL-1 beta or TNF-alpha, there was dramatic synergistic protection against a subsequent lethal LPS challenge. PMID:1552284

  15. Lethal Dietary Toxicities of Environmental Contaminants and Pesticides to Coturnix

    USGS Publications Warehouse

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

    1986-01-01

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

  16. Clinical applicability of biologically effective dose calculation for spinal cord in fractionated spine stereotactic body radiation therapy

    PubMed Central

    Lee, Seung Heon; Lee, Kyu Chan; Choi, Jinho; Ahn, So Hyun; Lee, Seok Ho; Sung, Ki Hoon; Kil, Se Hee

    2015-01-01

    Background. The aim of the study was to investigate whether biologically effective dose (BED) based on linear-quadratic model can be used to estimate spinal cord tolerance dose in spine stereotactic body radiation therapy (SBRT) delivered in 4 or more fractions. Patients and methods. Sixty-three metastatic spinal lesions in 47 patients were retrospectively evaluated. The most frequently prescribed dose was 36 Gy in 4 fractions. In planning, we tried to limit the maximum dose to the spinal cord or cauda equina less than 50% of prescription or 45 Gy2/2. BED was calculated using maximum point dose of spinal cord. Results. Maximum spinal cord dose per fraction ranged from 2.6 to 6.0 Gy (median 4.3 Gy). Except 4 patients with 52.7, 56.4, 62.4, and 67.9 Gy2/2, equivalent total dose in 2-Gy fraction of the patients was not more than 50 Gy2/2 (12.1–67.9, median 32.0). The ratio of maximum spinal cord dose to prescription dose increased up to 82.2% of prescription dose as epidural spinal cord compression grade increased. No patient developed grade 2 or higher radiation-induced spinal cord toxicity during follow-up period of 0.5 to 53.9 months. Conclusions. In fractionated spine SBRT, BED can be used to estimate spinal cord tolerance dose, provided that the dose per fraction to the spinal cord is moderate, e.g. < 6.0 Gy. It appears that a maximum dose of up to 45–50 Gy2/2 to the spinal cord is tolerable in 4 or more fractionation regimen. PMID:26029031

  17. Absorbed Dose and Dose Equivalent Calculations for Modeling Effective Dose

    NASA Technical Reports Server (NTRS)

    Welton, Andrew; Lee, Kerry

    2010-01-01

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

  18. Application and experience of a two-dosimeter algorithm for better estimation of effective dose during maintenance periods at Korea nuclear power plants.

    PubMed

    Kim, Hee Geun; Kong, Tae Young

    2009-01-01

    The application of a two-dosimeter and its algorithm and a test of its use in an inhomogeneous high radiation field are described. The goal was to develop an improved method for estimating the effective dose during maintenance periods at Korean nuclear power plants (NPPs). The application and experience to KNPPs was evaluated using data for each algorithm from two-dosimeter results for an inhomogeneous high radiation field during maintenance periods at Korean NPPs.

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

    PubMed Central

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

    2011-01-01

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

  20. Application of optically stimulated luminescence technique to evaluate simultaneously accumulated and single doses with the same dosimeter

    NASA Astrophysics Data System (ADS)

    Malthez, Anna Luiza M. C.; Freitas, Marcelo B.; Yoshimura, Elisabeth M.; Button, Vera L. S. N.

    2014-02-01

    Optically stimulated luminescence dosimeters (OSLD) can be read several times with a negligible loss (degradation) of signal. In this work, we explore this OSL property to estimate simultaneously the accumulated and single doses using a unique Al2O3 dosimeter, irradiated repeated times along over 4 months. This was done through several irradiations of OSLD (Landauer Luxel Dots) with two energies (28 keV X-rays and 1.25 MeV Co-60 gamma rays) and several doses distributed over time. Thermoluminescent dosimeters (TLD) were used as a reference to compare the estimated doses obtained with OSLD. For each irradiation, and both energies, a calibration curve was evaluated with OSLD and TLD to estimate the dose values. The OSL readouts were made with a MicroStar (Landauer) OSL reader. To estimate background (BG) over time, a set of OSLD and TLD (Bycron TLD100) was not irradiated and BG was monitored at each readout section. After irradiations, the OSL and TL signals were converted to dose and values were compared. As a set of OSLD suffered no bleaching after the readouts, it was possible to estimate simultaneously the accumulated and single doses with a unique OSLD. Each single dose was estimated through the subtraction of successive accumulated doses determined for each single OSLD. We concluded that the single doses determined by OSL and TL techniques were compatible, and that the accumulated dose, obtained with OSL technique was comparable to the sum of single doses determined with TLD. We can conclude that using OSL technique and Al2O3 dosimeters it is possible to estimate simultaneously accumulated and single doses with the same dosimeter irradiated with low or high energy photons.

  1. Direct and indirect tasks on assessment of dose and time distributions and thresholds of acute radiation exposure.

    PubMed

    Osovets, S V; Azizova, T V; Day, R D; Wald, N; Moseeva, M B

    2012-02-01

    Mathematical methods were developed to construct dose and time distributions and their associated risks and threshold values for lethal and non-lethal effects of acute radiation exposure to include mortality and incidence, prodromal vomiting, and agranulocytosis. A new distribution (T-model) was obtained to describe time parameters of acute radiation syndrome such as the latency period, time to onset of vomiting, and time to initiation of agranulocytosis. Based on the dose and time distributions, the parameter translation method was defined using an orthogonal regression, which allows one to solve for these distributions in the case of acute radiation exposure. The assessment of threshold doses was performed for some effects of acute radiation syndrome: for the latency period, ∼6-8 Gy absorbed dose and ∼0.7-0.9 h time to onset of vomiting; and for incidence (agranulocytosis), ∼2-3 Gy absorbed dose and ∼2-3 h time to onset of vomiting. The obtained new formula for assessment of radiation risk is applicable to the time parameters of acute radiation syndrome.

  2. Suppression of viral infectivity through lethal defection

    PubMed Central

    Grande-Pérez, Ana; Lázaro, Ester; Lowenstein, Pedro; Domingo, Esteban; Manrubia, Susanna C.

    2005-01-01

    RNA viruses replicate with a very high error rate and give rise to heterogeneous, highly plastic populations able to adapt very rapidly to changing environments. Viral diseases are thus difficult to control because of the appearance of drug-resistant mutants, and it becomes essential to seek mechanisms able to force the extinction of the quasispecies before adaptation emerges. An alternative to the use of conventional drugs consists in increasing the replication error rate through the use of mutagens. Here, we report about persistent infections of lymphocytic choriomeningitis virus treated with fluorouracil, where a progressive debilitation of infectivity leading to eventual extinction occurs. The transition to extinction is accompanied by the production of large amounts of RNA, indicating that the replicative ability of the quasispecies is not strongly impaired by the mutagen. By means of experimental and theoretical approaches, we propose that a fraction of the RNA molecules synthesized can behave as a defective subpopulation able to drive the viable class extinct. Our results lead to the identification of two extinction pathways, one at high amounts of mutagen, where the quasispecies completely loses its ability to infect and replicate, and a second one, at lower amounts of mutagen, where replication continues while the infective class gets extinct because of the action of defectors. The results bear on a potential application of increased mutagenesis as an antiviral strategy in that low doses of a mutagenic agent may suffice to drive persistent virus to extinction. PMID:15767582

  3. Methods for meta-analysis of pharmacodynamic dose-response data with application to multi-arm studies of alogliptin.

    PubMed

    Langford, Oliver; Aronson, Jeffrey K; van Valkenhoef, Gert; Stevens, Richard J

    2016-03-17

    Standard methods for meta-analysis of dose-response data in epidemiology assume a model with a single scalar parameter, such as log-linear relationships between exposure and outcome; such models are implicitly unbounded. In contrast, in pharmacology, multi-parameter models, such as the widely used Emax model, are used to describe relationships that are bounded above and below. We propose methods for estimating the parameters of a dose-response model by meta-analysis of summary data from the results of randomized controlled trials of a drug, in which each trial uses multiple doses of the drug of interest (possibly including dose 0 or placebo). We assume that, for each randomized arm of each trial, the mean and standard error of a continuous response measure and the corresponding allocated dose are available. We consider weighted least squares fitting of the model to the mean and dose pairs from all arms of all studies, and a two-stage procedure in which scalar inverse-variance meta-analysis is performed at each dose, and the dose-response model is fitted to the results by weighted least squares. We then compare these with two further methods inspired by network meta-analysis that fit the model to the contrasts between doses. We illustrate the methods by estimating the parameters of the Emax model to a collection of multi-arm, multiple-dose, randomized controlled trials of alogliptin, a drug for the management of diabetes mellitus, and further examine the properties of the four methods with sensitivity analyses and a simulation study. We find that all four methods produce broadly comparable point estimates for the parameters of most interest, but a single-stage method based on contrasts between doses produces the most appropriate confidence intervals. Although simpler methods may have pragmatic advantages, such as the use of standard software for scalar meta-analysis, more sophisticated methods are nevertheless preferable for their advantages in estimation.

  4. Induction of specific-locus and dominant lethal mutations in male mice by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU).

    PubMed

    Ehling, U H; Adler, I D; Favor, J; Neuhäuser-Klaus, A

    1997-10-06

    1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) induced dominant lethal and specific-locus mutations in male mice. For both compounds the germ cell stage sensitive to the induction of dominant lethal mutations was dose dependent. A dose of 5 mg BCNU per kg b.wt. induced dominant lethal mutations primarily in spermatocytes, whereas higher doses of BCNU induced dominant lethals in spermatids and spermatocytes. Following doses of 5 and 10 mg CCNU per kg b.wt. dominant lethals were induced in spermatids and spermatocytes similar to the results for higher doses of BCNU. Higher dose exposure to BCNU and CCNU was associated with dominant lethals expressed as pre-implantation loss (reduction in total number of implants). In addition, higher doses of CCNU showed a cytotoxic effect in differentiating spermatogonia. Both compounds induced specific-locus mutations in post-spermatogonial germ cell stages of mice. However, CCNU increased also the specific-locus mutation frequency in spermatogonia in two out of three experiments. We conclude in analogy with criteria developed by IARC, that BCNU and CCNU are potential human mutagens.

  5. Monte Carlo fast dose calculator for proton radiotherapy: application to a voxelized geometry representing a patient with prostate cancer.

    PubMed

    Yepes, Pablo; Randeniya, Sharmalee; Taddei, Phillip J; Newhauser, Wayne D

    2009-01-07

    The Monte Carlo method is used to provide accurate dose estimates in proton radiation therapy research. While it is more accurate than commonly used analytical dose calculations, it is computationally intense. The aim of this work was to characterize for a clinical setup the fast dose calculator (FDC), a Monte Carlo track-repeating algorithm based on GEANT4. FDC was developed to increase computation speed without diminishing dosimetric accuracy. The algorithm used a database of proton trajectories in water to calculate the dose of protons in heterogeneous media. The extrapolation from water to 41 materials was achieved by scaling the proton range and the scattering angles. The scaling parameters were obtained by comparing GEANT4 dose distributions with those calculated with FDC for homogeneous phantoms. The FDC algorithm was tested by comparing dose distributions in a voxelized prostate cancer patient as calculated with well-known Monte Carlo codes (GEANT4 and MCNPX). The track-repeating approach reduced the CPU time required for a complete dose calculation in a voxelized patient anatomy by more than two orders of magnitude, while on average reproducing the results from the Monte Carlo predictions within 2% in terms of dose and within 1 mm in terms of distance.

  6. NOTE: Monte Carlo fast dose calculator for proton radiotherapy: application to a voxelized geometry representing a patient with prostate cancer

    NASA Astrophysics Data System (ADS)

    Yepes, Pablo; Randeniya, Sharmalee; Taddei, Phillip J.; Newhauser, Wayne D.

    2009-01-01

    The Monte Carlo method is used to provide accurate dose estimates in proton radiation therapy research. While it is more accurate than commonly used analytical dose calculations, it is computationally intense. The aim of this work was to characterize for a clinical setup the fast dose calculator (FDC), a Monte Carlo track-repeating algorithm based on GEANT4. FDC was developed to increase computation speed without diminishing dosimetric accuracy. The algorithm used a database of proton trajectories in water to calculate the dose of protons in heterogeneous media. The extrapolation from water to 41 materials was achieved by scaling the proton range and the scattering angles. The scaling parameters were obtained by comparing GEANT4 dose distributions with those calculated with FDC for homogeneous phantoms. The FDC algorithm was tested by comparing dose distributions in a voxelized prostate cancer patient as calculated with well-known Monte Carlo codes (GEANT4 and MCNPX). The track-repeating approach reduced the CPU time required for a complete dose calculation in a voxelized patient anatomy by more than two orders of magnitude, while on average reproducing the results from the Monte Carlo predictions within 2% in terms of dose and within 1 mm in terms of distance.

  7. Monte Carlo fast dose calculator for proton radiotherapy: application to a voxelized geometry representing a patient with prostate cancer

    PubMed Central

    Yepes, Pablo; Randeniya, Sharmalee; Taddei, Phillip J; Newhauser, Wayne D

    2014-01-01

    The Monte Carlo method is used to provide accurate dose estimates in proton radiation therapy research. While it is more accurate than commonly used analytical dose calculations, it is computationally intense. The aim of this work was to characterize for a clinical setup the fast dose calculator (FDC), a Monte Carlo track-repeating algorithm based on GEANT4. FDC was developed to increase computation speed without diminishing dosimetric accuracy. The algorithm used a database of proton trajectories in water to calculate the dose of protons in heterogeneous media. The extrapolation from water to 41 materials was achieved by scaling the proton range and the scattering angles. The scaling parameters were obtained by comparing GEANT4 dose distributions with those calculated with FDC for homogeneous phantoms. The FDC algorithm was tested by comparing dose distributions in a voxelized prostate cancer patient as calculated with well-known Monte Carlo codes (GEANT4 and MCNPX). The track-repeating approach reduced the CPU time required for a complete dose calculation in a voxelized patient anatomy by more than two orders of magnitude, while on average reproducing the results from the Monte Carlo predictions within 2% in terms of dose and within 1 mm in terms of distance. PMID:19075361

  8. Bacillus anthracis lethal toxin reduces human alveolar epithelial barrier function.

    PubMed

    Langer, Marybeth; Duggan, Elizabeth Stewart; Booth, John Leland; Patel, Vineet Indrajit; Zander, Ryan A; Silasi-Mansat, Robert; Ramani, Vijay; Veres, Tibor Zoltan; Prenzler, Frauke; Sewald, Katherina; Williams, Daniel M; Coggeshall, Kenneth Mark; Awasthi, Shanjana; Lupu, Florea; Burian, Dennis; Ballard, Jimmy Dale; Braun, Armin; Metcalf, Jordan Patrick

    2012-12-01

    The lung is the site of entry for Bacillus anthracis in inhalation anthrax, the deadliest form of the disease. Bacillus anthracis produces virulence toxins required for disease. Alveolar macrophages were considered the primary target of the Bacillus anthracis virulence factor lethal toxin because lethal toxin inhibits mouse macrophages through cleavage of MEK signaling pathway components, but we have reported that human alveolar macrophages are not a target of lethal toxin. Our current results suggest that, unlike human alveolar macrophages, the cells lining the respiratory units of the lung, alveolar epithelial cells, are a target of lethal toxin in humans. Alveolar epithelial cells expressed lethal toxin receptor protein, bound the protective antigen component of lethal toxin, and were subject to lethal-toxin-induced cleavage of multiple MEKs. These findings suggest that human alveolar epithelial cells are a target of Bacillus anthracis lethal toxin. Further, no reduction in alveolar epithelial cell viability was observed, but lethal toxin caused actin rearrangement and impaired desmosome formation, consistent with impaired barrier function as well as reduced surfactant production. Therefore, by compromising epithelial barrier function, lethal toxin may play a role in the pathogenesis of inhalation anthrax by facilitating the dissemination of Bacillus anthracis from the lung in early disease and promoting edema in late stages of the illness.

  9. Bacillus anthracis Lethal Toxin Reduces Human Alveolar Epithelial Barrier Function

    PubMed Central

    Langer, Marybeth; Duggan, Elizabeth Stewart; Booth, John Leland; Patel, Vineet Indrajit; Zander, Ryan A.; Silasi-Mansat, Robert; Ramani, Vijay; Veres, Tibor Zoltan; Prenzler, Frauke; Sewald, Katherina; Williams, Daniel M.; Coggeshall, Kenneth Mark; Awasthi, Shanjana; Lupu, Florea; Burian, Dennis; Ballard, Jimmy Dale; Braun, Armin

    2012-01-01

    The lung is the site of entry for Bacillus anthracis in inhalation anthrax, the deadliest form of the disease. Bacillus anthracis produces virulence toxins required for disease. Alveolar macrophages were considered the primary target of the Bacillus anthracis virulence factor lethal toxin because lethal toxin inhibits mouse macrophages through cleavage of MEK signaling pathway components, but we have reported that human alveolar macrophages are not a target of lethal toxin. Our current results suggest that, unlike human alveolar macrophages, the cells lining the respiratory units of the lung, alveolar epithelial cells, are a target of lethal toxin in humans. Alveolar epithelial cells expressed lethal toxin receptor protein, bound the protective antigen component of lethal toxin, and were subject to lethal-toxin-induced cleavage of multiple MEKs. These findings suggest that human alveolar epithelial cells are a target of Bacillus anthracis lethal toxin. Further, no reduction in alveolar epithelial cell viability was observed, but lethal toxin caused actin rearrangement and impaired desmosome formation, consistent with impaired barrier function as well as reduced surfactant production. Therefore, by compromising epithelial barrier function, lethal toxin may play a role in the pathogenesis of inhalation anthrax by facilitating the dissemination of Bacillus anthracis from the lung in early disease and promoting edema in late stages of the illness. PMID:23027535

  10. The atypical excretion profile of meldonium: Comparison of urinary detection windows after single- and multiple-dose application in healthy volunteers.

    PubMed

    Görgens, Christian; Guddat, Sven; Bosse, Christina; Geyer, Hans; Pop, Valentin; Schänzer, Wilhelm; Thevis, Mario

    2017-05-10

    Following a one-year monitoring program providing unequivocal analytical evidence for a high prevalence in international elite sports, meldonium has been included in the World Anti-Doping Agency's (WADA) list of prohibited substances that came into effect on 1 January 2016. Despite of the polar and hydrophilic nature of the molecule, an unusual long detection window was observed in pilot elimination studies. Consequently, in the present study, urinary excretion profiles after single-dose (5 volunteers, 1×500mg) and multiple-dose oral application (5 volunteers; 2×500mg/day for 6days) were determined in order to facilitate the result management concerning meldonium findings in doping controls. Particularly the option to differentiate between recent use and tapering concentrations was studied. Urinary meldonium concentrations were determined using an analytical approach based on hydrophilic interaction liquid chromatography and high resolution tandem mass spectrometry. The study corroborates the hypothesis of a non-linear, dose-depended and biphasic excretion profile after oral application of meldonium and demonstrates that urinary detection windows are of considerable extent with up to 65 and 117days (concentrations>LOQ of 10ng/mL) following single- and multiple-dose applications, respectively.

  11. Shielding application of perturbation theory to determine changes in neutron and gamma doses due to changes in shield layers

    NASA Technical Reports Server (NTRS)

    Fieno, D.

    1972-01-01

    Perturbation theory formulas were derived and applied to determine changes in neutron and gamma-ray doses due to changes in various radiation shield layers for fixed sources. For a given source and detector position, the perturbation method enables dose derivatives with respect to density, or equivalently thickness, for every layer to be determined from one forward and one inhomogeneous adjoint calculation. A direct determination without the perturbation approach would require two forward calculations to evaluate the dose derivative due to a change in a single layer. Hence, the perturbation method for obtaining dose derivatives requires fewer computations for design studies of multilayer shields. For an illustrative problem, a comparison was made of the fractional change in the dose per unit change in the thickness of each shield layer in a two-layer spherical configuration as calculated by perturbation theory and by successive direct calculations; excellent agreement was obtained between the two methods.

  12. Protection against lethal Sendai virus infection by in vivo priming of virus-specific cytotoxic T lymphocytes with a free synthetic peptide.

    PubMed Central

    Kast, W M; Roux, L; Curren, J; Blom, H J; Voordouw, A C; Meloen, R H; Kolakofsky, D; Melief, C J

    1991-01-01

    The only peptide of Sendai virus that is recognized by cytotoxic T lymphocytes (CTL) in B6 mice was found with (i) the use of recombinant vaccinia virus constructs containing separate genes of Sendai virus and (ii) a set of overlapping peptides completely spanning the identified nucleoprotein (NP) gene product. This immunodominant NP peptide is recognized by Sendai virus-specific CTL that are known to have therapeutic effects in vivo. By subcutaneous immunization, this peptide induced Sendai virus and NP peptide-specific CTL memory responses in vivo. Most importantly, mice that had been immunized with this peptide were protected against a lethal virus dose, indicating that viral peptides can be used as antiviral T-cell vaccines. The induction of T-cell memory by free peptide immunization potentially has wide applicability in biology and medicine, including protection against infectious disease. PMID:1848698

  13. Protection Against Lethal Sendai Virus Infection by in vivo Priming of Virus-Specific Cytotoxic T Lymphocytes with a Free Synthetic Peptide

    NASA Astrophysics Data System (ADS)

    Kast, W. Martin; Roux, Laurent; Curren, Joseph; Blom, Hendrika J. J.; Voordouw, Arie C.; Meloen, Rob H.; Kolakofsky, Daniel; Melief, Cornelis J. M.

    1991-03-01

    The only peptide of Sendai virus that is recognized by cytotoxic T lymphocytes (CTL) in B6 mice was found with (i) the use of recombinant vaccinia virus constructs containing separate genes of Sendai virus and (ii) a set of overlapping peptides completely spanning the identified nucleoprotein (NP) gene product. This immunodominant NP peptide is recognized by Sendai virus-specific CTL that are known to have therapeutic effects in vivo. By subcutaneous immunization, this peptide induced Sendai virus and NP peptide-specific CTL memory responses in vivo. Most importantly, mice that had been immunized with this peptide were protected against a lethal virus dose, indicating that viral peptides can be used as antiviral T-cell vaccines. The induction of T-cell memory by free peptide immunization potentially has wide applicability in biology and medicine, including protection against infectious disease.

  14. Toxicology of cupric salts in honeybees. I. Hormesis effects of organic derivatives on lethality parameters.

    PubMed

    Bounias, M; Navone-Nectoux, M; Popeskovic, D S

    1995-07-01

    Feeding bees with organic cupric salts provides long-term control of the parasite Varroa jacobsoni. A set of new algebraic parameters (M. Bounias C.R. Acad. Sci. 310(3), 65-70, 1990) completely describing the population lethality function has been calculated following chronic administration of cupric gluconate, aspartate, and isoleucinate, with or without dietary pollen. Mortality curves allowed the calculation of LT50 (time for 50% lethality) as well as Hill coefficients (h) of the curves and the LD50 as a function of time. The tangent at the inflexion point of the sigmoidal time/mortality curves (delta i) gave the maximum mortality acceleration as an additional parameter. No toxicity (i.e., no decrease of TL50 vs doses and no LD50 values) was found for cupric gluconate and isoleucinate with pollen, whereas increases in LT50 and decreases in delta indicated hormesis effects. Doses decreasing by half-time LT50, h, or delta were used as objective lethality indexes for comparisons of toxicity in the other cases. Routine acute toxicity at high dosage was also compared with phosalone and lindane effects 24 hr after treatment.

  15. OUP: lethal gene drive selects inbreeding

    PubMed Central

    Bull, James J.

    2017-01-01

    The use of ‘selfish’ gene drive systems to suppress or even extinguish populations has been proposed on theoretical grounds for almost half a century. Creating these genes has recently become possible with CRISPR technology. One seemingly feasible approach, originally proposed by Burt, is to create a homing endonuclease gene (HEG) that inserts into an essential gene, enabling heterozygote viability but causing homozygote lethality. With 100% segregation distortion in gametes, such genes can cause profound population suppression if resistance does not evolve. Here, population genetic models are used to consider the evolution of inbreeding (specifically selfing) as a possible response to a recessively lethal HEG with complete segregation distortion. Numerical analyses indicate a rich set of outcomes, but selfing often evolves in response to the HEG, with a corresponding partial restoration of mean fitness. Whether selfing does indeed evolve and its effect in restoring fitness depends heavily on the magnitude of inbreeding depression. Overall, these results point toward an underappreciated evolutionary response to block the harmful effects of a selfish gene. They raise the possibility that extreme population suppression may be resisted by mechanisms that are independent of the molecular basis of gene drive. At the same time, the evolution of inbreeding is not assured even if the genetic basis for inbreeding is present. As the models here strictly apply to hermaphrodites (plants), an important next step is to consider inbreeding in populations with separate sexes. PMID:28013241

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

    ERIC Educational Resources Information Center

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

    2004-01-01

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

  17. Potential lethal and non-lethal effects of predators on dispersal of spider mites.

    PubMed

    Otsuki, Hatsune; Yano, Shuichi

    2014-11-01

    Predators can affect prey dispersal lethally by direct consumption or non-lethally by making prey hesitate to disperse. These lethal and non-lethal effects are detectable only in systems where prey can disperse between multiple patches. However, most studies have drawn their conclusions concerning the ability of predatory mites to suppress spider mites based on observations of their interactions on a single patch or on heavily infested host plants where spider mites could hardly disperse toward intact patches. In these systems, specialist predatory mites that penetrate protective webs produced by spider mites quickly suppress the spider mites, whereas generalist predators that cannot penetrate the webs were ineffective. By using a connected patch system, we revealed that a generalist ant, Pristomyrmex punctatus Mayr (Hymenoptera: Formicidae), effectively prevented dispersal of spider mites, Tetranychus kanzawai Kishida (Acari: Tetranychidae), by directly consuming dispersing individuals. We also revealed that a generalist predatory mite, Euseius sojaensis Ehara (Acari: Phytoseiidae), prevented between-patch dispersal of T. kanzawai by making them hesitate to disperse. In contrast, a specialist phytoseiid predatory mite, Neoseiulus womersleyi Schicha, allowed spider mites to escape an initial patch, increasing the number of colonized patches within the system. Our results suggest that ants and generalist predatory mites can effectively suppress Tetranychus species under some conditions, and should receive more attention as agents for conservation biological control in agroecosystems.

  18. Gonadosomatic mosaicism for lethal mutations in Drosophila lethal mutations disturbing larval development

    SciTech Connect

    Ivanov, A.I.; Sakharova, N.Yu.

    1988-11-01

    Phenogenetic analysis of autonomous lethal mutations obtained by the method of gonadosomatic mosaicism which manifested during larval stages, established that the nuclei of hypodermal cells, salivary glands suprapharyngeal ganglion, pharynx, esophagus, gizzard, and hindgut are the derivatives of the same nucleus (from the first two nuclei of cleavage) as the nuclei of the cells of the imaginal-somatic tissues.

  19. Matching target dose to target organ

    PubMed Central

    Bannon, Desmond I.; Williams, Marc A.

    2016-01-01

    In vitro assays have become a mainstay of modern approaches to toxicology with the promise of replacing or reducing the number of in vivo tests required to establish benchmark doses, as well as increasing mechanistic understanding. However, matching target dose to target organ is an often overlooked aspect of in vitro assays, and the calibration of in vitro exposure against in vivo benchmark doses is often ignored, inadvertently or otherwise.  An example of this was recently published in Environmental Health Perspectives by Wagner et al., where neural stems cells were used to model the molecular toxicity of lead.  On closer examination of the in vitro work, the doses used in media reflected in vivo lead doses that would be at the highest end of lead toxicity, perhaps even lethal.  Here we discuss the doses used and suggest more realistic doses for future work with stem cells or other neuronal cell lines. PMID:28163899

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

    PubMed

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

    2015-07-01

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

  1. Dosimetric evaluation of a newly designed low dose rate brachytherapy applicator for treatment of cervical cancer with extension into the lower vagina.

    PubMed

    Baker, Curtis; Dini, Sharifeh A; Kudrimoti, Mahesh; Awan, Shahid B; Meigooni, Ali S

    2007-04-19

    Currently, patients having cervical cancer with extension into the lower vagina are being treated with a combination of the Fletcher-Suit applicator, which treats the cervix, and a vaginal cylinder, which treats the lower vagina. With this method, patients receive two separate implants-a procedure that creates greater uncertainty in the dose distribution and unnecessary patient inconvenience. To reduce the uncertainty of the dose delivery and to eliminate patient inconvenience, a new applicator was designed and fabricated at the University of Kentucky for treatment of cervical cancer extending into the lower vagina. In addition, the geometric design of the new device allows for treatment of cervical cancer without extension into the lower vagina and simultaneously provides advantages relative to the commonly used Fletcher-Suit applicator. The dosimetric characteristics of this new applicator (hereafter called Meigooni applicator) were determined using experimental procedures. The measurements were performed using tissue-equivalent phantom material (Solid Water: Gammex RMI, Middleton, WI) that was machined to accommodate the applicator and LiF thermoluminescent dosimetry chips. The applicator was loaded with 137Cs brachytherapy sources in a standard loading scheme. A similar experimental procedure was performed using the currently available Fletcher-Suit mini-ovoid applicator. The results obtained with each applicator were compared with the values calculated by two commercially available treatment planning systems. The experiments showed that the Meigooni applicator allows for safe single treatment of cervical cancer that has extended into the lower vagina, eliminating the need for two separate treatment techniques. Moreover, the Meigooni applicator can function as an alternative to the Fletcher-Suit applicator for the treatment of patients with cervical cancer.

  2. A Combination of Podophyllotoxin and Rutin Attenuates Radiation Induced Gastrointestinal Injury by Negatively Regulating NF-κB/p53 Signaling in Lethally Irradiated Mice

    PubMed Central

    Kalita, Bhargab; Ranjan, Rajiv; Singh, Abhinav; Yashavarddhan, M. H.; Bajaj, Sania; Gupta, Manju Lata

    2016-01-01

    Development of an effective radio protector to minimise radiation-inflicted damages have largely failed owing to inherent toxicity of most of the agents examined so far. This study is centred towards delivering protection to lethally irradiated mice by pre-administration of a safe formulation G-003M (combination of podophyllotoxin and rutin) majorly through regulation of inflammatory and cell death pathways in mice. Single intramuscular dose of G-003M injected 60 min prior to 9 Gy exposure rescued 89% of whole body lethally irradiated C57BL/6J mice. Studies have revealed reduction in radiation induced reactive oxygen species (ROS), nitric oxide (NO) generation, prostaglandin E2 (PGE2) levels and intestinal apoptosis in G-003M pre-treated mice intestine. Restricted nuclear translocation of redox-sensitive Nuclear factor-κB (NF-κB) and subsequent downregulation of cyclo-oxygenase 2 (COX-2), inducible nitric oxide synthase (iNOS; EC 1.14.13.39) and tumor necrosis factor (TNF-α) levels demonstrated the anti-inflammatory effect that G-003M exerts. Support to early hematopoietic recovery was exhibited through G-003M mediated induction of granulocyte colony stimulating factor (G-CSF) and interleukin (IL-6) levels in lethally irradiated mice. Considerable attenuation in radiation induced morphological damage to the intestinal villi, crypts and mucosal layers was observed in G-003M pre-treated mice. Additionally, our formulation did not reduce the sensitivity of tumor tissue to radiation. Altogether, these results suggest that G-003M ameliorates the deleterious effects of radiation exposure by minimising ROS and NO generation and effectively regulating inflammatory and cell death pathways. Mechanism of protection elucidated in the current study demonstrates that G-003M can be used as a safe and effective radio protective agent in radiotherapy for human application. PMID:28036347

  3. Synthetic Lethality in Breast Cancer Cells: Genes Required for Tumor Survival

    DTIC Science & Technology

    2004-07-01

    that the goals of this grant and that of the Innovator award are distinct. The innovator award is to develop high-throughput procedures to create a...revised report The original goal of this application was to develop strategies to permit synthetic lethal screens to be carried out in mammalian cells. In...parallel, one needed to develop systems in which such interactions could be effectively tested. When this application was initially submitted four

  4. Clinical Application of High-Dose, Image-Guided Intensity-Modulated Radiotherapy in High-Risk Prostate Cancer

    SciTech Connect

    Bayley, Andrew; Rosewall, Tara; Craig, Tim; Bristow, Rob; Chung, Peter; Gospodarowicz, Mary; Menard, Cynthia; Milosevic, Michael; Warde, Padraig; Catton, Charles

    2010-06-01

    Purpose: To report the feasibility and early toxicity of dose-escalated image-guided IMRT to the pelvic lymph nodes (LN), prostate (P), and seminal vesicles (SV). Methods and Materials: A total of 103 high-risk prostate cancer patients received two-phase, dose-escalated, image-guided IMRT with 3 years of androgen deprivation therapy. Clinical target volumes (CTVs) were delineated using computed tomography/magnetic resonance co-registration and included the prostate, portions of the SV, and the LN. Planning target volume margins (PTV) used were as follows: P (10 mm, 7 mm posteriorly), SV (10 mm), and LN (5 mm). Organs at risk (OaR) were the rectal and bladder walls, femoral heads, and large and small bowel. The IMRT was planned with an intended dose of 55.1 Gy in 29 fractions to all CTVs (Phase 1), with P+SV consecutive boost of 24.7 Gy in 13 fractions. Daily online image guidance was performed using bony landmarks and intraprostatic markers. Feasibility criteria included delivery of intended doses in 80% of patients, 95% of CTV displacements incorporated within PTV during Phase 1, and acute toxicity rate comparable to that of lower-dose pelvic techniques. Results: A total of 91 patients (88%) received the total prescription dose. All patients received at least 72 Gy. In Phase 1, 63 patients (61%) received the intended 55.1 Gy, whereas 87% of patients received at least 50 Gy. Dose reductions were caused by small bowel and rectal wall constraints. All CTVs received the planned dose in >95% of treatment fractions. There were no Radiation Therapy Oncology Group acute toxicities greater than Grade 3, although there were five incidences equivalent to Grade 3 within a median follow-up of 23 months. Conclusion: These results suggest that dose escalation to the PLN+P+SV using IMRT is feasible, with acceptable rates of acute toxicity.

  5. Apparent lethal concentrations of pyrolysis products of some polymeric materials

    NASA Technical Reports Server (NTRS)

    Hilado, C. J.; Marcussen, W. H.; Furst, A.; Kourtides, D. A.; Parker, J. A.

    1976-01-01

    Thirty-nine samples of polymeric materials were evaluated to determine the apparent lethal concentrations of their pyrolysis products. The materials were compared on the basis of the apparent lethal concentration for 50 percent of the test animals. Relative toxicity rankings based o apparent lethal concentration values can differ significantly depending on whether they are based on weight of sample charged or weight of sample pyrolyzed. The ranking of polyphenylene sulfide is particularly sensitive to this difference.

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

    PubMed

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

    2009-10-15

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

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

    SciTech Connect

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

    2009-10-15

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

  8. Investigation of bias dependence on enhanced low dose rate sensitivity in SiGe HBTs for space application

    NASA Astrophysics Data System (ADS)

    Sun, Yabin; Fu, Jun; Xu, Jun; Wang, Yudong; Zhou, Wei; Zhang, Wei; Cui, Jie; Li, Gaoqing; Liu, Zhihong

    2014-02-01

    NPN silicon-germanium (SiGe) heterojunction bipolar transistors (HBTs) were exposed to 60Co gamma source at different dose rates under two bias conditions. Excess base currents and normalized current gains are used to quantify performance degradation. Experiment results demonstrate that the lower the dose rate, the more the irradiation damage, and some enhanced low dose rate sensitivity (ELDRS) exists in SiGe HBTs. The ELDRS effect is found to depend highly on the bias condition during exposure, and the transistors with forward active mode exhibit a more serious ELDRS effect compared to the floating case. The performance degradation at different dose rates and bias conditions is compared and discussed, and furthermore the underlying physical mechanisms are analyzed and investigated in detail.

  9. A shielding application of perturbation theory to determine changes in neutron and gamma doses due to changes in shield layers

    NASA Technical Reports Server (NTRS)

    Fieno, D.

    1972-01-01

    The perturbation theory for fixed sources was applied to radiation shielding problems to determine changes in neutron and gamma ray doses due to changes in various shield layers. For a given source and detector position the perturbation method enables dose derivatives due to all layer changes to be determined from one forward and one inhomogeneous adjoint calculation. The direct approach requires two forward calculations for the derivative due to a single layer change. Hence, the perturbation method for obtaining dose derivatives permits an appreciable savings in computation for a multilayered shield. For an illustrative problem, a comparison was made of the fractional change in the dose per unit change in the thickness of each shield layer as calculated by perturbation theory and by successive direct calculations; excellent agreement was obtained between the two methods.

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

    PubMed

    Agrafioti, Paraskevi; Athanassiou, Christos G; Vassilakos, Thomas N; Vlontzos, George; Arthur, Frank H

    2015-01-01

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

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

    PubMed Central

    Vlontzos, George; Arthur, Frank H.

    2015-01-01

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

  12. Clinical study on local application of low-dose insulin for promoting wound healing after operation for deep burns

    PubMed Central

    Zeng, Ming; Zhi, Yan; Liu, Wenjun; Zhang, Wei; Xu, Jinxiong

    2016-01-01

    Transplanted free skin flaps are often needed to treat deep burns; their survival, however, is less than optimal. This study examined whether local low-dose insulin injections can promote flap survival and wound healing after surgery. A total of 165 patients who underwent free skin flap transplantation for simple deep burns were enrolled in the study and divided into 5 groups of 33 patients each: Blank control group (no local subcutaneous drug injections), saline control group (saline injections), low-dose insulin group (0.5 units regular insulin injections), medium-dose group (1.0 units regular insulin injections) and high-dose group (2.0 units regular insulin injections). Wound healing and flap survival conditions were assessed and compared among groups. The best wound healing rate found was that of the low-dose insulin injection group where all the parameters measured improved significantly: The healing time was shorter; the blood flow volume, the flap survival, the number of fibroblasts and new vessels increased; the re-epithelialization occurred faster; the infiltration of inflammatory cells was reduced; the expression levels of heat shock protein-90, vascular endothelial growth factor, transforming growth factor-β and interleukin-1 were higher; and the plasma glucose levels only fluctuated slightly. The results clearly demonstrate that a local low-dose insulin regime after flap transplantation can accelerate the healing time and improve the surgical outcome without exerting detrimental secondary effects on the glucose plasma level of deep burn patients. PMID:27882141

  13. Quercetin but not luteolin suppresses the induction of lethal shock upon infection of mice with Salmonella typhimurium.

    PubMed

    Sugiyama, Tsuyoshi; Kawaguchi, Kiichiro; Dobashi, Hideki; Miyake, Ryo; Kaneko, Masahiro; Kumazawa, Yoshio

    2008-08-01

    Tumor necrosis factor-alpha (TNF-alpha) is important for the induction of systemic inflammatory responses that lead to lethal shock. Quercetin and luteolin, which differ by one hydroxyl group, are known to suppress the lipopolysaccharide-induced production of TNF-alpha in vitro. We show differing inhibitory effects of quercetin and luteolin on the induction of lethal shock in Salmonella typhimurium aroA-infected mice. In a time- and dose-dependent manner, quercetin reduced the plasma levels of TNF-alpha, lowered bacterial titers in livers, prevented liver damage and prolonged survival, while luteolin had little or no effect. Compared with luteolin, quercetin increased the infiltration of Gr-1(+)CD69(+) neutrophils into the peritoneal cavity and lowered heat shock protein 70 expression. Obviously, the additional hydroxyl group in quercetin is important for suppressing infection-induced lethal shock in mice.

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

    PubMed

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

    2017-01-01

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

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

    PubMed Central

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

    2017-01-01

    Systemic inflammation co-activates coagulation, which unchecked culminates in a lethal syndrome of multi-organ microvascular thrombosis known as disseminated intravascular coagulation (DIC). We studied an endotoxin-induced inflammatory state in rats to identify biomarkers of hemostatic imbalance favoring hypercoagulability. Intraperitoneal injection of LPS at 15 mg/kg body weight resulted in peripheral leukopenia and widespread neutrophilic sequestration characteristic of an acute systemic inflammatory response. Early indicators of hemostatic pathway activation developed within 4 hours, including increased circulating concentrations of procoagulant extracellular vesicles (EVs), EVs expressing endothelial cell and platelet membrane markers, and high concentration of soluble intercellular adhesion molecule-1 (sICAM-1), plasminogen activator inhibitor-1 (PAI-1), and D-dimers. Inflammation persisted throughout the 48-hour observation period; however, increases were found in a subset of serum microRNA (miRNA) that coincided with gradual resolution of hemostatic protein abnormalities and reduction in EV counts. Dose-adjusted LPS treatment in rats provides a time-course model to develop biomarker profiles reflecting procoagulant imbalance and rebalance under inflammatory conditions. PMID:28081568

  16. Ants defend aphids against lethal disease.

    PubMed

    Nielsen, Charlotte; Agrawal, Anurag A; Hajek, Ann E

    2010-04-23

    Social insects defend their own colonies and some species also protect their mutualist partners. In mutualisms with aphids, ants typically feed on honeydew produced by aphids and, in turn guard and shelter aphid colonies from insect natural enemies. Here we report that Formica podzolica ants tending milkweed aphids, Aphis asclepiadis, protect aphid colonies from lethal fungal infections caused by an obligate aphid pathogen, Pandora neoaphidis. In field experiments, bodies of fungal-killed aphids were quickly removed from ant-tended aphid colonies. Ant workers were also able to detect infective conidia on the cuticle of living aphids and responded by either removing or grooming these aphids. Our results extend the long-standing view of ants as mutualists and protectors of aphids by demonstrating focused sanitizing and quarantining behaviour that may lead to reduced disease transmission in aphid colonies.

  17. Lethal Synergism between Influenza and Streptococcus pneumoniae

    PubMed Central

    Rudd, Jennifer M; Ashar, Harshini K; Chow, Vincent TK; Teluguakula, Narasaraju

    2016-01-01

    The devastating synergism of bacterial pneumonia with influenza viral infections left its mark on the world over the last century. Although the details of pathogenesis remain unclear, the synergism is related to a variety of factors including pulmonary epithelial barrier damage which exposes receptors that influence bacterial adherence and the triggering of an exaggerated innate immune response and cytokine storm, which further acts to worsen the injury. Several therapeutics and combination therapies of antibiotics, anti-inflammatories including corticosteroids and toll-like receptor modifiers, and anti-virals are being discussed. This mini review summarizes recent developments in unearthing the pathogenesis of the lethal synergism of pneumococcal co-infection following influenza, as well as addresses potential therapeutic options and combinations of therapies currently being evaluated. PMID:27981251

  18. Statistical tests for recessive lethal-carriers.

    PubMed

    Hamilton, M A; Haseman, J K

    1979-08-01

    This paper presents a statistical method for testing whether a male mouse is a recessive lethal-carrier. The analysis is based on a back-cross experiment in which the male mouse is mated with some of his daughters. The numbers of total implantations and intrauterine deaths in each litter are recorded. It is assumed that, conditional on the number of total implantations, the number of intrauterine deaths follows a binomial distribution. Using computer-simulated experimentation it is shown that the proposed statistical method, which is sensitive to the pattern of intrauterine death rates, is more powerful than a test based only on the total number of implant deaths. The proposed test requires relatively simple calculations and can be used for a wide range of values of total implantations and background implant mortality rates. For computer-simulated experiments, there was no practical difference between the empirical error rate and the nominal error rate.

  19. Repair of sublethal and potentially lethal radiation damage by rat embryos exposed to gamma rays or helium lons.

    PubMed

    Ward, W F; Aceto, H; Sandusky, M

    1976-09-01

    Embryonic survival was examined in rats exposed to a 24-hour split-dose regimen of gamma rays or extended-Bragg-peak (EBP) helium ions on the fifth and sixth days of gestation. The data indicate that EBP helium ions, which are known to have a single-dose relative biological effectiveness (RBE) of 1.0, exhibit a split-dose RBE of 1.5 with respect to embryo killing. Using an experimental rat embryo system, delayed implantation, it was also noted that the embryocidal damage induced by EBP helium ions contains a smaller potentially lethal component than that induced by gamma rays.

  20. Pathogenesis, Lethality, and Immunizing Effect of Experimental Cutaneous Cryptococcosis

    PubMed Central

    Dykstra, Mark A.; Friedman, Lorraine

    1978-01-01

    Mice were subcutaneously inoculated with small numbers of virulent Cryptococcus neoformans and divided into groups. Numbers of viable yeasts at the site were estimated at weekly intervals for 5 weeks on the basis of cultures of minced tissue excised from sacrificed animals. Organisms multiplied at the site for at least 4 weeks and were still detectable after the 5th week, although in reduced numbers. Agglutinins appeared within a week, but these antibodies were not detectable during the 2nd through the 5th week. Cryptococcal polysaccharide began to appear in the sera at 3 weeks, persisting through the duration of 5 weeks. All animals appeared healthy, but a few sickened after many months and died of systemic cryptococcosis. All of these events were observed in many separate experiments. The immunizing capacity of a cutaneous lesion was tested by challenging some of the above animals with viable C. neoformans after various intervals of time, either subcutaneously at a site distant from that of the vaccination or intravenously. Although we were unable to demonstrate reduced multiplication of yeasts in the brains, lungs, and spleens of intravenously challenged animals, it was possible to show that multiplication was inhibited at the site of subcutaneous challenge. It was noted also that vaccinated animals lived longer after lethal intravenous challenge than did nonvaccinated animals. The latter protection was observed, however, only when challenge followed vaccination by 3 weeks or longer, and it was effective only against a relatively low challenge dose. Mice were protected against a higher dose if they had previously received killed cryptococci, alternating subcutaneous and intraperitoneal inoculations, one of which contained a microbial adjuvant. No protection was observed in animals that were subcutaneously vaccinated with inert materials such as chitin, latex spheres, or even cryptococcal cell walls themselves. PMID:352944

  1. A lethal case of DEET toxicity due to intentional ingestion.

    PubMed

    Wiles, Devin; Yee, Justin; Castillo, Uvidelio; Russell, Jason; Spiller, Henry; Casavant, Marcel

    2014-01-01

    A 37-year-old male with prior medical history of profound developmental delay experienced seizure and cardiac arrest following ingestion of 6 ounces of a 40% N, N-diethyl-meta-toluamide (DEET) containing solution. The patient was unresponsive, acidemic, tachycardic and hypotensive on presentation. Over three hospital days, the patient's vitals recovered to baseline but he remained unresponsive and areflexic with fixed and dilated pupils. Non-contrast brain magnetic resonance imaging showed cerebral edema, transtentorial and tonsillar herniations. A rapid, simple and sensitive high-performance liquid chromatography (HPLC) method was utilized for the analysis of postmortem plasma blood and urine samples of a lethal case of DEET intentional ingestion. The method combined the use of C18 SepPak cartridges for solid phase extraction and reversed-phase HPLC. One urine and five blood samples from this patient were analyzed for DEET concentration. Mixtures of serum/urine postcentrifuge were eluted and reduced to 1 mL using a solvent evaporator. Blood in ethylenediaminetetraacetic acid (EDTA), whole blood, serum, blood with heparin and urine DEET concentrations were 9.84, 9.21, 10.18, 8.66dl and 0.642 mg/dL, respectively. All samples were collected <1 h postingestion. Although seizures and cardiac toxicity have been described in other case reports, this case is atypical due to the exceptional dose ingested and the timing of the fluid test samples being drawn so soon following exposure. Although a widely used and extremely safe insect repellent, DEET can be highly toxic in large but easily obtainable doses.

  2. Radiation passport: an iPhone and iPod touch application to track radiation dose and estimate associated cancer risks.

    PubMed

    Baerlocher, Mark Otto; Talanow, Roland; Baerlocher, Adrian F

    2010-04-01

    The rapid increase in the use of radiology and related exams and procedures has led to a concomitant increase in associated radiation risk. An application for the iPhone and iPod Touch called 'Radiation Passport' is described, which provides radiation dose estimates and associated cancer risks (non fatal and fatal) and serves as a method by which to track an individual's cumulative exposure.

  3. Modeling dose-dependent neural processing responses using mixed effects spline models: with application to a PET study of ethanol.

    PubMed

    Guo, Ying; Bowman, F DuBois

    2008-04-01

    For functional neuroimaging studies that involve experimental stimuli measuring dose levels, e.g. of an anesthetic agent, typical statistical techniques include correlation analysis, analysis of variance or polynomial regression models. These standard approaches have limitations: correlation analysis only provides a crude estimate of the linear relationship between dose levels and brain activity; ANOVA is designed to accommodate a few specified dose levels; polynomial regression models have limited capacity to model varying patterns of association between dose levels and measured activity across the brain. These shortcomings prompt the need to develop methods that more effectively capture dose-dependent neural processing responses. We propose a class of mixed effects spline models that analyze the dose-dependent effect using either regression or smoothing splines. Our method offers flexible accommodation of different response patterns across various brain regions, controls for potential confounding factors, and accounts for subject variability in brain function. The estimates from the mixed effects spline model can be readily incorporated into secondary analyses, for instance, targeting spatial classifications of brain regions according to their modeled response profiles. The proposed spline models are also extended to incorporate interaction effects between the dose-dependent response function and other factors. We illustrate our proposed statistical methodology using data from a PET study of the effect of ethanol on brain function. A simulation study is conducted to compare the performance of the proposed mixed effects spline models and a polynomial regression model. Results show that the proposed spline models more accurately capture varying response patterns across voxels, especially at voxels with complex response shapes. Finally, the proposed spline models can be used in more general settings as a flexible modeling tool for investigating the effects of any

  4. Sticky foam as a less-than-lethal technology

    NASA Astrophysics Data System (ADS)

    Scott, Steven H.

    1997-01-01

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

  5. Sticky foam as a less-than-lethal technology

    SciTech Connect

    Scott, S.H.

    1996-12-31

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

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

    PubMed

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

    2012-12-01

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

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

    PubMed

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

    2015-12-22

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

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

    PubMed Central

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

    2015-01-01

    Short-term fasting protects mice from lethal doses of chemotherapy through undetermined mechanisms. Herein, we demonstrate that fasting preserves small intestinal (SI) architecture by maintaining SI stem cell viability and SI barrier function following exposure to high-dose etoposide. Nearly all SI stem cells were lost in fed mice, whereas fasting promoted sufficient SI stem cell survival to preserve SI integrity after etoposide treatment. Lineage tracing demonstrated that multiple SI stem cell populations, marked by Lgr5, Bmi1, or HopX expression, contributed to fasting-induced survival. DNA repair and DNA damage response genes were elevated in SI stem/progenitor cells of fasted etoposide-treated mice, which importantly correlated with faster resolution of DNA double-strand breaks and less apoptosis. Thus, fasting preserved SI stem cell viability as well as SI architecture and barrier function suggesting that fasting may reduce host toxicity in patients undergoing dose intensive chemotherapy. PMID:26644583

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

    PubMed

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

    2005-07-01

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

  10. SU-E-T-36: A GPU-Accelerated Monte-Carlo Dose Calculation Platform and Its Application Toward Validating a ViewRay Beam Model

    SciTech Connect

    Wang, Y; Mazur, T; Green, O; Hu, Y; Wooten, H; Yang, D; Zhao, T; Mutic, S; Li, H

    2015-06-15

    Purpose: To build a fast, accurate and easily-deployable research platform for Monte-Carlo dose calculations. We port the dose calculation engine PENELOPE to C++, and accelerate calculations using GPU acceleration. Simulations of a Co-60 beam model provided by ViewRay demonstrate the capabilities of the platform. Methods: We built software that incorporates a beam model interface, CT-phantom model, GPU-accelerated PENELOPE engine, and GUI front-end. We rewrote the PENELOPE kernel in C++ (from Fortran) and accelerated the code on a GPU. We seamlessly integrated a Co-60 beam model (obtained from ViewRay) into our platform. Simulations of various field sizes and SSDs using a homogeneous water phantom generated PDDs, dose profiles, and output factors that were compared to experiment data. Results: With GPU acceleration using a dated graphics card (Nvidia Tesla C2050), a highly accurate simulation – including 100*100*100 grid, 3×3×3 mm3 voxels, <1% uncertainty, and 4.2×4.2 cm2 field size – runs 24 times faster (20 minutes versus 8 hours) than when parallelizing on 8 threads across a new CPU (Intel i7-4770). Simulated PDDs, profiles and output ratios for the commercial system agree well with experiment data measured using radiographic film or ionization chamber. Based on our analysis, this beam model is precise enough for general applications. Conclusions: Using a beam model for a Co-60 system provided by ViewRay, we evaluate a dose calculation platform that we developed. Comparison to measurements demonstrates the promise of our software for use as a research platform for dose calculations, with applications including quality assurance and treatment plan verification.

  11. ORGAN DOSES AND EFFECTIVE DOSE FOR FIVE PET RADIOPHARMACEUTICALS.

    PubMed

    Andersson, Martin; Johansson, Lennart; Mattsson, Sören; Minarik, David; Leide-Svegborn, Sigrid

    2016-06-01

    Diagnostic investigations with positron-emitting radiopharmaceuticals are dominated by (18)F-fluorodeoxyglucose ((18)F-FDG), but other radiopharmaceuticals are also commercially available or under development. Five of them, which are all clinically important, are (18)F-fluoride, (18)F-fluoroethyltyrosine ((18)F-FET), (18)F-deoxyfluorothymidine ((18)F-FLT), (18)F-fluorocholine ((18)F-choline) and (11)C-raclopride. To estimate the potential risk of stochastic effects (mainly lethal cancer) to a population, organ doses and effective dose values were updated for all five radiopharmaceuticals. Dose calculations were performed using the computer program IDAC2.0, which bases its calculations on the ICRP/ICRU adult reference voxel phantoms and the tissue weighting factors from ICRP publication 103. The biokinetic models were taken from ICRP publication 128. For organ doses, there are substantial changes. The only significant change in effective dose compared with previous estimations was a 46 % reduction for (18)F-fluoride. The estimated effective dose in mSv MBq(-1) was 1.5E-02 for (18)F-FET, 1.5E-02 for (18)F-FLT, 2.0E-02 for (18)F-choline, 9.0E-03 for (18)F-fluoride and 4.4E-03 for (11)C-raclopride.

  12. Pegfilgrastim Improves Survival of Lethally Irradiated Nonhuman Primates.

    PubMed

    Hankey, Kim G; Farese, Ann M; Blaauw, Erica C; Gibbs, Allison M; Smith, Cassandra P; Katz, Barry P; Tong, Yan; Prado, Karl L; MacVittie, Thomas J

    2015-06-01

    Leukocyte growth factors (LGF), such as filgrastim, pegfilgrastim and sargramostim, have been used to mitigate the hematologic symptoms of acute radiation syndrome (ARS) after radiation accidents. Although these pharmaceuticals are currently approved for treatment of chemotherapy-induced myelosuppression, such approval has not been granted for myelosuppression resulting from acute radiation exposure. Regulatory approval of drugs used to treat radiological or nuclear exposure injuries requires their development and testing in accordance with the Animal Efficacy Rule, set forth by the U.S. Food and Drug Administration. To date, filgrastim is the only LGF that has undergone efficacy assessment conducted under the Animal Efficacy Rule. To confirm the efficacy of another LGF with a shorter dosing regimen compared to filgrastim, we evaluated the use of pegfilgrastim (Neulasta(®)) in a lethal nonhuman primate (NHP) model of hematopoietic acute radiation syndrome (H-ARS). Rhesus macaques were exposed to 7.50 Gy total-body irradiation (the LD(50/60)), delivered at 0.80 Gy/min using linear accelerator 6 MV photons. Pegfilgrastim (300 μg/kg, n = 23) or 5% dextrose in water (n = 23) was administered on day 1 and 8 postirradiation and all animals received medical management. Hematologic and physiologic parameters were evaluated for 60 days postirradiation. The primary, clinically relevant end point was survival to day 60; secondary end points included hematologic-related parameters. Pegfilgrastim significantly (P = 0.0014) increased 60 day survival to 91.3% (21/23) from 47.8% (11/23) in the control. Relative to the controls, pegfilgrastim also significantly: 1. decreased the median duration of neutropenia and thrombocytopenia; 2. improved the median time to recovery of absolute neutrophil count (ANC) ≥500/μL, ANC ≥1,000/μL and platelet (PLT) count ≥20,000/μL; 3. increased the mean ANC at nadir; and 4. decreased the incidence of Gram-negative bacteremia. These data

  13. Wnt/β-Catenin Signaling Drives Thioacetamide-Mediated Heteroprotection Against Acetaminophen-Induced Lethal Liver Injury

    PubMed Central

    Dadhania, Vivekkumar P.; Bhushan, Bharat

    2017-01-01

    Preplacement of compensatory tissue repair (CTR) by exposure to a nonlethal dose of a toxicant protects animals against a lethal dose of another toxicant. Although CTR is known to heteroprotect, the underlying molecular mechanisms are not completely known. Here, we investigated the mechanisms of heteroprotection using thioacetamide (TA): acetaminophen (APAP) heteroprotection model. Male Swiss Webster mice received a low dose of TA or distilled water (DW) vehicle 24 hours prior to a lethal dose of APAP. Liver injury, tissue repair, and promitogenic signaling were studied over a time course of 24 hours after APAP overdose to the TA- and DW-primed mice (TA + APAP and DW + APAP, respectively). Thioacetamide pretreatment afforded 100% protection against APAP overdose compared to 100% lethality in the DW + APAP-treated mice. Although hepatic Cyp2e1 was similar at the time of APAP administration, immediate activation of hepatic c-Jun N-terminal kinases (JNK) was observed in the TA + APAP-treated mice compared to its delayed activation in the DW + APAP group. In contrast to the DW + APAP group, the TA + APAP-treated mice exhibited extensive CTR, which was secondary to the timely activation of Wnt/β-catenin pathway. Our data indicate that rapid activation and appropriate termination of Wnt/β-catenin signaling and modulation of JNK activity underlie TA + APAP heteroprotection. PMID:28210203

  14. The Influence of Geographic Mobility on Nearly Lethal Suicide Attempts.

    ERIC Educational Resources Information Center

    Potter, Lloyd B.; Kresnow, Marcie-jo; Powell, Kenneth E.; Simon, Thomas R.; Mercy, James A.; Lee, Roberta K.; Frankowski, Ralph F.; Swann, Alan C.; Bayer, Timothy; O'Carroll, Patrick W.

    2002-01-01

    Presents a population-based, case-control study of nearly lethal suicide attempts with 153 cases and 513 controls. Results indicate that moving in the past year is positively associated with a nearly lethal suicide attempt, as are specific characteristics of the move. Findings confirm and extend prior research by demonstrating a relationship…

  15. BEDVH--A method for evaluating biologically effective dose volume histograms: Application to eye plaque brachytherapy implants

    SciTech Connect

    Gagne, Nolan L.; Leonard, Kara L.; Huber, Kathryn E.; Mignano, John E.; Duker, Jay S.; Laver, Nora V.; Rivard, Mark J.

    2012-02-15

    Purpose: A method is introduced to examine the influence of implant duration T, radionuclide, and radiobiological parameters on the biologically effective dose (BED) throughout the entire volume of regions of interest for episcleral brachytherapy using available radionuclides. This method is employed to evaluate a particular eye plaque brachytherapy implant in a radiobiological context. Methods: A reference eye geometry and 16 mm COMS eye plaque loaded with {sup 103}Pd, {sup 125}I, or {sup 131}Cs sources were examined with dose distributions accounting for plaque heterogeneities. For a standardized 7 day implant, doses to 90% of the tumor volume ( {sub TUMOR}D{sub 90}) and 10% of the organ at risk volumes ( {sub OAR}D{sub 10}) were calculated. The BED equation from Dale and Jones and published {alpha}/{beta} and {mu} parameters were incorporated with dose volume histograms (DVHs) for various T values such as T = 7 days (i.e., {sub TUMOR} {sup 7}BED{sub 10} and {sub OAR} {sup 7}BED{sub 10}). By calculating BED throughout the volumes, biologically effective dose volume histograms (BEDVHs) were developed for tumor and OARs. Influence of T, radionuclide choice, and radiobiological parameters on {sub TUMOR}BEDVH and {sub OAR}BEDVH were examined. The nominal dose was scaled for shorter implants to achieve biological equivalence. Results: {sub TUMOR}D{sub 90} values were 102, 112, and 110 Gy for {sup 103}Pd, {sup 125}I, and {sup 131}Cs, respectively. Corresponding {sub TUMOR} {sup 7}BED{sub 10} values were 124, 140, and 138 Gy, respectively. As T decreased from 7 to 0.01 days, the isobiologically effective prescription dose decreased by a factor of three. As expected, {sub TUMOR} {sup 7}BEDVH did not significantly change as a function of radionuclide half-life but varied by 10% due to radionuclide dose distribution. Variations in reported radiobiological parameters caused {sub TUMOR} {sup 7}BED{sub 10} to deviate by up to 46%. Over the range of {sub OAR

  16. Evolutionary demography of iteroparous plants: incorporating non-lethal costs of reproduction into integral projection models.

    PubMed

    Miller, Tom E X; Williams, Jennifer L; Jongejans, Eelke; Brys, Rein; Jacquemyn, Hans

    2012-07-22

    Understanding the selective forces that shape reproductive strategies is a central goal of evolutionary ecology. Selection on the timing of reproduction is well studied in semelparous organisms because the cost of reproduction (death) can be easily incorporated into demographic models. Iteroparous organisms also exhibit delayed reproduction and experience reproductive costs, although these are not necessarily lethal. How non-lethal costs shape iteroparous life histories remains unresolved. We analysed long-term demographic data for the iteroparous orchid Orchis purpurea from two habitat types (light and shade). In both the habitats, flowering plants had lower growth rates and this cost was greater for smaller plants. We detected an additional growth cost of fruit production in the light habitat. We incorporated these non-lethal costs into integral projection models to identify the flowering size that maximizes fitness. In both habitats, observed flowering sizes were well predicted by the models. We also estimated optimal parameters for size-dependent flowering effort, but found a strong mismatch with the observed flower production. Our study highlights the role of context-dependent non-lethal reproductive costs as selective forces in the evolution of iteroparous life histories, and provides a novel and broadly applicable approach to studying the evolutionary demography of iteroparous organisms.

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

    PubMed

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

    2017-04-01

    A new trend has been developed using vanadium and organic ligands to form novel compounds in order to improve the beneficial actions and reduce the toxicity of vanadium compounds. In present study, vanadyl trehalose was explored the oral acute toxicity, 28 days repeated dose toxicity and genotoxicity in Kunming mice. The Median Lethal Dose (LD50) of vanadyl trehalose was revealed to be 1000 mg/kg body weight in fasted Kunming mice. Stomach and intestine were demonstrated to be the main target organs of vanadyl trehalose through 28 days repeated dose toxicity study. And vanadyl trehalose also showed particular genotoxicity through mouse bone marrow micronucleus and mouse sperm malformation assay. In brief, vanadyl trehalose presented certain, but finite toxicity, which may provide experimental basis for the clinical application.

  18. Podophyllum hexandrum-Mediated Survival Protection and Restoration of Other Cellular Injuries in Lethally Irradiated Mice

    PubMed Central

    Sankhwar, Sanghmitra; Gupta, Manju Lata; Gupta, Vanita; Verma, Savita; Suri, Krishna Avtar; Devi, Memita; Sharma, Punita; Khan, Ehsan Ahmed; Alam, M. Sarwar

    2011-01-01

    This study aims at the development of a safe and effective formulation to counter the effects of lethal irradiation. The sub-fraction (G-001M), prepared from Podophyllum hexandrum has rendered high degree of survival (>90%) at a dose of 6 mg kg−1 body weight (intramuscular) in lethally irradiated mice. Therapeutic dose of G-001M, at about 20 times lower concentration than its LD100, has revealed a DRF of 1.62. Comet assay studies in peripheral blood leukocytes have reflected that, treatment of G-001M before irradiation has significantly reduced DNA tail length (P < .001) and DNA damage score (P < .001), as compared to radiation-only group. Spleen cell counts in irradiated animals had declined drastically at the very first day of exposure, and the fall continued till the 5th day (P < .001). In the treated irradiated groups, there was a steep reduction in the counts initially, but this phase did not prolong. More than 60% decline in thymocytes of irradiated group animals was registered at 5 h of irradiation when compared with controls, and the fall progressed further downwards with the similar pace till 5th day of exposure (P < .001). At later intervals, thymus was found fully regressed. In G-001M pre-treated irradiated groups also, thymocytes decreased till the 5th day but thereafter rejuvenated and within 30 days of treatment the values were close to normal. Current studies have explicitly indicated that, G-001M in very small doses has not only rendered high survivability in lethally irradiated mice, but also protected their cellular DNA, besides supporting fast replenishment of the immune system. PMID:19553386

  19. Reduction in mutation frequency by very low-dose gamma irradiation of Drosophila melanogaster germ cells.

    PubMed

    Ogura, Keiji; Magae, Junji; Kawakami, Yasushi; Koana, Takao

    2009-01-01

    To determine whether the linear no-threshold (LNT) model for stochastic effects of ionizing radiation is applicable to very low-dose radiation at a low dose rate, we irradiated immature male germ cells of the fruit fly, Drosophila melanogaster, with several doses of (60)Co gamma rays at a dose rate of 22.4 mGy/h. Thereafter, we performed the sex-linked recessive lethal mutation assay by mating the irradiated males with nonirradiated females. The mutation frequency in the group irradiated with 500 microGy was found to be significantly lower than that in the control group (P < 0.01), whereas in the group subjected to 10 Gy irradiation, the mutation frequency was significantly higher than that in the control group (P < 0.03). A J-shaped dose-response relationship was evident. Molecular experiments using DNA microarray and quantitative reverse transcription PCR indicated that several genes known to be expressed in response to heat or chemical stress and grim, a positive regulator of apoptosis, were up-regulated immediately after irradiation with 500 microGy. The involvement of an apoptosis function in the non-linear dose-response relationship was suggested.

  20. ASSESSING CHILDREN'S EXPOSURES TO PESTICIDES: AN IMPORTANT APPLICATION OF THE STOCHASTIC HUMAN EXPOSURE AND DOSE SIMULATION MODEL (SHEDS)

    EPA Science Inventory

    Accurately quantifying human exposures and doses of various populations to environmental pollutants is critical for the Agency to assess and manage human health risks. For example, the Food Quality Protection Act of 1996 (FQPA) requires EPA to consider aggregate human exposure ...

  1. Colistin Population Pharmacokinetics after Application of a Loading Dose of 9 MU Colistin Methanesulfonate in Critically Ill Patients

    PubMed Central

    Friberg, Lena E.; Pontikis, Konstantinos; Ioannidis, Konstantinos; Tsagkari, Vasiliki; Galani, Lamprini; Kostakou, Eirini; Baziaka, Fotini; Paskalis, Charalambos; Koutsoukou, Antonia; Giamarellou, Helen

    2015-01-01

    Colistin has been revived, in the era of extensively drug-resistant (XDR) Gram-negative infections, as the last-resort treatment in critically ill patients. Recent studies focusing on the optimal dosing strategy of colistin have demonstrated the necessity of a loading dose at treatment initiation (D. Plachouras, M. Karvanen, L. E. Friberg, E. Papadomichelakis, A. Antoniadou, I. Tsangaris, I. Karaiskos, G. Poulakou, F. Kontopidou, A. Armaganidis, O. Cars, and H. Giamarellou, Antimicrob Agents Chemother 53:3430–3436, 2009, http://dx.doi.org/10.1128/AAC.01361-08; A. F. Mohamed, I. Karaiskos, D. Plachouras, M. Karvanen, K. Pontikis, B. Jansson, E. Papadomichelakis, A. Antoniadou, H. Giamarellou, A. Armaganidis, O. Cars, and L. E. Friberg, Antimicrob Agents Chemother 56:4241– 4249, 2012, http://dx.doi.org/10.1128/AAC.06426-11; S. M. Garonzik, J. Li, V. Thamlikitkul, D. L. Paterson, S. Shoham, J. Jacob, F. P. Silveira, A. Forrest, and R. L. Nation, Antimicrob Agents Chemother 55:3284–3294, 2011, http://dx.doi.org/10.1128/AAC.01733-10). In 19 critically ill patients with suspected or microbiologically documented infections caused by XDR Gram-negative strains, a loading dose of 9 MU colistin methanesulfonate (CMS) (∼270 mg colistin base activity) was administered with a maintenance dose of 4.5 MU every 12 h, commenced after 24 h. Patients on renal replacement were excluded. CMS infusion was given over 30 min or 1 h. Repeated blood sampling was performed after the loading dose and after the 5th or 6th dose. Colistin concentrations and measured CMS, determined after hydrolization to colistin and including the partially sulfomethylated derivatives, were determined with a liquid chromatography-tandem mass spectrometry assay. Population pharmacokinetic analysis was conducted in NONMEM with the new data combined with data from previous studies. Measured colistimethate concentrations were described by 4 compartments for distribution and removal of sulfomethyl groups

  2. Colistin Population Pharmacokinetics after Application of a Loading Dose of 9 MU Colistin Methanesulfonate in Critically Ill Patients.

    PubMed

    Karaiskos, Ilias; Friberg, Lena E; Pontikis, Konstantinos; Ioannidis, Konstantinos; Tsagkari, Vasiliki; Galani, Lamprini; Kostakou, Eirini; Baziaka, Fotini; Paskalis, Charalambos; Koutsoukou, Antonia; Giamarellou, Helen

    2015-12-01

    Colistin has been revived, in the era of extensively drug-resistant (XDR) Gram-negative infections, as the last-resort treatment in critically ill patients. Recent studies focusing on the optimal dosing strategy of colistin have demonstrated the necessity of a loading dose at treatment initiation (D. Plachouras, M. Karvanen, L. E. Friberg, E. Papadomichelakis, A. Antoniadou, I. Tsangaris, I. Karaiskos, G. Poulakou, F. Kontopidou, A. Armaganidis, O. Cars, and H. Giamarellou, Antimicrob Agents Chemother 53:3430-3436, 2009, http://dx.doi.org/10.1128/AAC.01361-08; A. F. Mohamed, I. Karaiskos, D. Plachouras, M. Karvanen, K. Pontikis, B. Jansson, E. Papadomichelakis, A. Antoniadou, H. Giamarellou, A. Armaganidis, O. Cars, and L. E. Friberg, Antimicrob Agents Chemother 56:4241- 4249, 2012, http://dx.doi.org/10.1128/AAC.06426-11; S. M. Garonzik, J. Li, V. Thamlikitkul, D. L. Paterson, S. Shoham, J. Jacob, F. P. Silveira, A. Forrest, and R. L. Nation, Antimicrob Agents Chemother 55:3284-3294, 2011, http://dx.doi.org/10.1128/AAC.01733-10). In 19 critically ill patients with suspected or microbiologically documented infections caused by XDR Gram-negative strains, a loading dose of 9 MU colistin methanesulfonate (CMS) (∼ 270 mg colistin base activity) was administered with a maintenance dose of 4.5 MU every 12 h, commenced after 24 h. Patients on renal replacement were excluded. CMS infusion was given over 30 min or 1 h. Repeated blood sampling was performed after the loading dose and after the 5th or 6th dose. Colistin concentrations and measured CMS, determined after hydrolization to colistin and including the partially sulfomethylated derivatives, were determined with a liquid chromatography-tandem mass spectrometry assay. Population pharmacokinetic analysis was conducted in NONMEM with the new data combined with data from previous studies. Measured colistimethate concentrations were described by 4 compartments for distribution and removal of sulfomethyl groups, while

  3. Validation of an analytical method for nitrous oxide (N2O) laughing gas by headspace gas chromatography coupled to mass spectrometry (HS-GC-MS): forensic application to a lethal intoxication.

    PubMed

    Giuliani, N; Beyer, J; Augsburger, M; Varlet, V

    2015-03-01

    Drug abuse is a widespread problem affecting both teenagers and adults. Nitrous oxide is becoming increasingly popular as an inhalation drug, causing harmful neurological and hematological effects. Some gas chromatography-mass spectrometry (GC-MS) methods for nitrous oxide measurement have been previously described. The main drawbacks of these methods include a lack of sensitivity for forensic applications; including an inability to quantitatively determine the concentration of gas present. The following study provides a validated method using HS-GC-MS which incorporates hydrogen sulfide as a suitable internal standard allowing the quantification of nitrous oxide. Upon analysis, sample and internal standard have similar retention times and are eluted quickly from the molecular sieve 5Å PLOT capillary column and the Porabond Q column therefore providing rapid data collection whilst preserving well defined peaks. After validation, the method has been applied to a real case of N2O intoxication indicating concentrations in a mono-intoxication.

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

    PubMed Central

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

    2016-01-01

    Ovine interferon tau (IFN-τ) is a unique type I interferon with low toxicity and a broad host range in vivo. We report the generation of a nonreplicative recombinant adenovirus expressing biologically active IFN-τ. Using the B6.A2G-Mx1 mouse model, we showed that single-dose intranasal administration of recombinant Ad5-IFN-τ can effectively prevent lethality and disease induced by highly virulent hv-PR8 influenza virus by activating the interferon response and preventing viral replication. PMID:26739058

  5. Antidotes to anthrax lethal factor intoxication. Part 1: Discovery of potent lethal factor inhibitors with in vivo efficacy.

    PubMed

    Jiao, Guan-Sheng; Kim, Seongjin; Moayeri, Mahtab; Cregar-Hernandez, Lynne; McKasson, Linda; Margosiak, Stephen A; Leppla, Stephen H; Johnson, Alan T

    2010-11-15

    Sub-nanomolar small molecule inhibitors of anthrax lethal factor have been identified using SAR and Merck L915 (4) as a model compound. One of these compounds (16) provided 100% protection in a rat lethal toxin model of anthrax disease.

  6. Application of a statistical software package for analysis of large patient dose data sets obtained from RIS.

    PubMed

    Fazakerley, J; Charnock, P; Wilde, R; Jones, R; Ward, M

    2010-01-01

    For the purpose of patient dose audit, clinical audit and radiology workload analysis, data from Radiology Information Systems (RIS) at many hospitals are collected using a database and the analysis was automated using a statistical package and Visual Basic coding. The database is a Structured Query Language database, which can be queried using an off-the-shelf statistical package, Statistica. Macros were created to automatically format the data to a consistent format between different hospitals ready for analysis. These macros can also be used to automate further analysis such as detailing mean kV, mAs and entrance surface dose per room and per gender. Standard deviation and standard error of the mean are also generated. Graphs can also be generated to illustrate the trends in doses between different variables such as room and gender. Collectively, this information can be used to generate a report. A process that once could take up to 1 d to complete now takes around 1 h. A major benefit in providing the service to hospital trusts is that less resource is now required to report on RIS data, making the possibility of continuous dose audit more likely. Time that was spent on sorting through data can now be spent on improving the analysis to provide benefit to the customer. Using data sets from RIS is a good way to perform dose audits as the huge numbers of data available provide the bases for very accurate analysis. Using macros written in Statistica Visual Basic has helped sort and consistently analyse these data. Being able to analyse by exposure factors has provided a more detailed report to the customer.

  7. Antimutagenic effect of black tea extract using 'rodent dominant lethal mutation assay'.

    PubMed

    Shukla, Y; Taneja, P

    2001-11-30

    The antimutagenic effect of black tea extract has been evaluated with the 'Dominant Lethal Assay' in Swiss albino mice using benzo[a]pyrene [BaP] as a mutagen. BaP was given through the intraperitoneal (i.p.) route at a single dose of 100 mg/kg b.w. to male mice once only. The animals were given 1, 2 and 4% aqueous solution of black tea as sole source of drinking solution prior to BaP. The pregnant females were analyzed for living implants, pre- and post-implantation losses. The results revealed that during mating weeks, BaP caused a reduction in implants and an increase in pre- and post-implantation losses. The protective effect of tea solution on BaP-induced mutagenicity was observed. The number of living implants increased and dead implants decreased significantly in the animals kept on 2 and 4% tea solution. The increase in dominant lethal mutation rate by BaP was inhibited by black tea extract. Four percent tea solution alone did not produce dominant lethality, and reveals that it is non-toxic/non-mutagenic to sperm. Hence the study suggests that tea has a protective effect against BaP-induced genetic damage to germ cells in Swiss albino mice.

  8. Colchicine protects mice from the lethal effect of an agonistic anti-Fas antibody

    PubMed Central

    Feng, Guoping; Kaplowitz, Neil

    2000-01-01

    The aim of this study was to determine whether colchicine, which has been reported to protect against various hepatotoxic insults, influences the susceptibility of mice to the agonistic anti-Fas antibody, Jo2. All mice that were pretreated with colchicine (2 mg/kg) survived the lethal challenge of intraperitoneal administration of 10 μg of Jo2, whereas all control mice pretreated with γ-lumicolchicine succumbed to the challenge. Twelve micrograms of Jo2 killed less than half of colchicine-pretreated mice and its lethal effects were delayed relative to control mice, which all died within 8 hours. Other microtubule-disrupting agents such as Taxol, vinblastine, and nocodazole also improved the survival of mice treated with the lethal dose of Jo2. Histologic examination showed that colchicine protected against Jo2-induced fulminant liver injury, and TUNEL assay demonstrated that colchicine protected against massive apoptosis of hepatocytes. Hepatocytes isolated from colchicine-pretreated mice exhibited decreased susceptibility to Jo2-induced apoptosis. In addition, colchicine pretreatment reduced surface expression of Fas and decreased Jo2- and TNF-α–induced apoptosis of cultured hepatocytes in the presence of actinomycin D, but did not affect the susceptibility of cultured sinusoidal endothelial cells to Jo2-induced apoptosis. Remarkably, Fas and TNF receptor-1 mRNA and intracellular protein levels increased after colchicine treatment, indicating that colchicine protects against death ligand–induced apoptosis in the liver by decreasing death-receptor targeting to the cell surface. PMID:10675359

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

    PubMed

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

    2016-02-01

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

  10. Lethal body burdens of polar narcotics: Chlorophenols

    SciTech Connect

    Wezel, A.P. van; Punte, S.S.; Opperhuizen, A.

    1995-09-01

    The goal of the present study was to measure in fathead minnow (Pimephales promelas) the lethal body burden (LBB) of three chlorophenols that are known as polar narcotic chemicals. The LBBs of the chlorophenols were compared to LBBs of nonpolar narcotic chemicals to consider if the two classes of narcotic chemicals differ on a body burden level. The LBB of the most acidic chlorophenol was measured at two different levels of pH exposure to determine the influence of the degree of ionization on the magnitude of the LBB. Both n-octanol/water partition coefficients and n-hexane/water partition coefficients of the chlorophenols were determined at different pH levels to consider the influence of ionization on the partition coefficient and to determine the importance of a polar group in the organic phase on the partitioning behavior. Partitioning to n-octanol and n-hexane was used as input in a model to simulate the equilibrium partitioning between hydrophobic and nonhydrophobic and target and nontarget compartments in the fish.

  11. Inhibitors of the Metalloproteinase Anthrax Lethal Factor

    PubMed Central

    Goldberg, Allison B.; Turk, Benjamin E.

    2016-01-01

    Bacillus anthracis, a rod shaped, spore forming, gram positive bacteria, is the etiological agent of anthrax. B. anthracis virulence is partly attributable to two secreted bipartite protein toxins, which act inside host cells to disrupt signaling pathways important for host defense against infection. These toxins may also directly contribute to mortality in late stage infection. The zinc-dependent metalloproteinase anthrax lethal factor (LF) is a critical component of one of these protein toxins and a prime target for inhibitor development to produce anthrax therapeutics. Here, we describe recent efforts to identify specific and potent LF inhibitors. Derivatization of peptide substrate analogs bearing zinc-binding groups has produced potent and specific LF inhibitors, and X-ray crystallography of LF-inhibitor complexes has provided insight into features required for high affinity binding. Novel inhibitor scaffolds have been identified through several approaches, including fragment-based drug discovery, virtual screening, and high-throughput screening of diverse compound libraries. Lastly, efforts to discover LF inhibitors have led to the development of new screening strategies, such as the use of full-length proteins as substrates, that may prove useful for other proteases as well. Overall, these efforts have led to a collection of chemically and mechanistically diverse molecules capable of inhibiting LF activity in vitro and in cells, as well as in animal models of anthrax infection. PMID:27072692

  12. Tumor clone dynamics in lethal prostate cancer.

    PubMed

    Carreira, Suzanne; Romanel, Alessandro; Goodall, Jane; Grist, Emily; Ferraldeschi, Roberta; Miranda, Susana; Prandi, Davide; Lorente, David; Frenel, Jean-Sebastien; Pezaro, Carmel; Omlin, Aurelius; Rodrigues, Daniel Nava; Flohr, Penelope; Tunariu, Nina; S de Bono, Johann; Demichelis, Francesca; Attard, Gerhardt

    2014-09-17

    It is unclear whether a single clone metastasizes and remains dominant over the course of lethal prostate cancer. We describe the clonal architectural heterogeneity at different stages of disease progression by sequencing serial plasma and tumor samples from 16 ERG-positive patients. By characterizing the clonality of commonly occurring deletions at 21q22, 8p21, and 10q23, we identified multiple independent clones in metastatic disease that are differentially represented in tissue and circulation. To exemplify the clinical utility of our studies, we then showed a temporal association between clinical progression and emergence of androgen receptor (AR) mutations activated by glucocorticoids in about 20% of patients progressing on abiraterone and prednisolone or dexamethasone. Resistant clones showed a complex dynamic with temporal and spatial heterogeneity, suggesting distinct mechanisms of resistance at different sites that emerged and regressed depending on treatment selection pressure. This introduces a management paradigm requiring sequential monitoring of advanced prostate cancer patients with plasma and tumor biopsies to ensure early discontinuation of agents when they become potential disease drivers.

  13. Lethal methemoglobinemia and automobile exhaust inhalation.

    PubMed

    Vevelstad, Merete; Morild, Inge

    2009-05-30

    Inhalation of automobile exhaust gas often leads to death by CO intoxication. In some cases the measured carbon monoxide hemoglobin saturation level (COHb) is considerably below what is considered to be lethal. The death in such cases has been attributed to a combination of a high CO2 and a low O2 tension. In a recent case the deceased was found dead in a car equipped with a catalytic converter, with a hose leading exhaust from the engine to the interior of the car. Analysis revealed a moderately elevated COHb and a high methemoglobin saturation level (MetHb) in peripheral blood. No ethanol, narcotics or drugs were detected. Reports mentioning MetHb or methemoglobinemia in post-mortem cases are surprisingly scarce, and very few have related exhaust gas deaths to methemoglobinemia. High-degree methemoglobinemia causes serious tissue hypoxia leading to unconsciousness, arrhythmia and death. The existing literature in this field and the knowledge that exhaust fumes contain nitrogen oxide gases (NOx) that by inhalation and absorption can result in severe methemoglobinemia, led us to postulate that this death could possibly be attributed to a combination of methemoglobinemia and a moderately high COHb concentration.

  14. Tumor clone dynamics in lethal prostate cancer

    PubMed Central

    Carreira, Suzanne; Romanel, Alessandro; Goodall, Jane; Grist, Emily; Ferraldeschi, Roberta; Miranda, Susana; Prandi, Davide; Lorente, David; Frenel, Jean-Sebastien; Pezaro, Carmel; Omlin, Aurelius; Rodrigues, Daniel Nava; Flohr, Penelope; Tunariu, Nina; de Bono, Johann S.; Demichelis, Francesca; Attard, Gerhardt

    2015-01-01

    It is unclear whether a single clone metastasizes and remains dominant over the course of lethal prostate cancer. We describe the clonal architectural heterogeneity at different stages of disease progression by sequencing serial plasma and tumor samples from 16 ERG-positive patients. By characterizing the clonality of commonly occurring deletions at 21q22, 8p21, and 10q23, we identified multiple independent clones in metastatic disease that are differentially represented in tissue and circulation. To exemplify the clinical utility of our studies, we then showed a temporal association between clinical progression and emergence of androgen receptor (AR) mutations activated by glucocorticoids in about 20% of patients progressing on abiraterone and prednisolone or dexamethasone. Resistant clones showed a complex dynamic with temporal and spatial heterogeneity, suggesting distinct mechanisms of resistance at different sites that emerged and regressed depending on treatment selection pressure. This introduces a management paradigm requiring sequential monitoring of advanced prostate cancer patients with plasma and tumor biopsies to ensure early discontinuation of agents when they become potential disease drivers. PMID:25232177

  15. RECOVERY PATTERNS AND LETHAL MANIFESTATIONS OF LIVE E. COLI ORGANISM SHOCK

    DTIC Science & Technology

    The purpose of the present study was to develop a more clinically applicable animal shock model by withholding anesthetics while administering live E . coli organisms at a dosage producing the degree of lethality seen in clinical medicine and to study the animals in an unrestrained condition during a substantially extended post-shock period. Results from these experiments are thought to be of promise in regard to more closely approximating the manifestations of clinical shock in man.

  16. A real-time flat-panel X-ray pixel imaging system for low-dose medical diagnostics and craniofacial applications.

    PubMed

    Chapuy, S; Dimcovski, D; Dimcovski, Z; Grigoriev, E; Grob, E; Ligier, Y; Pachoud, M; Riondel, F; Rüfenacht, D; Sayegh, C; Terrier, F; Valley, J F; Verdun, F R

    2000-01-01

    The aim of this study was to evaluate on-line performance of a real-time digital imaging system based on amorphous silicon technology and to compare it with conventional film-screen equipment. The digital detecting imager consists of (1) a converter, which transforms the energy of the incident X rays into light; (2) a real-time digital detecting system, capable of producing as many as 10 pictures per second using a large-area pixel matrix (20 x 20 cm2) based on solid-state amorphous silicon sensor technology with a pitch of 400 microns; and (3) appropriate computer tools for control, real-time image treatment, data representation, and off-line analysis. Different phantoms were used for qualitative comparison with the conventional film-screen technique, with images obtained with both systems at the normal dose (used as a reference), as well as with dose reduction by a factor of 10 to 100. Basic image quality parameters evaluated showed that the response of the detector is linear in a wide range of entrance air kerma; the dynamic range is higher compared with the conventional film-screen combination; the spatial resolution is 1.25 lp per millimeter, as expected from the pixel size; and good image quality is ensured at doses substantially lower than for the film-screen technique. The flat-panel X-ray imager based on amorphous silicon technology implemented in standard radiographic equipment permits acquisition of real-time images in radiology (as many as 10 images per second) of diagnostic quality with a marked reduction of dose (as much as 100 times) and better contrast compared with the standard film technique. Preliminary results obtained with a 100-micron pitch imager based on the same technology show better quality but a less substantial dose reduction. Applications in craniofacial surgery look promising.

  17. SU-E-T-750: Three Dimensional in Silico Study of Brachytherapy Application with In-Situ Dose-Painting Administered Via Gold-Nanoparticle Eluters

    SciTech Connect

    Sinha, N; Cifter, G; Ngwa, W

    2015-06-15

    Purpose: Brachytherapy Application with in-situ Dose-painting Administered via Gold-Nanoparticle Eluters (BANDAGE) has been proposed as a new therapeutic strategy for radiation boosting of high-risk prostate tumor subvolume while minimizing dose to neighboring organs-at-risk. In a previous study the one-dimensional dose-painting with gold nanoparticles (GNP) released from GNP-loaded brachytherapy spacers was investigated. The current study investigates BANDAGE in three-dimensions. Methods: To simulate GNPs transport in prostrate tumors, a three dimensional, cylindrically symmetric transport model was generated using a finite element method (FEM). A mathematical model of Gold nanoparticle (GNPs) transport provides a useful strategy to optimize potential treatment planning for BANDAGE. Here, treatment of tumors with a radius of 2.5 cm was simulated in 3-D. This simulation phase considered one gold based cylindrical spacer (GBS of size 5mm × 0.8 mm) introduced at the center of the spherical tumor with initial concentration of 100 mg/g or 508 mol/m3 of GNP. Finite element mesh is used to stimulate the GNP transport. Gold concentrations within the tumor were obtained using a 3-D FEM solution implemented by COMSOL. Results: The analysis shows the spread of the GNPs through-out the tumor with the increase of concentration towards the periphery with time. The analysis also shows the concentration profiles and corresponding dose enhancement factors (dose boost factor) as a function of GNP size. Conclusion: This study demonstrates the use of computational modeling and optimal parameter estimation to predict local GNPs from central implant as a function of x, y and z axis . Such a study provides a useful reference for ongoing translational studies for the BANDAGE approach.

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

    PubMed

    Clark, D R; Kroll, J C

    1977-12-01

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

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

    USGS Publications Warehouse

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

    1977-01-01

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

  20. mRNA Expression Signature of Gleason Grade Predicts Lethal Prostate Cancer

    PubMed Central

    Penney, Kathryn L.; Sinnott, Jennifer A.; Fall, Katja; Pawitan, Yudi; Hoshida, Yujin; Kraft, Peter; Stark, Jennifer R.; Fiorentino, Michelangelo; Perner, Sven; Finn, Stephen; Calza, Stefano; Flavin, Richard; Freedman, Matthew L.; Setlur, Sunita; Sesso, Howard D.; Andersson, Swen-Olof; Martin, Neil; Kantoff, Philip W.; Johansson, Jan-Erik; Adami, Hans-Olov; Rubin, Mark A.; Loda, Massimo; Golub, Todd R.; Andrén, Ove; Stampfer, Meir J.; Mucci, Lorelei A.

    2011-01-01

    Purpose Prostate-specific antigen screening has led to enormous overtreatment of prostate cancer because of the inability to distinguish potentially lethal disease at diagnosis. We reasoned that by identifying an mRNA signature of Gleason grade, the best predictor of prognosis, we could improve prediction of lethal disease among men with moderate Gleason 7 tumors, the most common grade, and the most indeterminate in terms of prognosis. Patients and Methods Using the complementary DNA–mediated annealing, selection, extension, and ligation assay, we measured the mRNA expression of 6,100 genes in prostate tumor tissue in the Swedish Watchful Waiting cohort (n = 358) and Physicians' Health Study (PHS; n = 109). We developed an mRNA signature of Gleason grade comparing individuals with Gleason ≤ 6 to those with Gleason ≥ 8 tumors and applied the model among patients with Gleason 7 to discriminate lethal cases. Results We built a 157-gene signature using the Swedish data that predicted Gleason with low misclassification (area under the curve [AUC] = 0.91); when this signature was tested in the PHS, the discriminatory ability remained high (AUC = 0.94). In men with Gleason 7 tumors, who were excluded from the model building, the signature significantly improved the prediction of lethal disease beyond knowing whether the Gleason score was 4 + 3 or 3 + 4 (P = .006). Conclusion Our expression signature and the genes identified may improve our understanding of the de-differentiation process of prostate tumors. Additionally, the signature may have clinical applications among men with Gleason 7, by further estimating their risk of lethal prostate cancer and thereby guiding therapy decisions to improve outcomes and reduce overtreatment. PMID:21537050

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

    PubMed Central

    Zhou, Dunhua; Deoliveira, Divino; Kang, Yubin; Choi, Seung S.; Li, Zhiguo; Chao, Nelson J.; Chen, Benny J.

    2012-01-01

    Purpose To investigate whether and how insulin-like growth factor 1 (IGF-1) mitigates hematopoietic toxicity after total body irradiation. Methods and Materials BALB/c mice were irradiated with a lethal dose of radiation (7.5 Gy) and treated with IGF-1 at a dose of 100 μg/dose intravenously once a day for five consecutive days starting within one hour post exposure. Survival and hematopoietic recovery were monitored. The mechanisms by which IGF-1 promotes hematopoietic recovery were also studied using an in vitro culture system. Results IGF-1 protected 8 out of 20 mice (40%) from lethal irradiation while only 2 out of 20 mice (10%) in the saline control group survived for more than 100 days after irradiation. A single dose of IGF-1 (500 μg) was as effective as daily dosing for five days. Positive effects were noted even when the initiation of treatment was delayed up to six hours post irradiation. Compared with the saline control group, treatment with IGF-1 significantly accelerated the recovery of both platelets and red cells in peripheral blood, total cell numbers as well as hematopoietic stem cells and progenitors in the bone marrow when measured at day 14 post-irradiation. IGF-1 protected both hematopoietic stem cells and progenitors from radiation-induced apoptosis and cell death. In addition, IGF-1 was able to facilitate the proliferation and differentiation of non-irradiated and irradiated hematopoietic progenitors. Conclusions IGF-1 mitigates radiation-induced hematopoietic toxicity through protecting hematopoietic stem and progenitor cells from apoptosis and enhancing proliferation and differentiation of the surviving hematopoietic progenitors. PMID:23021438

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

    SciTech Connect

    Zhou, Dunhua; Deoliveira, Divino; Kang, Yubin; Choi, Seung S.; Li, Zhiguo; Chao, Nelson J.; Chen, Benny J.

    2013-03-15

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

  3. Development of a low-energy monoenergetic neutron source for applications in low-dose radiobiological and radiochemical research.

    PubMed

    Aslam; Prestwich, W V; McNeill, F E; Waker, A J

    2003-06-01

    The McMaster University 3 MV KN Van de Graff accelerator facility primarily dedicated to in vivo neutron activation measurements has been used to produce moderate dose rates of monoenergetic fast neutrons of energy ranging from 150 to 600 keV with a small energy spread of about 25 keV (1sigma width of Gaussian) by bombarding thin lithium targets with 2.00-2.40 MeV protons. The calculated dose rate of the monoenergetic neutrons produced using thin lithium targets as functions of beam energy, target thickness, lab angle relative to beam direction, and the solid angle subtended by the sample with the target has also been reported.

  4. Establishing Genetic Interactions by a Synthetic Dosage Lethality Phenotype

    PubMed Central

    Kroll, E. S.; Hyland, K. M.; Hieter, P.; Li, J. J.

    1996-01-01

    We have devised a genetic screen, termed synthetic dosage lethality, in which a cloned ``reference'' gene is inducibly overexpressed in a set of mutant strains carrying potential ``target'' mutations. To test the specificity of the method, two reference genes, CTF13, encoding a centromere binding protein, and ORC6, encoding a subunit of the origin of replication binding complex, were overexpressed in a large collection of mutants defective in either chromosome segregation or replication. CTF13 overexpression caused synthetic dosage lethality in combination with ctf14-42 (cbf2, ndc10), ctf17-61 (chl4), ctf19-58 and ctf19-26. ORC6 overexpression caused synthetic dosage lethality in combination with cdc2-1, cdc6-1, cdc14-1, cdc16-1 and cdc46-1. These relationships reflect specific interactions, as overexpression of CTF13 caused lethality in kinetochore mutants and overexpression of ORC6 caused lethality in replication mutants. In contrast, only one case of dosage suppression was observed. We suggest that synthetic dosage lethality identifies a broad spectrum of interacting mutations and is of general utility in detecting specific genetic interactions using a cloned wild-type gene as a starting point. Furthermore, synthetic dosage lethality is easily adapted to the study of cloned genes in other organisms. PMID:8722765

  5. Key tissue targets responsible for anthrax-toxin-induced lethality.

    PubMed

    Liu, Shihui; Zhang, Yi; Moayeri, Mahtab; Liu, Jie; Crown, Devorah; Fattah, Rasem J; Wein, Alexander N; Yu, Zu-Xi; Finkel, Toren; Leppla, Stephen H

    2013-09-05

    Bacillus anthracis, the causative agent of anthrax disease, is lethal owing to the actions of two exotoxins: anthrax lethal toxin (LT) and oedema toxin (ET). The key tissue targets responsible for the lethal effects of these toxins are unknown. Here we generated cell-type-specific anthrax toxin receptor capillary morphogenesis protein-2 (CMG2)-null mice and cell-type-specific CMG2-expressing mice and challenged them with the toxins. Our results show that lethality induced by LT and ET occurs through damage to distinct cell types; whereas targeting cardiomyocytes and vascular smooth muscle cells is required for LT-induced mortality, ET-induced lethality occurs mainly through its action in hepatocytes. Notably, and in contradiction to what has been previously postulated, targeting of endothelial cells by either toxin does not seem to contribute significantly to lethality. Our findings demonstrate that B. anthracis has evolved to use LT and ET to induce host lethality by coordinately damaging two distinct vital systems.

  6. Filtering, Smoothing, and Extrapolations in Dose-Response Experiments: With Application to Data on Respiratory Tumor in Rats.

    DTIC Science & Technology

    1990-01-01

    A method for inference and extrapolations in certain dose- response. damage-assessments and accelerated life-testing studies as been proposed by...Meinhold and Singpurwalla in 1986. The method is based on a use of the Kalman-filter algorithm and involves the double lognormal as the distributional...assumption. In this paper we discuss issues pertaining to a practical implementation of this methodology . This involves some insights based on a

  7. Calculation of internal dose from ingested soil-derived uranium in humans: Application of a new method.

    PubMed

    Träber, S C; Li, W B; Höllriegl, V; Nebelung, K; Michalke, B; Rühm, W; Oeh, U

    2015-08-01

    The aim of the present study was to determine the internal dose in humans after the ingestion of soil highly contaminated with uranium. Therefore, an in vitro solubility assay was performed to estimate the bioaccessibility of uranium for two types of soil. Based on the results, the corresponding bioavailabilities were assessed by using a recently published method. Finally, these bioavailability data were used together with the biokinetic model of uranium to assess the internal doses for a hypothetical but realistic scenario characterized by a daily ingestion of 10 mg of soil over 1 year. The investigated soil samples were from two former uranium mining sites of Germany with (238)U concentrations of about 460 and 550 mg/kg. For these soils, the bioavailabilities of (238)U were quantified as 0.18 and 0.28 % (geometric mean) with 2.5th percentiles of 0.02 and 0.03 % and 97.5th percentiles of 1.48 and 2.34 %, respectively. The corresponding calculated annual committed effective doses for the assumed scenario were 0.4 and 0.6 µSv (GM) with 2.5th percentiles of 0.2 and 0.3 µSv and 97.5th percentiles of 1.6 and 3.0 µSv, respectively. These annual committed effective doses are similar to those from natural uranium intake by food and drinking water, which is estimated to be 0.5 µSv. Based on the present experimental data and the selected ingestion scenario, the investigated soils-although highly contaminated with uranium-are not expected to pose any major health risk to humans related to radiation.

  8. Application of a key events dose-response analysis to nutrients: a case study with vitamin A (retinol).

    PubMed

    Ross, A Catharine; Russell, Robert M; Miller, Sanford A; Munro, Ian C; Rodricks, Joseph V; Yetley, Elizabeth A; Julien, Elizabeth

    2009-09-01

    The methodology used to establish tolerable upper intake levels (UL) for nutrients borrows heavily from risk assessment methods used by toxicologists. Empirical data are used to identify intake levels associated with adverse effects, and Uncertainty Factors (UF) are applied to establish ULs, which in turn inform public health decisions and standards. Use of UFs reflects lack of knowledge regarding the biological events that underlie response to the intake of a given nutrient, and also regarding the sources of variability in that response. In this paper, the Key Events Dose-Response Framework (KEDRF) is used to systematically consider the major biological steps that lead from the intake of the preformed vitamin A to excess systemic levels, and subsequently to increased risk of adverse effects. Each step is examined with regard to factors that influence whether there is progression toward the adverse effect of concern. The role of homeostatic mechanisms is discussed, along with the types of research needed to improve understanding of dose-response for vitamin A. This initial analysis illustrates the potential of the KEDRF as a useful analytical tool for integrating current knowledge regarding dose-response, generating questions that will focus future research efforts, and clarifying how improved knowledge and data could be used to reduce reliance on UFs.

  9. Application of the two-dose-rate method for general recombination correction for liquid ionization chambers in continuous beams

    NASA Astrophysics Data System (ADS)

    Andersson, Jonas; Tölli, Heikki

    2011-01-01

    A method to correct for the general recombination losses for liquid ionization chambers in continuous beams has been developed. The proposed method has been derived from Greening's theory for continuous beams and is based on measuring the signal from a liquid ionization chamber and an air filled monitor ionization chamber at two different dose rates. The method has been tested with two plane parallel liquid ionization chambers in a continuous radiation x-ray beam with a tube voltage of 120 kV and with dose rates between 2 and 13 Gy min-1. The liquids used as sensitive media in the chambers were isooctane (C8H18) and tetramethylsilane (Si(CH3)4). The general recombination effect was studied using chamber polarizing voltages of 100, 300, 500, 700 and 900 V for both liquids. The relative standard deviation of the results for the collection efficiency with respect to general recombination was found to be a maximum of 0.7% for isooctane and 2.4% for tetramethylsilane. The results are in excellent agreement with Greening's theory for collection efficiencies over 90%. The measured and corrected signals from the liquid ionization chambers used in this work are in very good agreement with the air filled monitor chamber with respect to signal to dose linearity.

  10. Application of the two-dose-rate method for general recombination correction for liquid ionization chambers in continuous beams.

    PubMed

    Andersson, Jonas; Tölli, Heikki

    2011-01-21

    A method to correct for the general recombination losses for liquid ionization chambers in continuous beams has been developed. The proposed method has been derived from Greening's theory for continuous beams and is based on measuring the signal from a liquid ionization chamber and an air filled monitor ionization chamber at two different dose rates. The method has been tested with two plane parallel liquid ionization chambers in a continuous radiation x-ray beam with a tube voltage of 120 kV and with dose rates between 2 and 13 Gy min(-1). The liquids used as sensitive media in the chambers were isooctane (C(8)H(18)) and tetramethylsilane (Si(CH(3))(4)). The general recombination effect was studied using chamber polarizing voltages of 100, 300, 500, 700 and 900 V for both liquids. The relative standard deviation of the results for the collection efficiency with respect to general recombination was found to be a maximum of 0.7% for isooctane and 2.4% for tetramethylsilane. The results are in excellent agreement with Greening's theory for collection efficiencies over 90%. The measured and corrected signals from the liquid ionization chambers used in this work are in very good agreement with the air filled monitor chamber with respect to signal to dose linearity.

  11. Application of a Key Events Dose-Response Analysis to Nutrients: A Case Study with Vitamin A (Retinol)

    PubMed Central

    ROSS, A. CATHARINE; RUSSELL, ROBERT M.; MILLER, SANFORD A.; MUNRO, IAN C.; RODRICKS, JOSEPH V.; YETLEY, ELIZABETH A.; JULIEN, ELIZABETH

    2009-01-01

    The methodology used to establish tolerable upper intake levels (UL) for nutrients borrows heavily from risk assessment methods used by toxicologists. Empirical data are used to identify intake levels associated with adverse effects, and Uncertainty Factors (UF) are applied to establish ULs, which in turn inform public health decisions and standards. Use of UFs reflects lack of knowledge regarding the biological events that underlie response to the intake of a given nutrient, and also regarding the sources of variability in that response. In this paper, the Key Events Dose-Response Framework (KEDRF) is used to systematically consider the major biological steps that lead from the intake of the preformed vitamin A to excess systemic levels, and subsequently to increased risk of adverse effects. Each step is examined with regard to factors that influence whether there is progression toward the adverse effect of concern. The role of homeostatic mechanisms is discussed, along with the types of research needed to improve understanding of dose-response for vitamin A. This initial analysis illustrates the potential of the KEDRF as a useful analytical tool for integrating current knowledge regarding dose-response, generating questions that will focus future research efforts, and clarifying how improved knowledge and data could be used to reduce reliance on UFs. PMID:19690996

  12. No evidence found for induction of dominant lethal mutations and heritable translocations in male mice by calcium cyclamate

    SciTech Connect

    Cain, K.T.; Cornett, C.V.; Cacheiro, L.A.; Hughes, L.A.; Owens, J.G.; Generoso, W.M.

    1988-01-01

    Calcium cyclamate, an artificial sweetener, was studied for its effectiveness in inducing transmissible chromosomal aberrations in germ cells of male mice. Both the dominant-lethal and the heritable translocation tests were carried out following daily treatment (on weekdays) of males by oral intubation with the maximum tolerated dose for 6 weeks. Calcium cyclamate is negative in both tests; therefore, there is no evidence of induced chromosome breakage and exchange.

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

    NASA Astrophysics Data System (ADS)

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

    2014-05-01

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

  14. A dose point kernel database using GATE Monte Carlo simulation toolkit for nuclear medicine applications: Comparison with other Monte Carlo codes

    SciTech Connect

    Papadimitroulas, Panagiotis; Loudos, George; Nikiforidis, George C.; Kagadis, George C.

    2012-08-15

    Purpose: GATE is a Monte Carlo simulation toolkit based on the Geant4 package, widely used for many medical physics applications, including SPECT and PET image simulation and more recently CT image simulation and patient dosimetry. The purpose of the current study was to calculate dose point kernels (DPKs) using GATE, compare them against reference data, and finally produce a complete dataset of the total DPKs for the most commonly used radionuclides in nuclear medicine. Methods: Patient-specific absorbed dose calculations can be carried out using Monte Carlo simulations. The latest version of GATE extends its applications to Radiotherapy and Dosimetry. Comparison of the proposed method for the generation of DPKs was performed for (a) monoenergetic electron sources, with energies ranging from 10 keV to 10 MeV, (b) beta emitting isotopes, e.g., {sup 177}Lu, {sup 90}Y, and {sup 32}P, and (c) gamma emitting isotopes, e.g., {sup 111}In, {sup 131}I, {sup 125}I, and {sup 99m}Tc. Point isotropic sources were simulated at the center of a sphere phantom, and the absorbed dose was stored in concentric spherical shells around the source. Evaluation was performed with already published studies for different Monte Carlo codes namely MCNP, EGS, FLUKA, ETRAN, GEPTS, and PENELOPE. A complete dataset of total DPKs was generated for water (equivalent to soft tissue), bone, and lung. This dataset takes into account all the major components of radiation interactions for the selected isotopes, including the absorbed dose from emitted electrons, photons, and all secondary particles generated from the electromagnetic interactions. Results: GATE comparison provided reliable results in all cases (monoenergetic electrons, beta emitting isotopes, and photon emitting isotopes). The observed differences between GATE and other codes are less than 10% and comparable to the discrepancies observed among other packages. The produced DPKs are in very good agreement with the already published data

  15. Coagulation and oxidation for controlling ultrafiltration membrane fouling in drinking water treatment: Application of ozone at low dose in submerged membrane tank.

    PubMed

    Yu, Wenzheng; Graham, Nigel J D; Fowler, Geoffrey D

    2016-05-15

    Coagulation prior to ultrafiltration (UF) is widely applied for treating contaminated surface water sources for potable supply. While beneficial, coagulation alone is unable to control membrane fouling effectively in many cases, and there is continuing interest in the use of additional, complementary methods such as oxidation in the pre-treatment of raw water prior to UF. In this study, the application of ozone at low dose in the membrane tank immediately following coagulation has been evaluated at laboratory-scale employing model raw water. In parallel tests with and without the application of ozone, the impact of applied ozone doses of 0.5 mg L(-1) and 1.5 mg L(-1) (approximately 0.18 mg L(-1) and 0.54 mg L(-1) consumed ozone, respectively) on the increase of trans-membrane pressure (TMP) was evaluated and correlated with the quantity and nature of membrane deposits, both as a cake layer and within membrane pores. The results showed that a dose of 0.5 mgO3 L(-1) gave a membrane fouling rate that was substantially lower than without ozone addition, while a dose of 1.5 mgO3 L(-1) was able to prevent fouling effects significantly (no increase in TMP). Ozone was found to decrease the concentration of bacteria (especially the concentration of bacteria per suspended solid) in the membrane tank, and to alter the nature of dissolved organic matter by increasing the proportion of hydrophilic substances. Ozone decreased the concentration of extracellular polymeric substances (EPS), such as polysaccharides and proteins, in the membrane cake layer; the reduced EPS and bacterial concentrations resulted in a much thinner cake layer, although the suspended solids concentration was much higher in the ozone added membrane tank. Ozone also decreased the accumulation and hydrophobicity of organic matter within the membrane pores, leading to minimal irreversible fouling. Therefore, the application of low-dose ozone within the UF membrane tank is a potentially important

  16. Noise correlation in CBCT projection data and its application for noise reduction in low-dose CBCT

    SciTech Connect

    Zhang, Hua; Ouyang, Luo; Wang, Jing E-mail: jing.wang@utsouthwestern.edu; Ma, Jianhua E-mail: jing.wang@utsouthwestern.edu; Huang, Jing; Chen, Wufan

    2014-03-15

    Purpose: To study the noise correlation properties of cone-beam CT (CBCT) projection data and to incorporate the noise correlation information to a statistics-based projection restoration algorithm for noise reduction in low-dose CBCT. Methods: In this study, the authors systematically investigated the noise correlation properties among detector bins of CBCT projection data by analyzing repeated projection measurements. The measurements were performed on a TrueBeam onboard CBCT imaging system with a 4030CB flat panel detector. An anthropomorphic male pelvis phantom was used to acquire 500 repeated projection data at six different dose levels from 0.1 to 1.6 mAs per projection at three fixed angles. To minimize the influence of the lag effect, lag correction was performed on the consecutively acquired projection data. The noise correlation coefficient between detector bin pairs was calculated from the corrected projection data. The noise correlation among CBCT projection data was then incorporated into the covariance matrix of the penalized weighted least-squares (PWLS) criterion for noise reduction of low-dose CBCT. Results: The analyses of the repeated measurements show that noise correlation coefficients are nonzero between the nearest neighboring bins of CBCT projection data. The average noise correlation coefficients for the first- and second-order neighbors are 0.20 and 0.06, respectively. The noise correlation coefficients are independent of the dose level. Reconstruction of the pelvis phantom shows that the PWLS criterion with consideration of noise correlation (PWLS-Cor) results in a lower noise level as compared to the PWLS criterion without considering the noise correlation (PWLS-Dia) at the matched resolution. At the 2.0 mm resolution level in the axial-plane noise resolution tradeoff analysis, the noise level of the PWLS-Cor reconstruction is 6.3% lower than that of the PWLS-Dia reconstruction. Conclusions: Noise is correlated among nearest neighboring

  17. Determination of 2,5-toluylenediamine (2,5-TDA) and aromatic amines in urine after personal application of hair dyes: kinetics and doses.

    PubMed

    Schettgen, Thomas; Heinrich, K; Kraus, T; Gube, Monika

    2011-02-01

    The personal use of hair dye products is currently under discussion due to the potentially increased risk of bladder cancer among long-time users described in epidemiological literature. In order to investigate the dermal absorption of aromatic diamines as well as aromatic amines possibly present as contaminants in hair dye formulations, we conducted a biomonitoring study under real-life conditions and calculated kinetics and doses for the urinary excretion. Urine samples of two female subjects were collected for a time period of 48 h after personal application of a hair dye cream and analysed for aromatic diamines as well as o-toluidine and 4-aminobiphenyl using highly specific GC/MS-methods. 2,5-Toluylenediamine (2,5-TDA) as active ingredient of hair dyes is rapidly absorbed dermally. After a distribution phase of 12 h, 2,5-TDA is excreted with a half-time of 8 h. Excretion was 90% complete within 24 h after application. The doses of 2,5-TDA excreted within 48 h were 700 μg for application of a brown-reddish hair dye cream and 1.5 mg for the application of a brown-black hair dye cream. Urinary 4-aminobiphenyl as well as contaminations with other aromatic diamines were not detectable in our study. Due to the artifactual formation of o-toluidine in the presence of high concentrations of urinary 2,5-TDA, our results could not prove an increased internal exposure of humans to carcinogenic amines after personal application of hair dyes.

  18. Somatic Mosaicism for a Lethal TRPV4 Mutation Results in Non-Lethal Metatropic Dysplasia

    PubMed Central

    Weinstein, Michael M.; Kang, Taekyu; Lachman, Ralph S.; Bamshad, Michael; Nickerson, Deborah A.; Krakow, Deborah; Cohn, Daniel H.

    2016-01-01

    Dominant mutations in TRPV4, which encodes the Transient Receptor Potential Cation Channel Subfamily V Member 4 calcium channel, result in a series of musculoskeletal disorders that include a set of peripheral neuropathies and a broad phenotypic spectrum of skeletal dysplasias. The skeletal pheno-types range from brachyolmia, in which there is scoliosis with mild short stature, through perinatal lethal metatropic dysplasia. We describe a case with phenotypic findings consistent with metatropic dysplasia, but in whom no TRPV4 mutation was detected by Sanger sequence analysis. Exome sequence analysis identified a known lethal metatropic dysplasia mutation, TRPV4L618P, which was present at lower frequency than would be expected for a heterozygous change. The affected individual was shown to be a somatic mosaic for the mutation, providing an explanation for the milder than expected phenotype. The data illustrate that high-throughput sequencing of genomic DNA can facilitate detection of mosaicism with higher sensitivity than Sanger sequence analysis and identify a new genetic mechanism for metatropic dysplasia. PMID:27530454

  19. Evaluation of patient dose using a virtual CT scanner: Applications to 4DCT simulation and Kilovoltage cone-beam imaging

    NASA Astrophysics Data System (ADS)

    DeMarco, J. J.; McNitt-Gray, M. F.; Cagnon, C. H.; Angel, E.; Agazaryan, N.; Zankl, M.

    2008-02-01

    This work evaluates the effects of patient size on radiation dose from simulation imaging studies such as four-dimensional computed tomography (4DCT) and kilovoltage cone-beam computed tomography (kV-CBCT). 4DCT studies are scans that include temporal information, frequently incorporating highly over-sampled imaging series necessary for retrospective sorting as a function of respiratory phase. This type of imaging study can result in a significant dose increase to the patient due to the slower table speed as compared with a conventional axial or helical scan protocol. Kilovoltage cone-beam imaging is a relatively new imaging technique that requires an on-board kilovoltage x-ray tube and a flat-panel detector. Instead of porting individual reference fields, the kV tube and flat-panel detector are rotated about the patient producing a cone-beam CT data set (kV-CBCT). To perform these investigations, we used Monte Carlo simulation methods with detailed models of adult patients and virtual source models of multidetector computed tomography (MDCT) scanners. The GSF family of three-dimensional, voxelized patient models, were implemented as input files using the Monte Carlo code MCNPX. The adult patient models represent a range of patient sizes and have all radiosensitive organs previously identified and segmented. Simulated 4DCT scans of each voxelized patient model were performed using a multi-detector CT source model that includes scanner specific spectra, bow-tie filtration, and helical source path. Standard MCNPX tally functions were applied to each model to estimate absolute organ dose based upon an air-kerma normalization measurement for nominal scanner operating parameters.

  20. High-dose metronidazole: pharmacokinetics and bioavailability using an iv preparation and application of its use as a radiosensitizer

    SciTech Connect

    Rabin, H.R.; Urtasun, R.C.; Partington, J.; Koziol, D.; Sharon, M.; Walker, K.

    1980-10-01

    As an extension of studies on the clinical use of nitroimidazoles as radiosensitizers, single-dose pharmacokinetic studies of iv metronidazole (500 mg/100-ml vials) were performed in eight consenting patients. Single doses of 0.5, 1.0, 1.5, and 2.0 g (0.29 to 1.21 g/m2) were administered iv by a zero-order infusion pump. Serial timed blood and urine samples were assayed for metronidazole and its two metabolites (acetic acid and ethoxy compounds) using a high-pressure liquid chromatographic assay. Open two-compartment kinetic characteristics of metronidazole were computed from simultaneous plasma infusion and urine excretion-rate equations using a nonlinear least-squares regression analysis program (NONLIN). Means of the four kinetic parameters were (h-1): k12, 1.18; k21, 0.86; k10, 0.22; and k'e, 0.46 x 10(-4). Means of the apparent volumes of distribution were (liters/kg): Vc, 0.41; VB, 1.02; and Vss, 0.75. The mean (+- SD) for alpha-half-life was 1.2 +- 1.3 hours, and that for beta-half-life was 9.8 +- 5.9 hours. Seven of the eight patients received a second identical dose orally 1 week later, and the absolute bioavailability was estimated to approximate 100%. Unless the oral route is not feasible and if immediate high peak blood levels are not necessary, oral metronidazole is the preferred route of administration of metronidazole for its radiosensitizing effects.

  1. Application of paclitaxel in low non-cytotoxic doses supports vaccination with melanoma antigens in normal mice.

    PubMed

    Sevko, Alexandra; Kremer, Veronika; Falk, Christine; Umansky, Ludmila; Shurin, Michael R; Shurin, Galina V; Umansky, Viktor

    2012-01-01

    Chemotherapeutic agents such as paclitaxel applied in ultra-low, non-cytotoxic doses were previously shown to stimulate dendritic cell activity and anti-tumor immune responses upon vaccination in mouse transplantable tumor models. However, the mechanisms of these alterations-termed chemoimmunomodulation or chemomodulation-are still not clear. This study investigated the effect of paclitaxel applied in ultra-low, non-cytotoxic doses on the efficiency of immunization of healthy C57BL/6 mice with the peptide derived from tyrosinase related protein (TRP)-2 as a model melanoma antigen. Using an IFNγ ELISPOT assay, it was found that administration of 1 mg paclitaxel/kg in combination with the peptide vaccination strongly increased the frequencies of TRP-2 specific spleen T-cells as compared to levels due to the vaccination alone. This was associated with a significant decrease in the levels of regulatory T-cells (T(reg)) and immature myeloid cells (known as a counterpart of myeloid derived suppressor cells [MDSC] in healthy mice). Such impairments of potential immunosuppressive cells were found to correlate with a strong increase in the amount of effector CD8+ and CD4+ T-cells in the bone marrow and spleen. Furthermore, in paclitaxel-treated mice, a significant augmentation of natural killer (NK) cell numbers in the bone marrow and their ability to produce IFNγ were observed. In addition, the level of NK-T-cells in the lymph nodes was also increased. It is suggested that paclitaxel applied in ultra-low, non-cytotoxic doses may potentially enhance the efficacy of anti-tumor vaccinations by neutralizing immunosuppressive T(reg) and MDSC populations in tumor-bearing hosts.

  2. A dose-controlled system for air-liquid interface cell exposure and application to zinc oxide nanoparticles

    PubMed Central

    2009-01-01

    Background Engineered nanoparticles are becoming increasingly ubiquitous and their toxicological effects on human health, as well as on the ecosystem, have become a concern. Since initial contact with nanoparticles occurs at the epithelium in the lungs (or skin, or eyes), in vitro cell studies with nanoparticles require dose-controlled systems for delivery of nanoparticles to epithelial cells cultured at the air-liquid interface. Results A novel air-liquid interface cell exposure system (ALICE) for nanoparticles in liquids is presented and validated. The ALICE generates a dense cloud of droplets with a vibrating membrane nebulizer and utilizes combined cloud settling and single particle sedimentation for fast (~10 min; entire exposure), repeatable (<12%), low-stress and efficient delivery of nanoparticles, or dissolved substances, to cells cultured at the air-liquid interface. Validation with various types of nanoparticles (Au, ZnO and carbon black nanoparticles) and solutes (such as NaCl) showed that the ALICE provided spatially uniform deposition (<1.6% variability) and had no adverse effect on the viability of a widely used alveolar human epithelial-like cell line (A549). The cell deposited dose can be controlled with a quartz crystal microbalance (QCM) over a dynamic range of at least 0.02-200 μg/cm2. The cell-specific deposition efficiency is currently limited to 0.072 (7.2% for two commercially available 6-er transwell plates), but a deposition efficiency of up to 0.57 (57%) is possible for better cell coverage of the exposure chamber. Dose-response measurements with ZnO nanoparticles (0.3-8.5 μg/cm2) showed significant differences in mRNA expression of pro-inflammatory (IL-8) and oxidative stress (HO-1) markers when comparing submerged and air-liquid interface exposures. Both exposure methods showed no cellular response below 1 μg/cm2 ZnO, which indicates that ZnO nanoparticles are not toxic at occupationally allowed exposure levels. Conclusion The ALICE

  3. Application of the Constant Exposure Time Technique to Transformation Experiments with Fission Neutrons; Failure to Demonstrate Dose-Rate Dependence

    DTIC Science & Technology

    1994-01-01

    morphologic character- linear energy YF= 21 k’Vipm. dose mean lineal energy YD istics to one with the characteristics ofa tumour cell, a = 42 keV’pm in...in icells is horizontal position at all times to ficilitate attach- described in the reports cited above. New batches or mentreattachment of mitotic ...calculationis Nerhinski et al. I )ui1iliv 198 1 at. b,. Briefly, the( mecan values of’ lineal energy init. 11 1 R. + I-3 141.2 +012 l lid based on

  4. On the Applicability of the Thermal Dose Cumulative Equivalent Minutes Metric to the Denaturation of Bovine Serum Albumin in a Polyacrylamide Tissue Phantom

    SciTech Connect

    Nandlall, Sacha D.; Arora, Manish; Schiffter, Heiko A.; Coussios, Constantin-C.

    2009-04-14

    Thermal dose has been proposed for various hyperthermic cancer treatment modalities as a measure of heat-induced tissue damage. However, the applicability of current thermal dose metrics to tissue is not well understood, particularly at the temperatures and rates of heating relevant to ablative cancer therapy using High-Intensity Focussed Ultrasound (HIFU). In this work, we assess whether the most widely employed thermal dose metric, Cumulative Equivalent Minutes (CEM), can adequately quantify heat-induced denaturation in a tissue-mimicking material (phantom) consisting of Bovine Serum Albumin (BSA) proteins embedded in a polyacrylamide matrix. The phantom is exposed to various temperature profiles and imaged under controlled lighting conditions against a black background as it denatures and becomes progressively more opaque. Under the assumption that the mean backscattered luminous intensity provides a good measure of the extent of BSA denaturation, we establish a relationship between the amount of thermal damage caused to the phantom, exposure time, and temperature. We demonstrate that, for monotonically increasing and bounded temperature profiles, the maximal degree to which the phantom can denature is dependent on the peak temperature it reaches, irrespective of exposure duration. We also show that when the CEM is computed using the commonly employed piecewise-constant approximation of the parameter R, the CEM values corresponding to the same degree of damage delivered using different temperature profiles do not agree well with each other in general.

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

    PubMed

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

    2014-06-06

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

  6. Anthrax lethal factor inhibitors as potential countermeasure of the infection.

    PubMed

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

    2014-01-01

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

  7. Effect of non-homogenous thermal stress during sub-lethal photodynamic antimicrobial chemotherapy

    NASA Astrophysics Data System (ADS)

    Gadura, N.; Kokkinos, D.; Dehipawala, S.; Cheung, E.; Sullivan, R.; Subramaniam, R.; Schneider, P.; Tremberger, G., Jr.; Holden, T.; Lieberman, D.; Cheung, T.

    2012-03-01

    Pathogens could be inactivated via a light source coupled with a photosensitizing agent in photodynamic antimicrobial chemotherapy (PACT). This project studied the effect of non-homogenous substrate on cell colony. The non-homogeneity could be controlled by iron oxide nano-particles doping in porous glassy substrates such that each cell would experience tens of hot spots when illuminated with additional light source. The substrate non-homogeneity was characterized by Atomic Force Microscopy, Transmission Electron Microscopy and Extended X-Ray Absorption Fine Structure at Brookhaven Synchrotron Light Source. Microscopy images of cell motion were used to study the motility. Laboratory cell colonies on non-homogenous substrates exhibit reduced motility similar to those observed with sub-lethal PCAT treatment. Such motility reduction on non-homogenous substrate is interpreted as the presence of thermal stress. The studied pathogens included E. coli and Pseudomonas aeruginosa. Non-pathogenic microbes Bacillus subtilis was also studied for comparison. The results show that sub-lethal PACT could be effective with additional non-homogenous thermal stress. The use of non-uniform illumination on a homogeneous substrate to create thermal stress in sub-micron length scale is discussed via light correlation in propagation through random medium. Extension to sub-lethal PACT application complemented with thermal stress would be an appropriate application.

  8. Eye-safe laser illuminators as less-than-lethal weapons

    NASA Astrophysics Data System (ADS)

    German, John D.; Adler, Dean S.

    1997-01-01

    Law enforcement and military forces are often faced with situations requiring less-than-lethal response options. Low- power, eye-safe laser illuminators have been shown to be effective, non-lethal weapons for a variety of law enforcement and other-than-war military applications. Through the effects of illumination, glare, and psychological impact; lasers can provide unequivocal warning, threat assessment based on reaction to the warning, hesitation, distraction, and reductions in combat and functional effectiveness. This paper discusses ongoing research and development by Science and Engineering Associates into laser illuminator concepts for civilian and military use. Topics include fundamental design and safety issues, laser diode requirements, and laser illuminator concepts, including a grenade shell laser system that converts a standard 40-mm grenade launcher into a laser illuminator.

  9. Perinatal-lethal Gaucher disease presenting as hydrops fetalis

    PubMed Central

    BenHamida, Emira; Ayadi, Imene; Ouertani, Ines; Chammem, Maroua; Bezzine, Ahlem; BenTmime, Riadh; Attia, Leila; Mrad, Ridha; Marrakchi, Zahra

    2015-01-01

    Perinatal-lethal Gaucher disease is very rare and is considered a variant of type 2 Gaucher disease that occurs in the neonatal period. The most distinct features of perinatal-lethal Gaucher disease are non-immune hydrops fetalis. Less common signs of the disease are hepatosplenomegaly, ichthyosis and arthrogryposis. We report a case of Gaucher's disease (type 2) diagnosed in a newborn who presented with Hydrops Fetalis. PMID:26327947

  10. Conflict Without Casualties: Non-Lethal Weapons in Irregular Warfare

    DTIC Science & Technology

    2007-09-01

    Recognizing this, in 2006 the British Royal Marines reached out to the international community and, along with U.S. Marines, established a non-lethal...obstruction. But as the scenario intensified, they moved into the city alleys for a more authentic feel. British Royal Marine Capt. Rhys Hopkins stated...89 United States Federal News Service, “ Royal Marines Teach Non-Lethal Crowd Control for 2007

  11. Field Evaluation of Lethal Ovitrap against Dengue Vectors

    DTIC Science & Technology

    2005-04-01

    AD Award Number: DAMD17-02-1-0217 TITLE: Field Evaluation of Lethal Ovitrap against Dengue Vectors PRINCIPAL INVESTIGATOR: Dr. Lane Foil CONTRACTING...2005 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Field Evaluation of Lethal Ovitrap against Dengue Vectors 5b. GRANT NUMBER DAMD17-02-1-0217 5c. PROGRAM...to effectively sample dengue mosquito vector populations, particularly Aedes aegypti for over a decade. Modifying a standard ovitrap by incorporating

  12. USE OF A PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL TO ESTIMATE ABSORBED CARBARYL DOSE IN CHILDREN AFTER TURF APPLICATION

    EPA Science Inventory

    A physiologically based pharmacokinetic (PBPK) model was developed to investigate exposure scenarios of children to carbaryl following turf application. Physiological, pharmacokinetic and pharmacodynamic parameters describing the fate and effects of carbaryl in rats were scaled ...

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

    PubMed

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

    2011-01-01

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

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

    SciTech Connect

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

    1989-05-01

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

  15. Estimation of the Dose and Dose Rate Effectiveness Factor

    NASA Technical Reports Server (NTRS)

    Chappell, L.; Cucinotta, F. A.

    2013-01-01

    Current models to estimate radiation risk use the Life Span Study (LSS) cohort that received high doses and high dose rates of radiation. Transferring risks from these high dose rates to the low doses and dose rates received by astronauts in space is a source of uncertainty in our risk calculations. The solid cancer models recommended by BEIR VII [1], UNSCEAR [2], and Preston et al [3] is fitted adequately by a linear dose response model, which implies that low doses and dose rates would be estimated the same as high doses and dose rates. However animal and cell experiments imply there should be curvature in the dose response curve for tumor induction. Furthermore animal experiments that directly compare acute to chronic exposures show lower increases in tumor induction than acute exposures. A dose and dose rate effectiveness factor (DDREF) has been estimated and applied to transfer risks from the high doses and dose rates of the LSS cohort to low doses and dose rates such as from missions in space. The BEIR VII committee [1] combined DDREF estimates using the LSS cohort and animal experiments using Bayesian methods for their recommendation for a DDREF value of 1.5 with uncertainty. We reexamined the animal data considered by BEIR VII and included more animal data and human chromosome aberration data to improve the estimate for DDREF. Several experiments chosen by BEIR VII were deemed inappropriate for application to human risk models of solid cancer risk. Animal tumor experiments performed by Ullrich et al [4], Alpen et al [5], and Grahn et al [6] were analyzed to estimate the DDREF. Human chromosome aberration experiments performed on a sample of astronauts within NASA were also available to estimate the DDREF. The LSS cohort results reported by BEIR VII were combined with the new radiobiology results using Bayesian methods.

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

    PubMed

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

    2010-06-01

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

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

    USGS Publications Warehouse

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

    1981-01-01

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

  18. Investigation into the potential of sub-lethal photodynamic antimicrobial chemotherapy (PACT) to reduce susceptibility of meticillin-resistant Staphylococcus aureus (MRSA) to antibiotics

    NASA Astrophysics Data System (ADS)

    Cassidy, C. M.; Donnelly, R. F.; Tunney, M. M.

    2009-06-01

    In PACT, a combination of a sensitising drug and visible light cause the selective destruction of microbial cells via singlet oxygen production. As singlet oxygen is a non-specific oxidizing agent and is only present during illumination, development of resistance to this treatment is thought to be unlikely. However, in response to oxidative stress, bacteria can up-regulate oxidative stress genes and associated antibiotic resistance genes. The up-regulation of these genes and potential transfer of genetic material may result in a resistant bacterial population. This study determined whether treatment of clinically isolated meticillin resistant Staphylococcus aureus (MRSA) strains with sub-lethal doses of methylene blue (MB) and meso-tetra (N-methyl-4-pyridyl) porphine tetra tosylate (TMP)-PACT resulted in reduced susceptibility to antibiotics and previously lethal PACT. Exposure of strains to sub-lethal doses of photosensitizer in combination with light had no effect on susceptibility to previously lethal photosensitization. Furthermore, exposure to sub-lethal concentrations of both photosensitizers caused no significant changes in the minimum inhibitory concentration (MIC) for each strain tested. Any differences in susceptibility were not significant as they did not cross breakpoints between resistant and susceptible for any organism or antibiotic tested. Therefore, PACT remains an attractive alternative option for treatment of MRSA infections.

  19. Novel Application of Stem Cell-Derived Neurons to Evaluate the Time- and Dose-Dependent Progression of Excitotoxic Injury

    PubMed Central

    Gut, Ian M.; Beske, Phillip H.; Hubbard, Kyle S.; Lyman, Megan E.; Hamilton, Tracey A.; McNutt, Patrick M.

    2013-01-01

    Glutamate receptor (GluR)-mediated neurotoxicity is implicated in a variety of disorders ranging from ischemia to neural degeneration. Under conditions of elevated glutamate, the excessive activation of GluRs causes internalization of pathologic levels of Ca2+, culminating in bioenergetic failure, organelle degradation, and cell death. Efforts to characterize cellular and molecular aspects of excitotoxicity and conduct therapeutic screening for pharmacologic inhibitors of excitogenic progression have been hindered by limitations associated with primary neuron culture. To address this, we evaluated glutamate-induced neurotoxicity in highly enriched glutamatergic neurons (ESNs) derived from murine embryonic stem cells. As of 18 days in vitro (DIV 18), ESNs were synaptically coupled, exhibited spontaneous network activity with neurotypic mEPSCs and expressed NMDARs and AMPARs with physiological current:voltage behaviors. Addition of 0.78–200 μM glutamate evoked reproducible time- and dose-dependent metabolic failure in 6 h, with a calculated EC50 value of 0.44 μM at 24 h. Using a combination of cell viability assays and electrophysiology, we determined that glutamate-induced toxicity was specifically mediated by NMDARs and could be inhibited by addition of NMDAR antagonists, increased extracellular Mg2+ or substitution of Ba2+ for Ca2+. Glutamate treatment evoked neurite fragmentation and focal swelling by both immunocytochemistry and scanning electron microscopy. Presentation of morphological markers of cell death was dose-dependent, with 0.78–200 μM glutamate resulting in apoptosis and 3000 μM glutamate generating a mixture of necrosis and apoptosis. Addition of neuroprotective small molecules reduced glutamate-induced neurotoxicity in a dose-dependent fashion. These data indicate that ESNs replicate many of the excitogenic mechanisms observed in primary neuron culture, offering a moderate-throughput model of excitotoxicity that combines the verisimilitude

  20. Misregulation of Sex-Lethal and Disruption of Male-Specific Lethal Complex Localization in Drosophila Species Hybrids

    PubMed Central

    Pal Bhadra, Manika; Bhadra, Utpal; Birchler, James A.

    2006-01-01

    A major model system for the study of evolutionary divergence between closely related species has been the unisexual lethality resulting from reciprocal crosses of Drosophila melanogaster and D. simulans. Sex-lethal (Sxl), a critical gene for sex determination, is misregulated in these hybrids. In hybrid males from D. melanogaster mothers, there is an abnormal expression of Sxl and a failure of localization of the male-specific lethal (MSL) complex to the X chromosome, which causes changes in gene expression. Introduction of a Sxl mutation into this hybrid genotype will allow expression of the MSL complex but there is no sequestration to the X chromosome. Lethal hybrid rescue (Lhr), which allows hybrid males from this cross to survive, corrects the SXL and MSL defects. The reciprocal cross of D. simulans mothers by D. melanogaster males exhibits underexpression of Sxl in embryos. PMID:16951071

  1. Developmental toxicity (dominant lethal mutation) study on agent lewisite. Dominant lethal study of lewisite in male rats. Final report, 15 September 1988-14 June 1990

    SciTech Connect

    Bucci, T.J.; Parker, R.M.; Dacre, J.C.; Denny, K.H.

    1993-12-01

    Lewisite (dichloro(2-chlorovinyl)arsine, Agent L) was investigated as part of the US Army Toxicological Program on Chemical Agents. The study was conducted during January - April, 1990. Dosing was performed during 3-12 January, 1990. Twenty male CD rats per dose group were given 1.5, 0.75 or 0.375 mg/kg Lewisite or vehicle control (one ml sesame seed oil) daily by gavage for 5 days. Positive control males were given one ml sesame seed oil by gavage on Day 1-4 and on Day 5 they were given an intraperitoneal injection of 100 mg/kg ethyl methanesulphonate, a known mutagen. Each male was mated to two virgin females (12 weeks of age) per counted and the uteri and contents were examined. Implantation sites were categorized as live/dead fetuses or early/late resorption. No significant differences inreproductive indices were seen between treatment groups and the control group with the exception of the positive control. Males were killed during Week 13 and necropsied. Sperm morphology/modify, testicular histopathologic evaluation and morphometric analysis of seminiferous tubule cross-sections revealed no differences among Lewisite-treated rats and rats given sesame seed oil. There was no indication of a dominant lethal mutagenic or other toxic effect on the male reproductive tract as a result of exposure to Lewisite, under the conditions of this study. The No Observable Adverse Effect Level was the highest dose used, 1.500 mg/kg.

  2. Protection from lethal and sub-lethal whole body exposures of mice to γ-radiation by Acorus calamus L.: studies on tissue antioxidant status and cellular DNA damage.

    PubMed

    Sandeep, Divyasree; Nair, Cherupally Krishnan Krishnan

    2012-01-01

    The radioprotecting activity of Acorus calamus extract after whole body exposure of mice to lethal and sub-lethal doses of γ-irradiation in terms of radiation induced mortality and damages to cellular DNA and tissue antioxidant levels were studied. A. calamus extract (250 mg/kg body weight) was orally administered to mice 1 h prior to whole body γ-radiation exposure. The antioxidant levels in the tissue homogenates of brain, liver and kidney of the irradiated mice were determined and cellular DNA damage was monitored by comet assay. Effect of administration of the extract on survival of the animals exposed to acute lethal dose of 10 Gy whole body γ-radiations was also monitored. Administration of the extract significantly increased the activities of major enzymes of the antioxidant defense system specially SOD, catalase and GPx and levels of GSH in 2, 6 and 10 Gy irradiated mice and decreased the formation MDA. The extract also decreased DNA strand breaks. The survival rate was found to be increased up to 5%. These studies highlight the role of A. calamus extract as good source of natural radioprotecting agent and its therapeutic implications for radiation-induced injuries.

  3. Assessment of shielding analysis methods, codes, and data for spent fuel transport/storage applications. [Radiation dose rates from shielded spent fuels and high-level radioactive waste

    SciTech Connect

    Parks, C.V.; Broadhead, B.L.; Hermann, O.W.; Tang, J.S.; Cramer, S.N.; Gauthey, J.C.; Kirk, B.L.; Roussin, R.W.

    1988-07-01

    This report provides a preliminary assessment of the computational tools and existing methods used to obtain radiation dose rates from shielded spent nuclear fuel and high-level radioactive waste (HLW). Particular emphasis is placed on analysis tools and techniques applicable to facilities/equipment designed for the transport or storage of spent nuclear fuel or HLW. Applications to cask transport, storage, and facility handling are considered. The report reviews the analytic techniques for generating appropriate radiation sources, evaluating the radiation transport through the shield, and calculating the dose at a desired point or surface exterior to the shield. Discrete ordinates, Monte Carlo, and point kernel methods for evaluating radiation transport are reviewed, along with existing codes and data that utilize these methods. A literature survey was employed to select a cadre of codes and data libraries to be reviewed. The selection process was based on specific criteria presented in the report. Separate summaries were written for several codes (or family of codes) that provided information on the method of solution, limitations and advantages, availability, data access, ease of use, and known accuracy. For each data library, the summary covers the source of the data, applicability of these data, and known verification efforts. Finally, the report discusses the overall status of spent fuel shielding analysis techniques and attempts to illustrate areas where inaccuracy and/or uncertainty exist. The report notes the advantages and limitations of several analysis procedures and illustrates the importance of using adequate cross-section data sets. Additional work is recommended to enable final selection/validation of analysis tools that will best meet the US Department of Energy's requirements for use in developing a viable HLW management system. 188 refs., 16 figs., 27 tabs.

  4. Development and application of a tomographic model from CT images for calculating internal dose to a pregnant woman

    NASA Astrophysics Data System (ADS)

    Shi, Chengyu

    Assessment of radiation dose and possible risk to a pregnant woman and her fetus is an important task in radiation protection. Although stylized models for male and female patients of different ages have been developed, tomographic models for pregnant women have not been developed to date. This dissertation presents an effort to construct a partial-body model of a pregnant woman from a set of CT images. The patient was 30-weeks pregnant, and the CT scan covered the portion of the body between the lower breast and the upper thigh in 70 slices, each 7 mm thick. The image resolution was 512 x 512 pixels in a 48 cm x 48 cm field. The images were carefully segmented to identify 34 organs and tissues, It has been found that the masses are different from the Reference Woman. The characteristics of the resulting model is discussed and compared with one existing stylized mathematical model for pregnant women. Based on this tomographic model, a Monte Carlo code, EGS4-VLSI, was used to derive Specific Absorbed Fractions. Monoenergetic and isotropic photon and electron emitters distributed in different source organs were assumed and the energies ranged from 10 keV to 4 MeV for photons and from 100 keV to 4 MeV for electrons. The results for high energy (>50 keV) photons showed general agreement with previous studies, however, the results for lower energy (<50 keV) photons showed differences of up to several hundreds percent for some source and target organs. For electron results, several tens of percent differences were found. Those differences can be explained by mass differences and the relative geometry differences between source and target organs. In summary, the stylized models for pregnant women are satisfactory for a very large size patient for most of the photon energies (between 50 keV and 4 MeV). However, a tomographic model has to be used to obtain acceptable dose assessments for electrons. The newly calculated SAF data set can provide the nuclear medicine dosimetry

  5. Anthrax Lethal Toxin Impairs Innate Immune Functions of Alveolar Macrophages and Facilitates Bacillus anthracis Survival

    DTIC Science & Technology

    2006-06-14

    germinate into vegetative bacteria (10, 23), which are capable of secreting anthrax lethal toxin (LT) and edema toxin . In the lymph nodes, bacteria ...inability of AM to completely eradicate bacteria suggests that intracellularly secreted lethal FIG. 5. Lethal toxin impairs bactericidal activity but...Microbiology. All Rights Reserved. Anthrax Lethal Toxin Impairs Innate Immune Functions of Alveolar Macrophages and Facilitates Bacillus anthracis

  6. Lethal and sublethal effects of a methomyl-based insecticide in Hoplobatrachus rugulosus

    PubMed Central

    Trachantong, Waret; Saenphet, Supap; Saenphet, Kanokporn; Chaiyapo, Monruedee

    2016-01-01

    The aim of this study was to investigate the lethal and sublethal toxicity of a methomyl-based insecticide in Hoplobatrachus rugulosus, as methomyl-based insecticides are applied in massive amounts and agrochemicals have effects on the decline in amphibian populations. To evaluate the toxic effects of methomyl from agricultural application, a methomyl-based insecticide containing 40% methomyl was selected. The median lethal concentration of 96 hours of methomyl exposure was 8.69 ppm for H. rugulosus tadpoles. The lethal concentration also produced severe histological damage in the livers and kidneys of the exposed tadpoles. The sublethal concentration used for methomyl was 144 ppb during the metamorphosis period. It was found that the sublethal concentration of the methomyl compound could decrease growth, metamorphosis time, and size, disturb biochemical parameters, and produce histological damage. In livers, methomyl effects increased oxidative stress and dramatically decreased the glycogen level of the treated froglets. Mononuclear infiltration, blood congestion, amorphous substances, and hepatocytes vacuolization were observed throughout liver tissue. The methomyl-based insecticide also increased oxidative stress and decreased nitric oxide levels in the kidneys of the exposed froglets. Renal tissue damage including blood congestion, amorphous substances, and Bowman’s capsule spaces reduction were found in the methomyl exposure group. The methomyl compound also produced vacuoles in various stages of oocytes, but no histological damage was found in testicular tissue. Our results indicated strong toxic effects of the methomyl-based insecticide on H. rugulosus, a broadly tolerant anuran. PMID:28190921

  7. Lethal and sublethal effects of a methomyl-based insecticide in Hoplobatrachus rugulosus.

    PubMed

    Trachantong, Waret; Saenphet, Supap; Saenphet, Kanokporn; Chaiyapo, Monruedee

    2017-01-01

    The aim of this study was to investigate the lethal and sublethal toxicity of a methomyl-based insecticide in Hoplobatrachus rugulosus, as methomyl-based insecticides are applied in massive amounts and agrochemicals have effects on the decline in amphibian populations. To evaluate the toxic effects of methomyl from agricultural application, a methomyl-based insecticide containing 40% methomyl was selected. The median lethal concentration of 96 hours of methomyl exposure was 8.69 ppm for H. rugulosus tadpoles. The lethal concentration also produced severe histological damage in the livers and kidneys of the exposed tadpoles. The sublethal concentration used for methomyl was 144 ppb during the metamorphosis period. It was found that the sublethal concentration of the methomyl compound could decrease growth, metamorphosis time, and size, disturb biochemical parameters, and produce histological damage. In livers, methomyl effects increased oxidative stress and dramatically decreased the glycogen level of the treated froglets. Mononuclear infiltration, blood congestion, amorphous substances, and hepatocytes vacuolization were observed throughout liver tissue. The methomyl-based insecticide also increased oxidative stress and decreased nitric oxide levels in the kidneys of the exposed froglets. Renal tissue damage including blood congestion, amorphous substances, and Bowman's capsule spaces reduction were found in the methomyl exposure group. The methomyl compound also produced vacuoles in various stages of oocytes, but no histological damage was found in testicular tissue. Our results indicated strong toxic effects of the methomyl-based insecticide on H. rugulosus, a broadly tolerant anuran.

  8. Dose-response modelling with two agents: application to the bioassay of oil and shoreline cleaning agents.

    PubMed

    Murado, Miguel A; Vázquez, José A; Rial, Diego; Beiras, Ricardo

    2011-01-30

    Single and joint effects of hydrocarbons and a shoreline cleaning agent (SCA) were studied by measuring the inhibition of the larval growth of sea urchin. Different dosage methods of hydrophobic compounds were compared. The results obtained in the evaluation of CytoSol toxicity revealed that the method of variable dilution of water accommodated fraction (WAF) led to the more conservative toxicological approach. Regarding to Libyan oil, the use of DMSO as carrier allowed us the evaluation of its potential toxicity in comparison with the limitations imposed to the use of WAF method. A reparametrised form of the Weibull equation was slightly modified to be useful for dose-response analysis. This was the basis for modelling single sigmoid responses, which were used to simulate biphasic profiles with addition of effects and to describe both the concentration addition (CA) and independent action (IA) hypotheses. In all cases, its descriptive ability was graphically and statistically satisfactory. The IA model was the best option to explain the combined experimental responses obtained.

  9. Variable selection models based on multiple imputation with an application for predicting median effective dose and maximum effect

    PubMed Central

    Wan, Y.; Datta, S.; Conklin, D.J.; Kong, M.

    2015-01-01

    The statistical methods for variable selection and prediction could be challenging when missing covariates exist. Although multiple imputation (MI) is a universally accepted technique for solving missing data problem, how to combine the MI results for variable selection is not quite clear, because different imputations may result in different selections. The widely applied variable selection methods include the sparse partial least-squares (SPLS) method and the penalized least-squares method, e.g. the elastic net (ENet) method. In this paper, we propose an MI-based weighted elastic net (MI-WENet) method that is based on stacked MI data and a weighting scheme for each observation in the stacked data set. In the MI-WENet method, MI accounts for sampling and imputation uncertainty for missing values, and the weight accounts for the observed information. Extensive numerical simulations are carried out to compare the proposed MI-WENet method with the other competing alternatives, such as the SPLS and ENet. In addition, we applied the MIWENet method to examine the predictor variables for the endothelial function that can be characterized by median effective dose (ED50) and maximum effect (Emax) in an ex-vivo phenylephrine-induced extension and acetylcholine-induced relaxation experiment. PMID:26412909

  10. Application of environmental dose-response models to epidemiology and animal data for the effects of ionizing radiation

    SciTech Connect

    Cothern, C.R. ); Crawford-Brown, D.J. ); Wrenn, M.E. )

    1990-01-01

    Previous extrapolations of risk from exposure to radiation at low levels (such as environmental exposures) have focused on various empirical models that have some axiomatic base, sometimes called state-vector models and usually involving linear and quadratic functions. Such models are based on representations of the physical processes occurring in irradiated cells, but do not include consideration of biological factors that could cause variability in biological response. Some mathematical models employed in environmental risk assessments (such statistically based models as the multistage, logit, probit, and Weibull) reverse this problem, showing little axiomatic support but incorporating variability, although this is not biological variability at doses of interest here. This paper presents the results of the predictions of these latter models as they apply to environmental levels of exposure to ionizing radiation compared to the estimates made by the more commonly used models. The study involves analysis of data from hard rock miner exposure to radon, exposure of rats to radon, the ingestion of radium by watch dial painters and beagle dogs, and the exposure of Japanese citizens to atomic bomb explosions. These results then are compared with inferences obtained using the more conventional axiomatic models, such as the linear/quadratic models. It is demonstrated that the results are similar, providing partial evidence that current ranges placed on risk estimates are not altered much by the selection of a particular class of models for use in quantitative risk assessment and uncertainty analysis. (Ranges are dependent on how far the data is to be extrapolated).

  11. Determining degree of saturation after application of transiently supersaturated metered dose aerosols for topical delivery of corticosteroids.

    PubMed

    Jones, Stuart A; Reid, Monica L; Brown, Marc B

    2009-02-01

    A transiently supersaturated drug delivery system has the potential to enhance topical drug delivery via heightened thermodynamic activity. The aim of this work was to quantify the degree of saturation (DS) for transiently supersaturated formulations using three traditional and one novel in vitro assessment methods. Metered dose aerosols (MDA) were formulated containing saturated levels of beclomethasone dipropionate monohydrate (BDP) or betamethasone 17-valerate (BMV) within a pressurised canister, and included ethanol (EtOH), hydrofluoroalkane 134a propellant and poly(vinyl pyrrolidone). Attempts to determine the DS via the measurement of drug flux through synthetic membranes did not correlate and was shown to be dependent on the EtOH concentration. The inability of these methods to accurately assess the drug DS may be due to the transient nature of the formulation and the volatile solvents dehydrating the membrane. A mathematical equation that used the evaporation rate of the formulation was derived to determine the theoretical DS at various time points after MDA actuation. It was shown that the MDAs became supersaturated with a high DS, this enhanced drug release from the formulation and therefore these preparations have the potential to increase the amount of drug delivered into the skin.

  12. Application of extracorporeal shock wave lithotripter (ECSWL) in orthopaedics. II. Dose-response and pressure distribution measurements.

    PubMed

    Park, J B; Park, S H; Weinstein, J N; Loening, S; Oster, D

    1991-01-01

    In order to apply the extracorporeal shock wave lithotripter (ECSWL) technique to the loosening of the bone-cement interface for the extraction of the cement during revision arthroplasty it is essential to know the dose-response characteristics. The present study shows that the number of shocks needed to break the interface between a 2- and 6-mm-thick bovine femoral bone and bone cement is similar to the fatigue behavior of a material, that is, Log(N) = C(kV) + D, where N is the number of shock impulses, kV is the power setting of the lithotripter machine in kilovolts, and C and D are constants. Iso-pressure distribution of the traveling shock wave front through a simulated bone in a Plexiglass tube using Fuji pressure film showed quantitative pressure contours from which one can understand the effective area of shock wave and its distribution. The most effective area of the shock wave was about 1.5 cm in diameter at 23 and 25 kV with pressure at least 7.0 MPa which is more than sufficient to break the bone-cement interface in tension.

  13. EFFECT OF MUTAGEN INDUCED CELL LETHALITY ON THE DOSE RESPONSE OF GERMLINE MUTATIONS. (R825810)

    EPA Science Inventory

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

  14. Dynamic RNA profiling in Plasmodium falciparum synchronized blood stages exposed to lethal doses of artesunate

    PubMed Central

    Natalang, Onguma; Bischoff, Emmanuel; Deplaine, Guillaume; Proux, Caroline; Dillies, Marie-Agnès; Sismeiro, Odile; Guigon, Ghislaine; Bonnefoy, Serge; Patarapotikul, Jintana; Mercereau-Puijalon, Odile; Coppée, Jean-Yves; David, Peter H

    2008-01-01

    Background Translation of the genome sequence of Plasmodium sp. into biologically relevant information relies on high through-put genomics technology which includes transcriptome analysis. However, few studies to date have used this powerful approach to explore transcriptome alterations of P. falciparum parasites exposed to antimalarial drugs. Results The rapid action of artesunate allowed us to study dynamic changes of the parasite transcriptome in synchronous parasite cultures exposed to the drug for 90 minutes and 3 hours. Developmentally regulated genes were filtered out, leaving 398 genes which presented altered transcript levels reflecting drug-exposure. Few genes related to metabolic pathways, most encoded chaperones, transporters, kinases, Zn-finger proteins, transcription activating proteins, proteins involved in proteasome degradation, in oxidative stress and in cell cycle regulation. A positive bias was observed for over-expressed genes presenting a subtelomeric location, allelic polymorphism and encoding proteins with potential export sequences, which often belonged to subtelomeric multi-gene families. This pointed to the mobilization of processes shaping the interface between the parasite and its environment. In parallel, pathways were engaged which could lead to parasite death, such as interference with purine/pyrimidine metabolism, the mitochondrial electron transport chain, proteasome-dependent protein degradation or the integrity of the food vacuole. Conclusion The high proportion of over-expressed genes encoding proteins exported from the parasite highlight the importance of extra-parasitic compartments as fields for exploration in drug research which, to date, has mostly focused on the parasite itself rather than on its intra and extra erythrocytic environment. Further work is needed to clarify which transcriptome alterations observed reflect a specific response to overcome artesunate toxicity or more general perturbations on the path to cellular death. PMID:18706115

  15. Changes in Tissue Cyclic AMP Concentrations following an Intravenous Lethal Dose of Cholera Enterotoxin in Rabbits,

    DTIC Science & Technology

    1981-01-13

    systemically in an animal model. For the treatment of cholera in human patients, a continuous iv administration of water, electrolytes and bicarbonate...usually reverses the disease processes of severe dehydration [16-18). However, some cholera patients still die, despite the conventional fluid treatment ...correlations with acute tubular necrosis and hypokalemic nephropathy . Ann Intern Med 52:960-975, 1960. 3. Serebro, H. A., McGonagle, T., Iber, F. L., Royall