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Sample records for hepatocarcinogenic dose induces

  1. Hepatocellular proliferation and hepatocarcinogen bioactivation in mice with diet-induced fatty liver and obesity.

    Science.gov (United States)

    Iatropoulos, M J; Duan, J-D; Jeffrey, A M; Leach, M W; Hayes, A N; Stedman, N L; Williams, G M

    2013-05-01

    Human liver cancer is in part associated with obesity and related metabolic diseases. The present study was undertaken in a mouse model of diet-induced obesity (DIO) and hepatic steatosis, conditions which can be associated with hepatic neoplasia, to determine whether the rates of cell proliferation or hepatocarcinogen bioactivation were altered in ways which could facilitate hepatocarcinogenesis. DIO mice were generated by feeding C57BL/6 (B6) male mice a high-fat diet beginning at 4 weeks of age; age-matched conventional lean (LEAN) B6 mice fed a low fat diet (10% Kcal from fat) were used for comparison. Groups of 28 week old DIO and LEAN mice were dosed with the bioactivation-dependent DNA-reactive hepatocarcinogen 2-acetylaminofluorene (AAF), at 2.24 or 22.4 mg/kg, given by gavage 3 times per week for 31 days, or received no treatment (DIO and LEAN control groups). Compared with the LEAN control group, the DIO control group had a higher mean body weight (16.5 g), higher mean absolute (1.4 g) and mean relative (25.5%) liver weights, higher (394%) liver triglyceride concentrations, and an increased incidence and severity of hepatocellular steatosis at the end of the dosing phase. The DIO control group also had a higher mean hepatocellular replicating fraction (31% increase, determined by proliferating cell nuclear antigen immunohistochemistry). Hepatocarcinogen bioactivation, based on formation of AAF DNA adducts as measured by nucleotide (32)P-postlabeling, was similar in both DIO and LEAN AAF-dosed groups. Thus, hepatocellular proliferation, but not hepatocarcinogen bioactivation, was identified as an alteration in livers of DIO mice which could contribute to their susceptibility to hepatocarcinogenesis. Copyright © 2012 Elsevier GmbH. All rights reserved.

  2. The natural basil flavonoid nevadensin protects against induction of markers of hepatocarcinogenicity by methyleugenol in male F344 rat

    NARCIS (Netherlands)

    Alhusainy, W.; Williams, G.; Jeffrey, A.M.; Iatropoulos, M.J.; Taylor, S.; Adams, T.B.; Rietjens, I.

    2014-01-01

    The alkenylbenzene methyleugenol occurs naturally in a variety of spices and herbs, including basil, and their essential oils. At high dose levels methyleugenol induces hepatocarcinogenicity in rodents following bioactivation to 1'-sulfooxymethyleugenol which forms DNA adducts. This study

  3. Prediction model of potential hepatocarcinogenicity of rat hepatocarcinogens using a large-scale toxicogenomics database

    International Nuclear Information System (INIS)

    Uehara, Takeki; Minowa, Yohsuke; Morikawa, Yuji; Kondo, Chiaki; Maruyama, Toshiyuki; Kato, Ikuo; Nakatsu, Noriyuki; Igarashi, Yoshinobu; Ono, Atsushi; Hayashi, Hitomi; Mitsumori, Kunitoshi; Yamada, Hiroshi; Ohno, Yasuo; Urushidani, Tetsuro

    2011-01-01

    The present study was performed to develop a robust gene-based prediction model for early assessment of potential hepatocarcinogenicity of chemicals in rats by using our toxicogenomics database, TG-GATEs (Genomics-Assisted Toxicity Evaluation System developed by the Toxicogenomics Project in Japan). The positive training set consisted of high- or middle-dose groups that received 6 different non-genotoxic hepatocarcinogens during a 28-day period. The negative training set consisted of high- or middle-dose groups of 54 non-carcinogens. Support vector machine combined with wrapper-type gene selection algorithms was used for modeling. Consequently, our best classifier yielded prediction accuracies for hepatocarcinogenicity of 99% sensitivity and 97% specificity in the training data set, and false positive prediction was almost completely eliminated. Pathway analysis of feature genes revealed that the mitogen-activated protein kinase p38- and phosphatidylinositol-3-kinase-centered interactome and the v-myc myelocytomatosis viral oncogene homolog-centered interactome were the 2 most significant networks. The usefulness and robustness of our predictor were further confirmed in an independent validation data set obtained from the public database. Interestingly, similar positive predictions were obtained in several genotoxic hepatocarcinogens as well as non-genotoxic hepatocarcinogens. These results indicate that the expression profiles of our newly selected candidate biomarker genes might be common characteristics in the early stage of carcinogenesis for both genotoxic and non-genotoxic carcinogens in the rat liver. Our toxicogenomic model might be useful for the prospective screening of hepatocarcinogenicity of compounds and prioritization of compounds for carcinogenicity testing. - Highlights: →We developed a toxicogenomic model to predict hepatocarcinogenicity of chemicals. →The optimized model consisting of 9 probes had 99% sensitivity and 97% specificity.

  4. Predicting the hepatocarcinogenic potential of alkenylbenzene flavoring agents using toxicogenomics and machine learning

    International Nuclear Information System (INIS)

    Auerbach, Scott S.; Shah, Ruchir R.; Mav, Deepak; Smith, Cynthia S.; Walker, Nigel J.; Vallant, Molly K.; Boorman, Gary A.; Irwin, Richard D.

    2010-01-01

    Identification of carcinogenic activity is the primary goal of the 2-year bioassay. The expense of these studies limits the number of chemicals that can be studied and therefore chemicals need to be prioritized based on a variety of parameters. We have developed an ensemble of support vector machine classification models based on male F344 rat liver gene expression following 2, 14 or 90 days of exposure to a collection of hepatocarcinogens (aflatoxin B1, 1-amino-2,4-dibromoanthraquinone, N-nitrosodimethylamine, methyleugenol) and non-hepatocarcinogens (acetaminophen, ascorbic acid, tryptophan). Seven models were generated based on individual exposure durations (2, 14 or 90 days) or a combination of exposures (2 + 14, 2 + 90, 14 + 90 and 2 + 14 + 90 days). All sets of data, with the exception of one yielded models with 0% cross-validation error. Independent validation of the models was performed using expression data from the liver of rats exposed at 2 dose levels to a collection of alkenylbenzene flavoring agents. Depending on the model used and the exposure duration of the test data, independent validation error rates ranged from 47% to 10%. The variable with the most notable effect on independent validation accuracy was exposure duration of the alkenylbenzene test data. All models generally exhibited improved performance as the exposure duration of the alkenylbenzene data increased. The models differentiated between hepatocarcinogenic (estragole and safrole) and non-hepatocarcinogenic (anethole, eugenol and isoeugenol) alkenylbenzenes previously studied in a carcinogenicity bioassay. In the case of safrole the models correctly differentiated between carcinogenic and non-carcinogenic dose levels. The models predict that two alkenylbenzenes not previously assessed in a carcinogenicity bioassay, myristicin and isosafrole, would be weakly hepatocarcinogenic if studied at a dose level of 2 mmol/kg bw/day for 2 years in male F344 rats; therefore suggesting that these

  5. Inter-laboratory comparison of turkey in ovo carcinogenicity assessment (IOCA) of hepatocarcinogens.

    Science.gov (United States)

    Enzmann, H; Brunnemann, K; Iatropoulos, M; Shpyleva, S; Lukyanova, N; Todor, I; Moore, M; Spicher, K; Chekhun, V; Tsuda, H; Williams, G

    2013-09-01

    In three independent laboratories carcinogens (diethylnitrosamine, DEN, 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone, NNK) and non-carcinogens (N-nitrosoproline, nicotine) were evaluated in turkey eggs for in ovo carcinogenicity assessment (IOCA). Compounds were injected into aseptic fertilized eggs. After incubation for 24 days, foci of altered hepatocytes (FAH), some with a pseudoglandular structure and/or signs of compression of the surrounding tissue were observed in the fetal liver. All laboratories were able to distinguish unequivocally the hepatocarcinogen-exposed groups from those exposed to non-carcinogens or the vehicle controls, based on the pre-specified evaluation parameters: tumor-like lesions, pseudoglandular areas and FAH. In addition to focal changes, only the carcinogens induced hepatocellular karyomegaly. Lower doses of the carcinogens, which did not induce FAH, were sufficient to induce hepatocellular karyomegaly. After exposure to 4 mg DEN, gall bladder agenesis was observed in all fetuses. The IOCA may be a valuable tool for early investigative studies on carcinogenicity and since it does not use rodents may complement chronic rat or mouse bioassays. Test substances that are positive in both rodents and fertilized turkey eggs are most probably trans-species carcinogens with particular significance for humans. The good concordance observed among the three laboratories demonstrates that the IOCA is a reliable and robust method. Copyright © 2012 Elsevier GmbH. All rights reserved.

  6. Transplacental exposure to inorganic arsenic at a hepatocarcinogenic dose induces fetal gene expression changes in mice indicative of aberrant estrogen signaling and disrupted steroid metabolism

    International Nuclear Information System (INIS)

    Liu Jie; Xie Yaxiong; Cooper, Ryan; Ducharme, Danica M.K.; Tennant, Raymond; Diwan, Bhalchandra A.; Waalkes, Michael P.

    2007-01-01

    Exposure to inorganic arsenic in utero in C3H mice produces hepatocellular carcinoma in male offspring when they reach adulthood. To help define the molecular events associated with the fetal onset of arsenic hepatocarcinogenesis, pregnant C3H mice were given drinking water containing 0 (control) or 85 ppm arsenic from day 8 to 18 of gestation. At the end of the arsenic exposure period, male fetal livers were removed and RNA isolated for microarray analysis using 22K oligo chips. Arsenic exposure in utero produced significant (p < 0.001) alterations in expression of 187 genes, with approximately 25% of aberrantly expressed genes related to either estrogen signaling or steroid metabolism. Real-time RT-PCR on selected genes confirmed these changes. Various genes controlled by estrogen, including X-inactive-specific transcript, anterior gradient-2, trefoil factor-1, CRP-ductin, ghrelin, and small proline-rich protein-2A, were dramatically over-expressed. Estrogen-regulated genes including cytokeratin 1-19 and Cyp2a4 were over-expressed, although Cyp3a25 was suppressed. Several genes involved with steroid metabolism also showed remarkable expression changes, including increased expression of 17β-hydroxysteroid dehydrogenase-7 (HSD17β7; involved in estradiol production) and decreased expression of HSD17β5 (involved in testosterone production). The expression of key genes important in methionine metabolism, such as methionine adenosyltransferase-1a, betaine-homocysteine methyltransferase and thioether S-methyltransferase, were suppressed. Thus, exposure of mouse fetus to inorganic arsenic during a critical period in development significantly alters the expression of various genes encoding estrogen signaling and steroid or methionine metabolism. These alterations could disrupt genetic programming at the very early life stage, which could impact tumor formation much later in adulthood

  7. Mutagenicity of the potent rat hepatocarcinogen 6BT to the liver of transgenic (lacI) rats: consideration of a reduced mutation assay protocol.

    Science.gov (United States)

    Lefevre, P A; Tinwell, H; Ashby, J

    1997-01-01

    6-(p-dimethylaminophenylazo)benzothiazole (6BT) is an unusually potent rat hepatocarcinogen, producing large malignant liver tumours after only 2-3 months of dietary administration in a riboflavin-deficient diet. This azocarcinogen has been evaluated in a Big Blue F344 transgenic rat (lacI) gene mutation assay. In a reproduction of the early stages of the carcinogenesis bioassay of this agent, rats were maintained on a riboflavin-deficient diet and were given 10 consecutive daily doses of 6BT (10 mg/kg) by oral gavage. The animals were killed and the livers examined 11 days after the final dose. The livers of 6BT-treated rats showed evidence of hepatocellular hypertrophy in centrolobular areas, with some indication of an increased incidence of mitotic figures. An approximately 10-fold increase in the mutation frequency of DNA isolated from an aliquot of the combined liver homogenates of 6BT-treated rats was observed over that obtained from an equivalent aliquot from control animals. Examination of DNA samples isolated from the livers of individual animals confirmed that 6BT was mutagenic in Big Blue rat livers. These data extend the sensitivity of this transgenic assay to include azo hepatocarcinogens. The determination of mutation frequencies using pooled tissue samples represented a major resource-saving adaptation of the assay protocol in the present study; the general advantages and disadvantages of this practice are discussed.

  8. Carcinogenesis induced by low-dose radiation

    Directory of Open Access Journals (Sweden)

    Piotrowski Igor

    2017-11-01

    Full Text Available Although the effects of high dose radiation on human cells and tissues are relatively well defined, there is no consensus regarding the effects of low and very low radiation doses on the organism. Ionizing radiation has been shown to induce gene mutations and chromosome aberrations which are known to be involved in the process of carcinogenesis. The induction of secondary cancers is a challenging long-term side effect in oncologic patients treated with radiation. Medical sources of radiation like intensity modulated radiotherapy used in cancer treatment and computed tomography used in diagnostics, deliver very low doses of radiation to large volumes of healthy tissue, which might contribute to increased cancer rates in long surviving patients and in the general population. Research shows that because of the phenomena characteristic for low dose radiation the risk of cancer induction from exposure of healthy tissues to low dose radiation can be greater than the risk calculated from linear no-threshold model. Epidemiological data collected from radiation workers and atomic bomb survivors confirms that exposure to low dose radiation can contribute to increased cancer risk and also that the risk might correlate with the age at exposure.

  9. Metabolism and binding to DNA of a novel hepatocarcinogen: methapyrilene

    International Nuclear Information System (INIS)

    Lampe, M.A.

    1987-01-01

    The purpose of this study was to characterize the metabolism and macromolecular binding of [ 14 C]-MPH. When rats were treated for up to sixteen weeks with 1000 ppm MPH, they excreted at least six MPH related compounds in their urine including 2-hydroxymethyl-thiophene, N-2-pyridyl-N'-dimethylethylenediamine, (5-hydroxypyridyl)methapyrilene, (5-hydroxypyridyl)N-2-pyridyl-N'-dimethylethylenediamine and MPH. In vitro metabolism is also affected by chronic treatment of rats with MPH, with the most remarkable change observed being an increase in the mass balance to approximately 100% after 8 or 16 weeks pretreatment. Metabolism of MPH by rat liver microsomes is dependent on the activity of cytochrome P-450 enzymes, as metabolism in vitro was inhibited by the addition 2,4-dichloro-6-phenylphenoxyethylamine (DPEA) and 2-diethylaminoethyl-2,2-diphenylvalerate (SKF-525A). Treatment of rats with phenobarbital or 3-methylcholanthrene induced metabolism of MPH while pretreatment of rats with isosafole or pregnenolone-16α-carbonitrile had a more selective effect on MPH metabolism, and only increased the formation of methapyrilene-amide

  10. DNA adducts and liver DNA replication in rats during chronic exposure to N-nitrosodimethylamine (NDMA) and their relationships to the dose-dependence of NDMA hepatocarcinogenesis.

    Science.gov (United States)

    Souliotis, Vassilis L; Henneman, John R; Reed, Carl D; Chhabra, Saranjit K; Diwan, Bhalchandra A; Anderson, Lucy M; Kyrtopoulos, Soterios A

    2002-03-20

    Exposure of rats to the hepatocarcinogen N-nitrosodimethylamine (NDMA) (0.2-2.64 ppm in the drinking water) for up to 180 days resulted in rapid accumulation of N7- and O6-methylguanine in liver and white blood cell DNA, maximum adduct levels being reached within 1-7 days, depending on the dose. The levels of both adducts remained constant up to treatment day 28, subsequently declining slowly to about 40% of maximal levels for the liver and 60% for white blood cells by day 180. In order to elucidate the role of DNA replication in NDMA hepatocarcinogenesis, changes in liver cell labeling index (LI) were also measured on treatment days 21, 120 and 180. Although the time- and dose-dependence of the observed effects were complex, a clear trend towards increased rates of hepatocyte LI, as indicated by BrdU incorporation, with increasing NDMA doses was evident, particularly above 1 ppm, a concentration above which NDMA hepatocarcinogenicity is known to increase sharply. In contrast, no increase in Kupffer cell DNA replication was found at any of the doses employed, in accordance with the low susceptibility of these cells to NDMA-induced carcinogenesis. No significant increase in the occurrence of necrotic or apoptotic cells was noted under the treatment conditions employed. These results suggest that, in addition to the accumulation of DNA damage, alterations in hepatocyte DNA replication during the chronic NDMA exposure may influence the dose-dependence of its carcinogenic efficacy.

  11. Evaluation of a liver micronucleus assay in young rats (IV): a study using a double-dosing/single-sampling method by the Collaborative Study Group for the Micronucleus Test (CSGMT)/Japanese Environmental Mutagen Society (JEMS)-Mammalian Mutagenicity Study Group (MMS).

    Science.gov (United States)

    Takasawa, Hironao; Suzuki, Hiroshi; Ogawa, Izumi; Shimada, Yasushi; Kobayashi, Kazuo; Terashima, Yukari; Matsumoto, Hirotaka; Oshida, Keiyu; Ohta, Ryo; Imamura, Tadashi; Miyazaki, Atsushi; Kawabata, Masayoshi; Minowa, Shigenori; Maeda, Akihisa; Hayashi, Makoto

    2010-04-30

    A collaborative study was conducted to evaluate whether a liver micronucleus assay using four-week-old male F344 rats can be used to detect genotoxic rat hepatocarcinogens using double-dosing with a single-sampling 4 days after the second dose. The assay methods were thoroughly validated by the seven laboratories involved in the study. Seven chemicals, 2,4-diaminotoluene, diethyl nitrosamine, p-dimethylaminoazobenzene, 1,2-dimethylhydrazine dihydrochloride, 2,4-dinitrotolunene, 2,6-dinitrotoluene and mitomycin C, known to produce positive responses in the single-dosing/triple-sampling method were selected for use in the present study, and each chemical was examined in two laboratories with the exception of 2,4-dinitrotolunene. Although several of the compounds were examined at lower doses for reasons of toxicity than in the single-dosing/triple-sampling method, all chemicals tested in the present study induced micronuclei in liver cells indicating a positive result. These findings suggest that the liver micronucleus assay can be used in young rats to detect genotoxic rat hepatocarcinogens using a double-dosing/single-sampling procedure. Further, the number of animals used in the liver micronucleus assay can be reduced by one-third to a half by using the double-dosing/single-sampling method. This reduction in animal numbers also has significant savings in time and resource for liver perfusion and hepatocyte isolation. Copyright 2010 Elsevier B.V. All rights reserved.

  12. Motion-induced dose artifacts in helical tomotherapy

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    Kim, Bryan; Chen, Jeff; Battista, Jerry [London Regional Cancer Program, London Health Sciences Centre, London, ON (Canada); Kron, Tomas [Peter MacCallum Cancer Center, Melbourne (Australia)], E-mail: bryan.kim@lhsc.on.ca

    2009-10-07

    Tumor motion is a particular concern for a complex treatment modality such as helical tomotherapy, where couch position, gantry rotation and MLC leaf opening all change with time. In the present study, we have investigated the impact of tumor motion for helical tomotherapy, which could result in three distinct motion-induced dose artifacts, namely (1) dose rounding, (2) dose rippling and (3) IMRT leaf opening asynchronization effect. Dose rounding and dose rippling effects have been previously described, while the IMRT leaf opening asynchronization effect is a newly discovered motion-induced dose artifact. Dose rounding is the penumbral widening of a delivered dose distribution near the edges of a target volume along the direction of tumor motion. Dose rippling is a series of periodic dose peaks and valleys observed within the target region along the direction of couch motion, due to an asynchronous interplay between the couch motion and the longitudinal component of tumor motion. The IMRT leaf opening asynchronization effect is caused by an asynchronous interplay between the temporal patterns of leaf openings and tumor motion. The characteristics of each dose artifact were investigated individually as functions of target motion amplitude and period for both non-IMRT and IMRT helical tomotherapy cases, through computer simulation modeling and experimental verification. The longitudinal dose profiles generated by the simulation program agreed with the experimental data within {+-}0.5% and {+-}1.5% inside the PTV region for the non-IMRT and IMRT cases, respectively. The dose rounding effect produced a penumbral increase up to 20.5 mm for peak-to-peak target motion amplitudes ranging from 1.0 cm to 5.0 cm. Maximum dose rippling magnitude of 25% was calculated, when the target motion period approached an unusually high value of 10 s. The IMRT leaf opening asynchronization effect produced dose differences ranging from -29% to 7% inside the PTV region. This information

  13. Low doses of neutrons induce changes in gene expression

    International Nuclear Information System (INIS)

    Woloschak, G.E.; Chang-Liu, C.M.; Panozzo, J.; Libertin, C.R.

    1993-01-01

    Studies were designed to identify genes induced following low-dose neutron but not following γ-ray exposure in fibroblasts. Our past work had shown differences in the expression of β-protein kinase C and c-fos genes, both being induced following γ-ray but not neutron exposure. We have identified two genes that are induced following neutron, but not γ-ray, exposure: Rp-8 (a gene induced by apoptosis) and the long terminal repeat (LTR) of the human immunodeficiency (HIV). Rp-8 mRNA induction was demonstrated in Syrian hamster embryo fibroblasts and was found to be induced in cells exposed to neutrons administered at low (0.5 cGy/min) and at high dose rate (12 cGy/min). The induction of transcription from the LTR of HIV was demonstrated in HeLa cells bearing a transfected construct of the chloramphenicol acetyl transferase (CAT) gene driven by the HIV-LTR promoter. Measures of CAT activity and CAT transcripts following irradiation demonstrated an unresponsiveness to γ rays over a broad range of doses. Twofold induction of the HIV-LTR was detected following neutron exposure (48 cGy) administered at low (0.5 cGy/min) but not high (12 cGy/min) dose rates. Ultraviolet-mediated HIV-LTR induction was inhibited by low-dose-rate neutron exposure

  14. Beta induced Bremsstrahlung dose rate in concrete shielding

    International Nuclear Information System (INIS)

    Manjunatha, H.C.

    2013-01-01

    Dosimetric study of beta-induced Bremsstrahlung in concrete is importance in the field of radiation protection. The efficiency, intensity and dose rate of beta induced Bremsstrahlung by 113 pure beta nuclides in concrete shielding is computed. The Bremsstrahlung dosimetric parameters such as the efficiency (yield), Intensity and dose rate of Bremsstrahlung are low for 199 Au and high for 104 Tc in concrete. The efficiency, Intensity and dose rate of Bremsstrahlung increases with maximum energy of beta nuclide (Emax) and modified atomic number (Zmod) of the target. The estimated Bremsstrahlung efficiency, Intensity and dose rate are useful in the calculations photon track-length distributions. These parameters are useful to determine the quality and quantity of the radiation (known as the source term). Precise estimation of this source term is very important in planning of radiation shielding. (author)

  15. Low dose DDT inhibition of hepatocarcinogenesis initiated by diethylnitrosamine in male rats: Possible mechanisms

    International Nuclear Information System (INIS)

    Kushida, Masahiko; Sukata, Tokuo; Uwagawa, Satoshi; Ozaki, Keisuke; Kinoshita, Anna; Wanibuchi, Hideki; Morimura, Keiichirou; Okuno, Yasuyoshi; Fukushima, Shoji

    2005-01-01

    Previously we reported a tendency for reduction of the development of glutathione-S-transferase placental form (GST-P) positive foci, recognized as preneoplastic changes in rat liver, by a low dose of 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethane (DDT), which belongs to the same group of hepatic cytochrome P-450 inducers as phenobarbital and is itself a non-genotoxic hepatocarcinogen. In order to clarify the biological significance of this phenomenon, we investigated the reproducibility and changes in other parameters using an initiation-promotion model in which male F344 rats were treated with DDT at doses of 0, 0.005, 0.5, 500 ppm in the diet for 11 or 43 weeks after initiation of hepatocarcinogenesis with N-diethylnitrosamine (DEN). When 500 ppm DDT was applied, the formation of GST-P positive foci and tumor were markedly elevated. In contrast, induction of GST-P positive foci and liver tumors tended to be inhibited at a dose of 0.005 ppm, correlating with protein levels of cytochrome P450 2B1 and 3A2 (CYP2B1 and 3A2) and generation of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage. mRNA levels for 8-oxoguanine glycosylase 1 (OGG1), an 8-OHdG repair enzyme, connexin 32 (Cx32), a major component of Gap junctions, and hepatic nuclear factor 1α (HNF-1α), a Cx32 regulator, were inversely correlated with GST-P positive foci and tumor formation. These results indicate that low dose DDT may indeed exhibit inhibitory effects on chemically initiated-rat hepatocarcinogenicity, in contrast to the promotion observed with high doses, and that this is related to changes in metabolizing enzymes, cell communication, and DNA damage and its repair

  16. Dose rate effectiveness in radiation-induced teratogenesis in mice

    International Nuclear Information System (INIS)

    Kato, F.; Ootsuyama, A.; Norimura, T.

    2000-01-01

    To investigate the role of p53 gene in tissue repair of teratogenic injury, we compared incidence of radiation-induced malformations in homozygous p53(-/-) mice, heterozygous p53(+/-) mice and wild-type p53(+/+) mice. After X-irradiation with 2 Gy at high dose rate on 9.5 days of gestation, p53(-/-) mice showed higher incidences of anomalies and higher resistance to prenatal deaths than p53(+/+) mice. This reciprocal relationship of radiosensitivity to anomalies and deaths supports the notion that embryos or fetuses have a p53-dependent 'guardian' that aborts cells bearing radiation-induced teratogenic DNA damage. In fact, after X-irradiation, the number of apoptotic cells was greatly increased in p53(+/+) fetuses but not in p53(-/-) fetuses. The same dose of γ-ray exposure at low dose rate on 9.5-10.5 day of gestation produced significant reduction of radiation-induced malformation in p53(+/+) and p53(+/-) mice, remained teratogenic for p53(-/-) mice. These results suggest that complete elimination of teratogenic damage from irradiated tissues requires the concerted cooperation of two mechanisms; proficient DNA repair and the p53-dependent apoptotic tissue repair. When concerted DNA repair and apoptosis functions efficiently, there is a threshold dose-rate for radiation-induced malformations. (author)

  17. Low-Dose Radiation Induces Genes Promoting Cell Survival

    International Nuclear Information System (INIS)

    Liu, Shu-Zheng; Chen, Dong; Mu, Ying

    1999-01-01

    Apoptosis is an important process controlling homeostasis of the body. It is influenced by stimuli constantly arising from the external and internal environment of the organism. It is well known that radiation could induce apoptosis of cells in vitro and in vivo. However, the dose-effect relationship of apoptosis extending to the low-dose range has scarcely been studied. Here, the molecular basis of the phenomenon is explored by examining the changes in expression of some of the proapoptotic and antiapoptotic genes

  18. Cystoid Macular Edema Induced by Low Doses of Nicotinic Acid

    Directory of Open Access Journals (Sweden)

    Daniela Domanico

    2013-01-01

    Full Text Available Cystoid macular edema (CME is a condition that involves the macula, causing painless vision loss. In this paper, we report a case of niacin-induced bilateral cystoid macular edema (CME in a middle-age woman taking low dose of niacin (18 mg of nicotinic acid. Optical coherence tomography (OCT showed retinal thickening and cystoid spaces in both eyes, whereas fluorescein angiography (FA; HRA 2, Heidelberg Engineering revealed the absence of fluorescein leakage also in later phases. Four weeks after discontinuation of therapy there were a complete disappearance of macular edema at funduscopic examination and an improvement of visual acuity in both eyes. Furthermore OCT showed a normal retinal profile in both eyes. In our opinion considering the wide availability of niacin, medical monitoring and periodical examination should be considered during niacin administration. To our knowledge, this is the first report in the literature that described the very low-dose niacin-induced bilateral niacin maculopathy.

  19. Low-dose radiation-induced endothelial cell retraction

    International Nuclear Information System (INIS)

    Kantak, S.S.; Onoda, J.M.; Diglio, C.A.; Harper Hospital, Detroit, MI

    1993-01-01

    The data presented here are representative of a series of studies designed to characterize low-dose radiation effects on pulmonary microvascular endothelium. Data suggest that post-irradiation lung injuries (e.g. oedema) may be induced with only a single fraction of therapeutic radiation, and thus microscopic oedema may initiate prior to the lethal effects of radiation on the microvascular endothelium, and much earlier than would be suggested by the time course for clinically-detectable oedema. (author)

  20. Low dose radiation prevents doxorubicin-induced cardiotoxicity.

    Science.gov (United States)

    Jiang, Xin; Hong, Yaqiong; Zhao, Di; Meng, Xinxin; Zhao, Lijing; Du, Yanwei; Wang, Zan; Zheng, Yan; Cai, Lu; Jiang, Hongyu

    2018-01-02

    This study aimed to develop a novel and non-invasive approach, low-dose radiation (LDR, 75 mGy X-rays), to prevent doxorubicin (DOX)-induced cardiotoxicity. BALB/c mice were randomly divided into five groups, Control, LDR (a single exposure), Sham (treated same as LDR group except for irradiation), DOX (a single intraperitoneal injection of DOX at 7.5 mg/kg), and LDR/DOX (received LDR and 72 h later received DOX). Electrocardiogram analysis displayed several kinds of abnormal ECG profiles in DOX-treated mice, but less in LDR/DOX group. Cardiotoxicity indices included histopathological changes, oxidative stress markers, and measurements of mitochondrial membrane permeability. Pretreatment of DOX group with LDR reduced oxidative damages (reactive oxygen species formation, protein nitration, and lipid peroxidation) and increased the activities of antioxidants (superoxide dismutase and glutathione peroxidase) in the heart of LDR/DOX mice compared to DOX mice. Pretreatment of DOX-treated mice with LDR also decreased DOX-induced cardiac cell apoptosis (TUNEL staining and cleaved caspase-3) and mitochondrial apoptotic pathway (increased p53, Bax, and caspase-9 expression and decreased Bcl2 expression and ΔΨm dissipation). These results suggest that LDR could induce adaptation of the heart to DOX-induced toxicity. Cardiac protection by LDR may attribute to attenuate DOX-induced cell death via suppressing mitochondrial-dependent oxidative stress and apoptosis signaling.

  1. Radiation induced skeletal changes in beagle: dose rates, dose, and age effect analysis from 226Ra

    International Nuclear Information System (INIS)

    Momeni, M.H.; Williams, J.R.; Rosenblatt, L.S.

    1976-01-01

    Radiation-induced skeletal injury (E) and the rate of skeletal injury were studied as a function of time and dose in beagles administered 226 Ra Cl 2 in eight semimonthly iv injections starting at 2, 4, or 14 months of age. Skeletal changes were evaluated with a radiographic x-ray scoring system in 20 skeletal regions; each region was scored on a 0 to 6 scale. Bone changes in six regions of humeri were qualitatively analyzed for comparison with total skeletal changes. Skeletal changes were classified by endosteal or periosteal cortical sclerosis and thickening, fractures, osteolytic lesions, and trabecular coarsening

  2. Radiation-induced hypopituitarism is dose-dependent

    International Nuclear Information System (INIS)

    Littley, M.D.; Shalet, S.M.; Beardwell, C.G.; Robinson, E.L.; Sutton, M.L.

    1989-01-01

    Radiation-induced hypopituitarism has been studies prospectively for up to 12 years in 251 adult patients treated for pituitary disease with external radiotherapy, ranging in dose from 20 Gy in eight fractions over 11 days to 45 Gy in 15 fractions over 21 days. Ten further patients were studied 2-4 years after whole-body irradiation for haematological malignancies using 12 Gy in six fractions over 3 days and seven patients were studied 3-11 years after whole-brain radiotherapy for a primary brain tumour (30 Gy, eight fractions, 11 days). Five years after treatment, patients who received 20 Gy had an incidence of TSH deficiency of 9% and in patients treated with 35-37 Gy, 40 Gy and 42-45 Gy, the incidence of TSH deficiency increased significantly with increasing dose. A similar relationship was observed for both ACTH and gonadotrophin deficiencies when the 20 Gy group was compared to patients treated with 35-45 Gy. Growth hormone deficiency was universal by 5 years over the dose range 35-45 Gy. In seven patients who were treated with 30 Gy in eight fractions over 11 days, deficiencies were observed at a similar frequency to the 40 Gy group (15 fractions, 21 days). No evidence of pituitary dysfunction was detected in the ten patients who received 12 Gy (six fractions, 3 days). (author)

  3. Galactic cosmic ray-induced radiation dose on terrestrial exoplanets.

    Science.gov (United States)

    Atri, Dimitra; Hariharan, B; Grießmeier, Jean-Mathias

    2013-10-01

    This past decade has seen tremendous advancements in the study of extrasolar planets. Observations are now made with increasing sophistication from both ground- and space-based instruments, and exoplanets are characterized with increasing precision. There is a class of particularly interesting exoplanets that reside in the habitable zone, which is defined as the area around a star where the planet is capable of supporting liquid water on its surface. Planetary systems around M dwarfs are considered to be prime candidates to search for life beyond the Solar System. Such planets are likely to be tidally locked and have close-in habitable zones. Theoretical calculations also suggest that close-in exoplanets are more likely to have weaker planetary magnetic fields, especially in the case of super-Earths. Such exoplanets are subjected to a high flux of galactic cosmic rays (GCRs) due to their weak magnetic moments. GCRs are energetic particles of astrophysical origin that strike the planetary atmosphere and produce secondary particles, including muons, which are highly penetrating. Some of these particles reach the planetary surface and contribute to the radiation dose. Along with the magnetic field, another factor governing the radiation dose is the depth of the planetary atmosphere. The higher the depth of the planetary atmosphere, the lower the flux of secondary particles will be on the surface. If the secondary particles are energetic enough, and their flux is sufficiently high, the radiation from muons can also impact the subsurface regions, such as in the case of Mars. If the radiation dose is too high, the chances of sustaining a long-term biosphere on the planet are very low. We have examined the dependence of the GCR-induced radiation dose on the strength of the planetary magnetic field and its atmospheric depth, and found that the latter is the decisive factor for the protection of a planetary biosphere.

  4. Radiation Sialadenitis Induced by High-dose Radioactive Iodine Therapy

    International Nuclear Information System (INIS)

    Jeong, Shin Young; Lee, Jaetae

    2010-01-01

    Radioactive iodine ( 131 I) is accumulated in the thyroid tissue and plays an important role in the treatment of differentiated papillary and follicular cancers after thyroidectomy. Simultaneously, 131 I is concentrated in the salivary glands and secreted into the saliva. Dose-related damage to the salivary parenchyma results from the 131 I irradiation. Salivary gland swelling and pain, usually involving the parotid, can be seen. The symptoms may develop immediately after a therapeutic dose of 131 I and/or months later and progress in intensity with time. In conjunction with the radiation sialadenitis, secondary complications reported include xerostomia, taste alterations, infection, increases in caries, facial nerve involvement, candidiasis, and neoplasia. Prevention of 131 I sialadenitis may involve the use of sialogogic agents to hasten the transit time of the radioactive iodine through the salivary glands. However, studies are not available to delineate the efficacy of this approach. Treatment of the varied complications that may develop encompass numerous approaches and include gland massage, sialogogic agents, duct probing, antibiotics, mouthwashes, good oral hygiene, and adequate hydration. Recently interventional sialoendoscopy has been introduced an effective tool for the management of patients with 131 I-induced sialadenitis that is unresponsive to medical treatment.

  5. Radiation Sialadenitis Induced by High-dose Radioactive Iodine Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Jeong, Shin Young; Lee, Jaetae [Kyungpook National University Hospital, Daegu (Korea, Republic of)

    2010-06-15

    Radioactive iodine ({sup 131}I) is accumulated in the thyroid tissue and plays an important role in the treatment of differentiated papillary and follicular cancers after thyroidectomy. Simultaneously, {sup 131}I is concentrated in the salivary glands and secreted into the saliva. Dose-related damage to the salivary parenchyma results from the {sup 131}I irradiation. Salivary gland swelling and pain, usually involving the parotid, can be seen. The symptoms may develop immediately after a therapeutic dose of {sup 131}I and/or months later and progress in intensity with time. In conjunction with the radiation sialadenitis, secondary complications reported include xerostomia, taste alterations, infection, increases in caries, facial nerve involvement, candidiasis, and neoplasia. Prevention of {sup 131}I sialadenitis may involve the use of sialogogic agents to hasten the transit time of the radioactive iodine through the salivary glands. However, studies are not available to delineate the efficacy of this approach. Treatment of the varied complications that may develop encompass numerous approaches and include gland massage, sialogogic agents, duct probing, antibiotics, mouthwashes, good oral hygiene, and adequate hydration. Recently interventional sialoendoscopy has been introduced an effective tool for the management of patients with {sup 131}I-induced sialadenitis that is unresponsive to medical treatment.

  6. Studies on adaptive response of lymphocyte transformation induced by low-dose irradiation

    International Nuclear Information System (INIS)

    Du Zeji; Su Liaoyuan; Tian Hailin; Zou Huawei

    1995-10-01

    Human peripheral blood lymphocytes stimulated by mitogen in vitro for 24 h were exposed to low-dose γ-ray irradiation (0.5∼4.0 cGy, adaptive dose). They showed an adaptive response to the inhibition of 3 H-TdR incorporation by subsequent higher acute doses of γ-ray (challenge dose). At the interval of 24 h between adaptive dose and challenge dose, the strongest adaptive response induced by low-dose irradiation was found. It is also found that the response induced by 1.0 cGy of adaptive dose was more obvious than that by other doses and that 3.0 Gy of challenge dose produced the strongest adaptive response. As the challenge doses increased, the adaptive response reduced. (2 figs., 2 tabs.)

  7. Low level dose induced chromosome aberrations in human blood lymphocytes

    International Nuclear Information System (INIS)

    Pohl-Rueling, J.

    1992-01-01

    Unstable structural aberrations in chromosomes of human blood lymphocytes cannot be used as biological dosemeters in the low dose range, when extrapolating from high doses using a linear dose response, as required by the original formula of the dual radiation action theory. A survey is given of experimental dose-response curves of chromosome aberrations, obtained in investigations not only by this institute, in cooperation with many other laboratories, but also by various authors in different areas of the world. The results are not compatible with the predicted linear dose relationships at in vivo dose ranges up to 30 mGy.y -1 . The aberration frequencies rise sharply with dose within the normal environmental exposure up to about twice that level. At higher doses, aberration frequencies increase less rapidly and reach a plateau. Some in vitro experiments of various authors with higher doses of low LET radiations, up to about 400 mGy have found dose responses with steps. (author)

  8. Low-dose radiation-induced adaptive response in bone marrow cells of mice

    International Nuclear Information System (INIS)

    Farooqi, Zeba; Kesavan, P.C.

    1993-01-01

    Using bone marrow cells of whole body irradiated mice, the cytogenetic adaptive response induced by low conditioning doses of gamma-rays was investigated. The conditioning doses (0.025 and 0.05 Gy) were given at a dose-rate of 1.67 Gy/min. The challenging dose of 1 Gy was given at a dose-rate of 0.045 Gy/s. The challenging dose was given at different time intervals after the conditioning dose. The time intervals between the conditioning dose and challenging dose were 2, 7.5, 13, 18.5 and 24 h. When the time interval between the conditioning dose and the challenging dose was 2 h, both conditioning doses (0.025 and 0.05 Gy) reduced the frequency of MNPCEs and chromosomal aberrations in the bone marrow cells. The data collected at different time intervals (7.5, 13, 18.5 h) reveal that the radioadaptive response persisted for a longer time when the lower conditioning dose (0.025 Gy) was given. With the higher conditioning dose (0.05 Gy), the radioadaptive response disappeared after a time interval of 13 h. When the time interval between the conditioning dose and the challenging doses was 18.5 or 24 h, only the lower conditioning dose appeared effective in inducing the radioadaptive response

  9. Study on cellular survival adaptive response induced by low dose irradiation of 153Sm

    International Nuclear Information System (INIS)

    Zhu Shoupeng; Xiao Dong

    1999-01-01

    The present study engages in determining whether low dose irradiation of 153 Sm could cut down the responsiveness of cellular survival to subsequent high dose exposure of 153 Sm so as to make an inquiry into approach the protective action of adaptive response by second irradiation of 153 Sm. Experimental results indicate that for inductive low dose of radionuclide 153 Sm 3.7 kBq/ml irradiated beforehand to cells has obvious resistant effect in succession after high dose irradiation of 153 Sm 3.7 x 10 2 kBq/ml was observed. Cells exposed to low dose irradiation of 153 Sm become adapted and therefore the subsequent cellular survival rate induced by high dose of 153 Sm is sufficiently higher than high dose of 153 Sm merely. It is evident that cellular survival adaptive response could be induced by pure low dose irradiation of 153 Sm only

  10. Study of genomic instability induced by low dose ionizing radiation

    International Nuclear Information System (INIS)

    Seoane, A.; Crudeli, C.; Dulout, F.

    2006-01-01

    The crews of commercial flights and services staff of radiology and radiotherapy from hospitals are exposed to low doses of ionizing radiation. Genomic instability includes those adverse effects observed in cells, several generations after the exposure occurred. The purpose of this study was to analyze the occurrence of genomic instability by very low doses of ionizing radiation [es

  11. Review of low dose-rate epidemiological studies and biological mechanisms of dose-rate effects on radiation induced carcinogenesis

    International Nuclear Information System (INIS)

    Iwasaki, Toshiyasu; Otsuka, Kensuke; Yoshida, Kazuo

    2015-01-01

    Radiation protection system adopts the linear non-threshold model with using dose and dose-rate effectiveness factor (DDREF). The dose-rate range where DDREF is applied is below 100 mGy per hour, and it is regarded that there are no dose-rate effects at very low dose rate, less than of the order of 10 mGy per year, even from the biological risk evaluation model based on cellular and molecular level mechanisms for maintenance of genetic integrity. Among low dose-rate epidemiological studies, studies of residents in high natural background areas showed no increase of cancer risks at less than about 10 mGy per year. On the other hand, some studies include a study of the Techa River cohort suggested the increase of cancer risks to the similar degree of Atomic bomb survivor data. The difference of those results was supposed due to the difference of dose rate. In 2014, International Commission on Radiological Protection opened a draft report on stem cell biology for public consultations. The report proposed a hypothesis based on the new idea of stem cell competition as a tissue level quality control mechanism, and suggested that it could explain the dose-rate effects around a few milligray per year. To verify this hypothesis, it would be needed to clarify the existence and the lowest dose of radiation-induced stem cell competition, and to elucidate the rate of stem cell turnover and radiation effects on it. As for the turnover, replenishment of damaged stem cells would be the important biological process. It would be meaningful to collect the information to show the difference of dose rates where the competition and the replenishment would be the predominant processes. (author)

  12. Alterations in offspring behavior induced by chronic prenatal cocaine dosing.

    Science.gov (United States)

    Smith, R F; Mattran, K M; Kurkjian, M F; Kurtz, S L

    1989-01-01

    Sperm-positive female Long-Evans hooded rats were dosed subcutaneously with 10 mg/kg/day cocaine or an equal volume of vehicle (0.9% sterile saline) from gestation day 4 (GD4) through GD18. Offspring were assessed for development of negative geotaxis, righting reflex, spontaneous alternation, and open field activity, and for adult behaviors including DRL-20 acquisition, water maze, visual discrimination, barbiturate sleep time, shuttlebox avoidance, footshock sensitivity, and tail flick latency. Cocaine dosing produced no significant effects on dam weight gain, any measure of litter size and weight, or early postnatal behavioral tests, but there were significant drug effects on development of spontaneous alternation, development of open field activity, DRL-20 acquisition, water maze performance, tail flick, and footshock sensitivity. These data suggest that chronic administration of a modest dose of cocaine during gestation in the rat alters a number of behaviors in the offspring.

  13. Okadaic acid for radiation dose estimation using drug-induced premature chromosome condensation

    International Nuclear Information System (INIS)

    Wang Chunyan; Zhang Wei; Su Xu

    2005-01-01

    Objective: To establish simple biological method for high irradiation dose estimation using drug-induced prematurely condensed chromosomes (PCC) aberrations. Methods: Peripheral blood was taken from healthy adults and irradiated by 0, 1, 2, 5, 10, 15, 20 and 25 Gy 60 Co γ-rays. Then the blood samples were cultured for 48 hrs. One hr before the end of culture , okadaic acid was added into culture medium to induce PCC rings, which were counted for each dose point. Results: The yield of PCC rings was increased with the dose of radiation until 20 Gy. Within the range of 1 to 20 Gy, there was a good dose-response relationship between the yield of PCC rings and radiation dose. Conclusion: Compared with the analysis of frequency of dicentrics, the yield of PCC rings could be a good biodosimetry indicator for estimation of high dose irradiation. (authors)

  14. ACDOS2: an improved neutron-induced dose rate code

    International Nuclear Information System (INIS)

    Lagache, J.C.

    1981-06-01

    To calculate the expected dose rate from fusion reactors as a function of geometry, composition, and time after shutdown a computer code, ACDOS2, was written, which utilizes up-to-date libraries of cross-sections and radioisotope decay data. ACDOS2 is in ANSI FORTRAN IV, in order to make it readily adaptable elsewhere

  15. ACDOS2: an improved neutron-induced dose rate code

    Energy Technology Data Exchange (ETDEWEB)

    Lagache, J.C.

    1981-06-01

    To calculate the expected dose rate from fusion reactors as a function of geometry, composition, and time after shutdown a computer code, ACDOS2, was written, which utilizes up-to-date libraries of cross-sections and radioisotope decay data. ACDOS2 is in ANSI FORTRAN IV, in order to make it readily adaptable elsewhere.

  16. A blinded, randomized, controlled trial of three doses of high-dose insulin in poison-induced cardiogenic shock.

    Science.gov (United States)

    Cole, J B; Stellpflug, S J; Ellsworth, H; Anderson, C P; Adams, A B; Engebretsen, K M; Holger, J S

    2013-05-01

    High dose insulin (HDI) has proven superior to glucagon and catecholamines in the treatment of poison-induced cardiogenic shock (PICS) in previous animal studies. Standard recommendations for dosing of insulin vary and the optimal dose of HDI in PICS has not been established. Our hypothesis was a dose of 10 U/kg/hr of HDI would be superior to 1 U/kg/hr with cardiac output (CO) as our primary outcome measure in pigs with propranolol-induced PICS. This was a blinded, prospective, randomized trial with 4 arms consisting of 4 pigs in each arm. The arms were as follows: placebo (P), 1 U/kg/hr (HDI-1), 5 U/kg/hr (HDI-5), and 10 U/kg/hr (HDI-10). Cardiogenic shock was induced with a bolus of 0.5 mg/kg of propranolol followed by an infusion of 0.25 mg/kg/min until the point of toxicity, defined as 0.75 x (HR x MAP) was reached. At this point the propranolol infusion was decreased to 0.125 mg/kg/min and a 20 mL/kg bolus of normal saline (NS) was administered. The protocol was continued for 6 hours or until the animals died. 2 pigs died in the P arm, 1 pig died each in the HDI-1 and HDI-5 arms, and all pigs lived in the HDI-10 arm. There was a statistically significant difference in dose by time interaction on CO of 1.13 L/min over the 6 hr study period (p = < 0.001). There was also a statistically significant difference in dose by time interaction on MAP, HR, and systemic vascular resistance (SVR). No statistically significant difference was found between any of the arms regarding glucose utilization. HDI was statistically and clinically significantly superior to placebo in this propranolol model of PICS. Furthermore a dose response over time was found where CO increased corresponding to increases in doses of HDI.

  17. Radiation effect and response of DNA synthesis in lymphocytes induced by low dose irradiation

    International Nuclear Information System (INIS)

    Zhao Yujie; Su Liaoyuan; Zou Huawei; Kong Xiangrong

    1999-01-01

    The ability of DNA synthesis in lymphocytes were measured by using 3 H-TdR incorporation method. This method was used to observe the damage of lymphocytes irradiated by several challenge doses (0.5-0.8 Gy) and adaptive response induced by previous low dose irradiation. The results show that DNA synthesis was inhibited by challenge dose of radiation and was adapted by previous 0.048 Gy irradiation

  18. Pb low doses induced genotoxicity in Lactuca sativa plants.

    Science.gov (United States)

    Silva, S; Silva, P; Oliveira, H; Gaivão, I; Matos, M; Pinto-Carnide, O; Santos, C

    2017-03-01

    Soil and water contamination by lead (Pb) remains a topic of great concern, particularly regarding crop production. The admissible Pb values in irrigation water in several countries range from ≈0.1 to ≈5 mg L -1 . In order to evaluate putative effects of Pb within legal doses on crops growth, we exposed Lactuca sativa seeds and seedlings to increasing doses of Pb(NO 3 ) 2 up to 20 mg L -1 . The OECD parameter seed germination and seedling/plant growth were not affected by any of the Pb-concentrations used. However, for doses higher than 5 mg L -1 significant DNA damage was detected: Comet assay detected DNA fragmentation at ≥ 5 mg L -1 and presence of micronuclei (MN) were detected for 20 mg L -1 . Also, cell cycle impairment was observed for doses as low as 0.05 mg L -1 and 0.5 mg L -1 (mostly G 2 arrest). Our data show that for the low doses of Pb used, the OECD endpoints were not able to detect toxicity, while more sensitive endpoints (related with DNA damage and mitotic/interphase disorders) identified genotoxic and cytostatic effects. Furthermore, the nature of the genotoxic effect was dependent on the concentration. Finally, we recommend that MN test and the comet assay should be included as sensitive endpoints in (eco)toxicological assays. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  19. Effects of dose, dose-rate and fraction on radiation-induced breast and lung cancers

    International Nuclear Information System (INIS)

    Howe, G.R.

    1992-01-01

    Recent results from a large Canadian epidemiologic cohort study of low-LET radiation and cancer will be described. This is a study of 64,172 tuberculosis patients first treated in Canada between 1930 and 1952, of whom many received substantial doses to breast and lung tissue from repeated chest fluoroscopies. The mortality of the cohort between 1950 and 1987 has been determined by computerized record linkage to the National Mortality Data Base. There is a strong positive association between radiation and breast cancer risk among the females in the cohort, but in contrast very little evidence of any increased risk in lung cancer. The results of this and other studies suggest that the effect of dose-rate and/or fractionation on cancer risk may will differ depending upon the particular cancer being considered. (author)

  20. Effects of Respiration-Induced Density Variations on Dose Distributions in Radiotherapy of Lung Cancer

    International Nuclear Information System (INIS)

    Mexner, Vanessa; Wolthaus, Jochem W.H.; Herk, Marcel van; Damen, Eugene M.F.; Sonke, Jan-Jakob

    2009-01-01

    Purpose: To determine the effect of respiration-induced density variations on the estimated dose delivered to moving structures and, consequently, to evaluate the necessity of using full four-dimensional (4D) treatment plan optimization. Methods and Materials: In 10 patients with large tumor motion (median, 1.9 cm; range, 1.1-3.6 cm), the clinical treatment plan, designed using the mid-ventilation ([MidV]; i.e., the 4D-CT frame closest to the time-averaged mean position) CT scan, was recalculated on all 4D-CT frames. The cumulative dose was determined by transforming the doses in all breathing phases to the MidV geometry using deformable registration and then averaging the results. To determine the effect of density variations, this cumulative dose was compared with the accumulated dose after similarly deforming the planned (3D) MidV-dose in each respiratory phase using the same transformation (i.e., 'blurring the dose'). Results: The accumulated tumor doses, including and excluding density variations, were almost identical. Relative differences in the minimum gross tumor volume (GTV) dose were less than 2% for all patients. The relative differences were even smaller in the mean lung dose and the V20 (<0.5% and 1%, respectively). Conclusions: The effect of respiration-induced density variations on the dose accumulated over the respiratory cycle was very small, even in the presence of considerable respiratory motion. A full 4D-dose calculation for treatment planning that takes into account such density variations is therefore not required. Planning using the MidV-CT derived from 4D-CT with an appropriate margin for geometric uncertainties is an accurate and safe method to account for respiration-induced anatomy variations.

  1. Effect of dose on radiation-induced conductivity in polymers

    International Nuclear Information System (INIS)

    Tyutnev, A.P.; Saenko, V.S.; Pozhidaev, E.D.; Ikhsanov, R.Sh.

    2007-01-01

    Numerical simulation of radiation-induced conductivity in polymers upon long-term irradiation on the basis of the generalized Rose-Fowler-Vaisberg model, which allows for both dipolar carrier transport and generation of radiation traps during irradiation, was performed. The unusual properties of radiation-induced conductivity, such as the appearance of a maximum on current transients, the absence of a steady state, and a substantial difference between these curves for the first and subsequent irradiation, are rationalized in terms of the formation of free radicals, the major feature of radiolysis in the chemical aspect. This interpretation does not require the involvement of degradation or crosslinking processes, unlike other interpretations that appear in the literature. With the use of low-density polyethylene as an example, it was shown that radiation-induced conductivity both upon pulse and continuous irradiation can satisfactorily be described with the unified set of parameters of the generalized Rose-Fowler-Vaisberg model [ru

  2. Effects of the hepatocarcinogen nafenopin, a peroxisome proliferator, on the activities of rat liver glutathione-requiring enzymes and catalase in comparison to the action of phenobarbital.

    Science.gov (United States)

    Furukawa, K; Numoto, S; Furuya, K; Furukawa, N T; Williams, G M

    1985-10-01

    The biochemical effects in the livers of male rats of prolonged administration of the experimental hepatocarcinogen nafenopin, a hypolipidemic agent and peroxisome proliferator, were compared to those of another experimental liver carcinogen, phenobarbital, which acts as a neoplasm promoter. Feeding of nafenopin, 0.03 mmol/kg basal diet for up to 24 weeks increased the numbers of hepatic peroxisomes, increased catalase activity, markedly decreased cytosolic glutathione transferase activities toward two substrates, decreased cytosolic glutathione peroxidase activities toward H2O2 and two organic peroxides, and suppressed the age-related increase in gamma-glutamyl transpeptidase activity. In contrast the livers of rats fed an equimolar concentration of phenobarbital displayed increases in cytosolic glutathione transferase activities and enhancement of gamma-glutamyl transpeptidase activity but no changes in glutathione peroxidase activities. There was also an enhancement of catalase activity without apparent increase in peroxisome number. Enzyme kinetic analyses revealed that the cytosolic glutathione transferase activities toward two halogenonitrobenzene substrates were inhibited in the rats fed nafenopin and displayed elevated Km and decreased Vmax. Kinetic studies of glutathione transferase activities in which nafenopin was mixed with normal rat liver cytosols in the assay system revealed competitive type inhibition toward 1-chloro-2,4-dinitrobenzene and a noncompetitive type of inhibition toward 3,4-dichloronitrobenzene. Likewise activities of glutathione peroxidases toward H2O2 and cumene hydroperoxide were suppressed by in vitro addition. Thus the effects of nafenopin and phenobarbital on liver biochemistry were very different. The inhibition of hepatic biotransformation and scavenger systems by nafenopin is suggested to be relevant to its hepatocarcinogenicity.

  3. Study of the effect of dose-rate on radiation-induced damage to human erythrocytes

    Energy Technology Data Exchange (ETDEWEB)

    Krokosz, Anita [Department of Molecular Biophysics, University of Lodz, Banacha 12/16, Lodz (Poland)]. E-mail: krokosz@biol.uni.lodz.pl; Koziczak, Renata [Department of Molecular Biophysics, University of Lodz, Banacha 12/16, Lodz (Poland); Gonciarz, Marta [Department of Molecular Biophysics, University of Lodz, Banacha 12/16, Lodz (Poland); Szweda-Lewandowska, Zofia [Department of Molecular Biophysics, University of Lodz, Banacha 12/16, Lodz (Poland)

    2006-01-15

    Human erythrocytes suspended in an isotonic Na-phosphate buffer, pH 7.4 (hematocrit of 2%) were irradiated with {gamma}-rays at three dose-rates of 66.7, 36.7, 25 Gy min{sup -1} in order to investigate the influence of the dose-rate on radiation-induced membrane damage, hemoglobin oxidation and loss of reduced glutathione. The obtained results showed that such processes as erythrocyte hemolysis, lipid and protein destruction depend on the radiation dose-rate. The parameter values describing these processes showed an inverse dose-rate effect.

  4. Study of the effect of dose-rate on radiation-induced damage to human erythrocytes

    International Nuclear Information System (INIS)

    Krokosz, Anita; Koziczak, Renata; Gonciarz, Marta; Szweda-Lewandowska, Zofia

    2006-01-01

    Human erythrocytes suspended in an isotonic Na-phosphate buffer, pH 7.4 (hematocrit of 2%) were irradiated with γ-rays at three dose-rates of 66.7, 36.7, 25 Gy min -1 in order to investigate the influence of the dose-rate on radiation-induced membrane damage, hemoglobin oxidation and loss of reduced glutathione. The obtained results showed that such processes as erythrocyte hemolysis, lipid and protein destruction depend on the radiation dose-rate. The parameter values describing these processes showed an inverse dose-rate effect

  5. Dose rate effect on the yield of radiation induced response with thermal fading

    International Nuclear Information System (INIS)

    Chernov, V.; Rogalev, B.; Barboza-Flores, M.

    2005-01-01

    A model describing the dependences of the accumulation of thermally unstable radiation induced defects on the dose and dose rate is proposed. The model directly takes into account the track nature of the ionizing radiation represented as accumulation processes of defects in tracks averaged over a crystal volume considering various degrees of overlapping in space and time. The accumulation of the defects in the tracks is phenomenologically described. General expressions are obtained that allows radiation yield simulation of defects involving known creation and transformation processes. The cases considered, of linear accumulation (constant increment of the defects in tracks) and accumulation with saturation (complete saturation of the defects in one track), lead to a set of linear dose dependences with saturation, which are routinely used in luminescence and ESR dating. The accumulation, with increase of sensitivity in regions overlapped by two or more tracks, gave a set of dose dependences, from linear-sublinear-linear-saturation, distinctive of quartz up to linear-supralinear-linear-saturation. It is shown that the effect of the dose rate on dose dependences is determined by a dimensionless parameter a=Pτ/D0, where P is the dose rate, τ is the defect lifetime and D0 is the track dose. At a-bar 1 the dose rate influences basically the accumulation of thermally unstable defects. In the reverse case the dose dependences did not seems to be influenced by the dose rate

  6. Risk of radiation-induced cancer at low doses and low dose rates for radiation protection purposes

    International Nuclear Information System (INIS)

    1995-01-01

    The aim of this report is to provide an updated, comprehensive review of the data available for assessing the risk of radiation-induced cancer for radiation protection purposes. Particular emphasis is placed on assessing risks at low doses and low dose rates. The review brings together the results of epidemiological investigations and fundamental studies on the molecular and cellular mechanisms involved in radiation damage. Additionally, this information is supplemented by studies with experimental animals which provide further guidance on the form of the dose-response relationship for cancer induction, as well as on the effect of dose rate on the tumour yield. The emphasis of the report is on cancer induction resulting from exposure to radiations with a low linear energy transfer (LET). The work was performed under contract for the Institut de Protection et de Surete Nucleaire, Fontenay-aux-Roses, Paris, France, whose agreement to publish is gratefully ackowledged. It extends the advice on radiation risks given in Documents of the NRPB, 4 No. 4 (1993). (Author)

  7. Dose-response relationships for radium-induced bone sarcomas

    International Nuclear Information System (INIS)

    Rowland, R.E.; Stehney, A.F.; Lucas, H.F. Jr.

    1981-01-01

    The incidence of bone sarcomas among 3055 female radium-dial workers who entered the dial industry before 1950 was used to determine dose-response relationships for the induction of bone sarcomas by radium. Two subpopulations were analyzed: all measured cases who survived at last five years after the start of employment and all cases who survived at least two years after first measurement. The first constituted a group based on year of entry; it contained 1468 women who experienced 42 bone sarcomas; the expected number was 0.4. The second comprised a group based on first measurement; it contained 1257 women who experienced 13 bone sarcomas; the expected number was 0.2. The dose-response function, I = (C + αD + #betta#D 2 )e/sup -#betta#D/, and simplifications of this general form, were fit to each data set. Two functions, I = (C + αD + #betta#D 2 )e/sup -#betta#D/ and I = (C + #betta#D 2 )e/sup -#betta#D/, fit the data for year of entry (p greater than or equal to 0.05); both these functions and I = (C + αD) fit the data for first measurement. The function I = (C + #betta#D 2 )e/sup -#betta#D/ was used to predict the number of bone sarcomas in all other pre-1950 radium cases (medical, laboratory, and other exposure); fewer were actually observed than the fit of this function to the female dial workers predicted

  8. Effect and adaptive response of lymphocytes DNA induced by low dose irradiation

    International Nuclear Information System (INIS)

    Du Zeji; Su Liaoyuan; Tian Hailin

    1994-09-01

    Fluorometric analysis of DNA unwinding (FADU) was conducted and was proved to be an optimal method for studying DNA strand breaks induced by low dose irradiation. The linear dose response curve was obtained. The minimum detected dose was 0.3 Gy. There was no effect of low dose γ-rays (0.5∼8.0 cGy) on DNA strand breaks of quiescent and mitogen-induced lymphocytes. The 0.5∼4.0 cGy γ-rats could induce adaptive response of lymphocytes' DNA strand breaks, especially, at the doses of 2.0 and 4.0 cGy. The challenge doses of 5∼20 Gy could make the adaptive response appearance, and the 15 Gy was the best one. The 3-AB could powerfully inhibit the adaptive response. The repair of DNA strand breaks (37 degree C, 15∼60 min) caused by 15 Gy γ-rays could be promoted by the low dose γ-ray irradiation (2.0 cGy), but no difference was found at 37 degree C, 120 min

  9. Very low dose and dose-rate X-ray induced adaptive response in human lymphocytes at various cell cycle stages against bleomycin induced chromatid aberrations

    International Nuclear Information System (INIS)

    Hossein Mozdarani; Moghadam, R.N.

    2007-01-01

    Complete text of publication follows. Objective: To study the adaptive response induced by very low doses of X-rays at very low dose rate in human lymphocytes at different cell cycle stages followed by a challenge dose of bleomycin sulphate at G2 phase. Materials and Methods: Human peripheral blood lymphocytes before (G0) and after PHA stimulation (G1 and G2) were exposed to 1 and 5 cGy X-rays generated by a fluoroscopy unit with a dose rate of 5.56 mGy/min and challenged with 5 μg/ml bleomycin sulphate (BLM) 48 hours after culture initiation. Mitotic cells were arrested at metaphase by addition of colcemid in cultures 1.5 h before harvesting. Harvesting and slide preparation was performed using standard method. 100 well spread metaphases were analyzed for the presence of chromatid type aberrations for each sample. Results: Results obtained indicate that there is a linear relationship between the dose of BLM and chromatid aberrations below 5 μg/ml (R=0.93, p<0.0001). The results also show that pretreatment of lymphocytes with low dose X-rays at G0, G1 and G2 phases of the cell cycle significantly reduced the sensitivity of lymphocytes to the clastogenic effects of BLM in G2. Much lower frequencies of chromatid aberrations were observed in X-ray irradiated lymphocytes following BLM treatment (p<0.05). The magnitudes of adaptation induced at different phases of the cell cycle were not significantly different. Furthermore, there was no a significant difference in the magnitude of adaptive response induced by either 1 or 5 cGy X-rays. Conclusion: These observations might indicate that resistance of pre-exposure of lymphocytes to very low doses of X-rays protects them from clastogenic effects of BLM. This effect might be due to initial DNA damage induced in these cells leading to provocation of an active DNA repair mechanism independent of cell cycle stage.

  10. Low-dose ionizing radiation alleviates Aβ42-induced defective phenotypes in Drosophila Alzheimer's disease models

    International Nuclear Information System (INIS)

    Hwang, SooJin; Jeong, Hae Min; Nam, Seon Young

    2017-01-01

    Alzheimer's disease (AD) is the most common neurodegenerative disease that is characterized by amyloid plaques, progressive neuronal loss, and gradual deterioration of memory. Amyloid imaging using positron emission tomography (PET) radiotracers have been developed and approved for clinical use in the evaluation of suspected neurodegenerative disease, including AD. Particularly, previous studies involving low-dose ionizing radiation on Aβ 42-treated mouse hippocampal neurons have suggested a potential role for low-dose ionizing radiation in the treatment of AD. However, associated in vivo studies involving the therapy effects of low-dose ionizing radiation on AD are still insufficient. As a powerful cell biological system, Drosophila AD models have been generated and established a useful model organism for study on the etiology of human AD. In this study, we investigated the hormesis effects of low-dose ionizing radiation on Drosophila AD models. Our results suggest that low-dose ionizing radiation have the beneficial effects on not only the Aβ42-induced developmental defective phenotypes but also motor defects in Drosophila AD models. These results might be due to a regulation of apoptosis, and provide insight into the hormesis effects of low-dose ionizing radiation. Our results suggest that low-dose ionizing radiation have the beneficial effects on not only the Aβ42-induced developmental defective phenotypes but also motor defects in Drosophila AD models. These results might be due to a regulation of apoptosis, and provide insight into the hormesis effects of low-dose ionizing radiation.

  11. Studies on chromosome aberrations induced in human lymphocytes by very low-dose exposure to tritium

    International Nuclear Information System (INIS)

    Hori, T.; Moriya, Junko; Nakai, Sayaka

    1978-01-01

    Assessment of potential hazard from environmental tritium to man becomes very important with increasing the development of nuclear-power industry. However, little data are available as to the determination on the genetic effect of tritium especially at the low levels. The object of the present study is to obtain quantitative data for chromosome aberrations in human lymphocytes, as an indicator for genetic risk estimation, induced by tritium at very low dose levels. Leukocyte cultures of human peripheral blood were chronically exposed for 48h to tritiated water and 3 H-thymidine using a wide range of tritium doses, and aberrations in lymphocyte chromosomes at the first metaphases were examined. In the experimental conditions, the types of aberrations induced by radiation emitted from both tritiated water and 3 H-thymidine were mostly chromatid types, such as chromatid gaps and deletions. The dose-response relations for chromatid breaks per cell exhibited unusual dose-dependency in both cases. It was demonstrated that at higher dose range the yields of chromatid breaks increased linearly with dose, while those at lower dose range were significantly higher than would be expected by a downward extraporation from the linear relation. Partial-hit or partial-target kinetics events appeared at very low dose exposure. (author)

  12. Prevention of Aflatoxin B1-Induced DNA Breaks by β-D-Glucan

    Directory of Open Access Journals (Sweden)

    Eduardo Madrigal-Bujaidar

    2015-06-01

    Full Text Available Aflatoxins are a group of naturally-occurring carcinogens that are known to contaminate different human and animal foodstuffs. Aflatoxin B1 (AFB1 is the most genotoxic hepatocarcinogenic compound of all of the aflatoxins. In this report, we explore the capacity of β-D-glucan (Glu to reduce the DNA damage induced by AFB1 in mouse hepatocytes. For this purpose, we applied the comet assay to groups of animals that were first administered Glu in three doses (100, 400 and 700 mg/kg bw, respectively and, 20 min later, 1.0 mg/kg of AFB1. Liver cells were obtained at 4, 10 and 16 h after the chemical administration and examined. The results showed no protection of the damage induced by AFB1 with the low dose of the polysaccharide, but they did reveal antigenotoxic activity exerted by the two high doses. In addition, we induced a co-crystallization between both compounds, determined their fusion points and analyzed the molecules by UV spectroscopy. The data suggested the formation of a supramolecular complex between AFB1 and β-D-glucan.

  13. Dose-effect relationship of apoptosis induced by fission-neutron in murine thymocytes

    International Nuclear Information System (INIS)

    Yuan Bin; Li Liang; Xue Wencheng; Sun Jianmin; Wang Baoqin

    2000-01-01

    Objective: To investigate the effectiveness of high LET fission-neutron to induce apoptosis in murine thymocytes and to compare it with that of low LET 60 Co γ-ray. Methods: Apoptosis induction was studied qualitatively by light and transmission electron microscopy and DNA gel electrophoresis,also quantitatively by flow cytometry(FCM) and diphenylamine (DPA)methods. Results: DNA ladders of murine thymocytes were detectable, the typical apoptosis of thymocytes could be observed morphologically by means of light and electron microscopy at 6 h after fission-neutron irradiation with doses ranging from 0.5 to 5.0 Gy, meanwhile the percentages of apoptosis increased with increasing doses. After exposure to γ-rays with doses ranging from 1.0 to 30 Gy, the experimental results were similar to those from neutron radiation. The incidence of apoptosis peaked at about 20 Gy, the percentages did not increase further when doses increased. Conclusion: Apoptosis of murine thymocytes can be induced when mice are exposed to either fission-neutron (0.5-5.0 Gy) or to γ-ray (1-30 Gy). Although the relationship between apoptosis and radiation doses is similar, the percentage of apoptosis induced by neutron irradiation is higher than that induced by γ-irradiation. The RBE values of fission-neutron for inducing apoptosis murine thymocytes are 2.09 (by FCM method) and 2.37 (by DPA method), respectively. These results also suggest that fission-neutron-induced murine immune tissue is more severe than that induced by γ-rays at several hours post-irradiation and this might be the basis for heavy damage to immune tissues induced by fission-neutron-irradiation in later period

  14. Radiation retinopathy caused by low dose irradiation and antithyroid drug-induced systemic vasculitis

    International Nuclear Information System (INIS)

    Sonoda, Koh-hei; Ishibashi, Tatsuro

    2005-01-01

    We report on a patient with Graves' disease with radiation retinopathy caused by low-dose irradiation and antithyroid drug-induced antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis. A 38-year-old woman with Graves' disease presented with bilateral blurred vision, micro-aneurysms, telangiectasia, and macular edema. The patient was examined by ophthalmoscopy and fluorescein angiography, and radiation retinopathy was diagnosed. The patient had been treated with low-dose irradiation for her Graves' ophthalmopathy a few years earlier. She also had ANCA-positive vasculitis induced by the antithyroid drug (propylthiouracil, PTU) that had been prescribed for her at that time. Because of multiple avascular areas on both retinas, she was treated by intensive retinal photocoagulation to control progressive retinopathy. The radiation doses used to treat Graves' disease ophthalmopathy are low. Nevertheless, there is still a risk of radiation retinopathy developing in patients with PTU-induced ANCA-positive vasculitis. (author)

  15. The genetic effects induced by an irradiation in low doses at Drosophila melanogaster

    International Nuclear Information System (INIS)

    Zajnullin, V.G.; Taskaev, A.I.; Moskalev, A.A.; Shaposhnikov, M.V.

    2006-01-01

    The review generalizes the results obtained in researches of genetic radiation effects for Drosophila melanogaster from contamination regions near the Chernobylsk NPP. The results of laboratory investigations of low dose irradiation effects on genotype variability and lifetime of Drosophila are presented too. It supposed that the main effect of low dose irradiation is caused by the induced genetic instability against the background of which the realization of different-directed radiobiological reactions is possible [ru

  16. Estimation of the Radon-induced Dose for Russia's Population: Methods and Results

    International Nuclear Information System (INIS)

    Marenny, A.M.; Savkin, M.N.; Shinkarev, S.M.

    2000-01-01

    A model is proposed for inferring the radon-induced annual average collective and personal doses, as well as the dose distribution of the population, all over Russia from selective radon monitoring in some regions of Russia. The model assumptions and the selective radon monitoring results that underlie the numerical estimates obtained for different population groups are presented. The current estimate of the collective radon-induced dose received by the population of Russia (148,100,000 as of 1996) is about 130,000 man Sv, of which 55,000 man Sv is for the rural population (27% of the total population) and 75,000 man Sv for the urban population (73% of the total). The average radon-induced personal dose in Russia is estimated to be about 0.87 mSv. About 1,000,000 people receive annual doses above 10 mSv, including some 200,000 people who receive doses above 20 mSv annually. The ways of making the current estimates more accurate are outlined. (author)

  17. Low-dose radiation induces drosophila innate immunity through toll pathway activation

    International Nuclear Information System (INIS)

    Seong, Ki Moon; Kim, Cha Soon; Lee, Byung-Sub; Nam, Seon Young; Yang, Kwang Hee; Kim, Ji-Young; Jin, Young-Woo; Park, Joong-Jean; Min, Kyung-Jin

    2012-01-01

    Numerous studies report that exposing certain organisms to low-dose radiation induces beneficial effects on lifespan, tumorigenesis, and immunity. By analyzing survival after bacterial infection and antimicrobial peptide gene expression in irradiated flies, we demonstrate that low-dose irradiation of Drosophila enhances innate immunity. Low-dose irradiation of flies significantly increased resistance against gram-positive and gram-negative bacterial infections, as well as expression of several antimicrobial peptide genes. Additionally, low-dose irradiation also resulted in a specific increase in expression of key proteins of the Toll signaling pathway and phosphorylated forms of p38 and N-terminal kinase (JNK). These results indicate that innate immunity is activated after low-dose irradiation through Toll signaling pathway in Drosophila. (author)

  18. Correlation between induced embryo toxicity and absorption dose of enriched uranium in testes

    International Nuclear Information System (INIS)

    Zhu Shoupeng; Lun Mingyue

    1996-01-01

    Doses of enriched uranium in testes inducing dominant lethality and skeletal abnormalities in offsprings are estimated. When intra-testicular injection dose is 0.4∼60 μg enriched uranium; from intake to insemination, testes could receive 9.14 x 10 -5 ∼1.38 x 10 -2 Gy radiation dose. Experimental results show that with the increase in the absorption dose, the number of living fetuses in a litter decreases, dominant lethality and skeletal abnormalities rise. It should be noted that relationship between the injected dose (I in μg) and the incidence of dominant skeletal abnormalities (S in %) in the offsprings can be represented by equation: S = 28.84 + 0.84I

  19. Correlation between induced embryo toxicity and absorption dose of enriched uranium in testes

    Energy Technology Data Exchange (ETDEWEB)

    Shoupeng, Zhu; Mingyue, Lun [Suzhou Medical Coll., JS (China)

    1996-08-01

    Doses of enriched uranium in testes inducing dominant lethality and skeletal abnormalities in offsprings are estimated. When intra-testicular injection dose is 0.4{approx}60 {mu}g enriched uranium; from intake to insemination, testes could receive 9.14 x 10{sup -5}{approx}1.38 x 10{sup -2} Gy radiation dose. Experimental results show that with the increase in the absorption dose, the number of living fetuses in a litter decreases, dominant lethality and skeletal abnormalities rise. It should be noted that relationship between the injected dose (I in {mu}g) and the incidence of dominant skeletal abnormalities (S in %) in the offsprings can be represented by equation: S = 28.84 + 0.84I.

  20. Adaptive repair induced by small doses of γ radiation in repair-defective human cells

    International Nuclear Information System (INIS)

    Zasukhina, G.D.; L'vova, G.N.; Vasil'eva, I.M.; Sinel'shchikova, T.A.; Semyachkina, A.N.

    1993-01-01

    Adaptive repair induced by small doses of gamma radiation was studied in repair-defective xeroderma pigmentosum, gout, and homocystinuria cells. The adaptation of cells induced by small doses of radiation was estimated after subsequent exposure to gamma radiation, 4-nitroquinoline-1-oxide, and N-methyl-N-nitro-N-nitrosoguanidine by three methods: (1) by the reduction in DNA breaks; (2) by induction of resistant DNA synthesis; and (3) by increased reactivation of vaccinia virus. The three cell types in response to the three different mutagens revealed differences in the mechanism of cell defense in excision repair, in the adaptive response, and in Weigl reactivation

  1. Radiation-induced attenuation in polarization maintaining fibers: low dose rate response, stress, and materials effects

    International Nuclear Information System (INIS)

    Gingerich, M.E.; Friebele, E.J.; Hickey, S.J.; Brambani, L.A.; Onstott, J.R.

    1989-01-01

    The loss induced in polarization-maintaining (PM) fibers by low dose rate <0.01 Gy/h, where 1 Gy = 100 rads(Si) radiation exposure has been found to vary from <0.4 to ∼6 dB/km-10 Gy, depending on the wavelength of measurement and the fiber. Correlations have been established between low dose rate response and the ''permanent'' induced loss determined by fitting the recovery of the induced loss following high dose rate exposure to nth-order kinetics. Using this technique, both 0.85- and 1.3-μm PM fibers have been found which show virtually no permanent incremental loss and would therefore appear to be resistant to low dose rate radiation environments. The asymmetric stress inherent in PM fibers has been shown to reduce the permanent induced loss, while the recovery of the radiation-induced attenuation was found to be enhanced in fibers with Ge-F-doped silica clads

  2. Search for the lowest irradiation dose from literatures on radiation-induced breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Yoshizawa, Y; Kusama, T [Tokyo Univ. (Japan). Faculty of Medicine

    1975-12-01

    A survey of past case reports concerning radiation-induced breast cancer was carried out in order to find the lowest irradiation dose. The search of literature published since 1951 revealed 10 cases of radiation-induced breast cancer. Only 5 cases had precise descriptions of the irradiation dose. The lowest irradiation dose was estimated at 1470 rads in the case of external X-ray irradiation for tuberous angioma. All of cases of radiation-induced breast cancer had received radiation for the treatment of nonmalignant tumors, such as pulmonary tuberculosis, mastitis, and tuberous angioma. There also were three statistical studies. The first concerned atomic bomb survivors, the second, pulmoanry tuberculous patients subjected to frequent fluoroscopies, and the third, patients of acute post partum mastitis. These statistical studies had revealed a significant increase in the incidence of breast cancer in the irradiated group, but there was little information about the lowest irradiation dose. It was noticed that radiation-induced breast cancer was more numerous in the upper inner quadrant of the breast. Most histopathological findings of radiation-induced breast cancer involved duct cell carcinoma. The latent period was about 15 years.

  3. Photonic activation of plasminogen induced by low dose UVB.

    Directory of Open Access Journals (Sweden)

    Manuel Correia

    Full Text Available Activation of plasminogen to its active form plasmin is essential for several key mechanisms, including the dissolution of blood clots. Activation occurs naturally via enzymatic proteolysis. We report that activation can be achieved with 280 nm light. A 2.6 fold increase in proteolytic activity was observed after 10 min illumination of human plasminogen. Irradiance levels used are in the same order of magnitude of the UVB solar irradiance. Activation is correlated with light induced disruption of disulphide bridges upon UVB excitation of the aromatic residues and with the formation of photochemical products, e.g. dityrosine and N-formylkynurenine. Most of the protein fold is maintained after 10 min illumination since no major changes are observed in the near-UV CD spectrum. Far-UV CD shows loss of secondary structure after illumination (33.4% signal loss at 206 nm. Thermal unfolding CD studies show that plasminogen retains a native like cooperative transition at ~70 ºC after UV-illumination. We propose that UVB activation of plasminogen occurs upon photo-cleavage of a functional allosteric disulphide bond, Cys737-Cys765, located in the catalytic domain and in van der Waals contact with Trp761 (4.3 Å. Such proximity makes its disruption very likely, which may occur upon electron transfer from excited Trp761. Reduction of Cys737-Cys765 will result in likely conformational changes in the catalytic site. Molecular dynamics simulations reveal that reduction of Cys737-Cys765 in plasminogen leads to an increase of the fluctuations of loop 760-765, the S1-entrance frame located close to the active site. These fluctuations affect the range of solvent exposure of the catalytic triad, particularly of Asp646 and Ser74, which acquire an exposure profile similar to the values in plasmin. The presented photonic mechanism of plasminogen activation has the potential to be used in clinical applications, possibly together with other enzymatic treatments for the

  4. Dose and effect relationship of radiation induced cancer and its influencing factors in experimental animals, 1

    International Nuclear Information System (INIS)

    Sasaki, Shunsaku; Sato, Fumiaki; Eto, Hideo

    1975-01-01

    The data of risk evaluation of external irradiation were integrated with animal experiments from the aspects of qualitative generalizations of characteristics of radiation induced tumors. Studies covered competition of cause of death, figure of dose-to-effect relationship, characteristics of low dose rate of irradiation, relative biological effectiveness (RBE) of high LET radiation, effects of feactionated irradiation, complex actions with chemical substances, effects of protectional medium, differences of radiosensitivity by species and strains, and age dependency of sensitivities. Competition of cause of death by time length of latent period and degree of malignancy of the disease. Discussion on competition of death suggested the following idea: 1) incidence of tumor induction in the individual level did not correspond to transformation in the cellular level, and 2) relative incidence of tumor induction after a certain dose of whole body irradiation did not indicate the relative sensitivity of each tissue, for the relationship between tumor incidence and exposure dose was not a linear relationship. The dose-to-effect relationship of tumor induction was decided by following factors: i) sensitivity on transformation of cells, ii) sensitivity on the death of potential tumor cells, and iii) competition of the cause of death. Tumor induction by low dose rate irradiation was also studied by comparing qualitative and quantitative differences between high dose rate single irradiation and a series of low dose rate irradiation. (Serizawa, K.)

  5. Low-Dose Adefovir-Induced Hypophosphatemic Osteomalacia on Whole-Body Bone Scintigraphy

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sung Hoon; Won, Kyoung Sook; Song, Bongil; Jo, Il; Zeon, Seok Kil [Keimyung Univ., Daegu (Korea, Republic of)

    2013-12-15

    While adefovir dipivoxil (ADV) effectively suppresses the hepatitis B virus, it can cause proximal renal tubular dysfunction leading to phosphate wasting. The safety of low-dose ADV (a dose of 10 mg/day), which does not induce clinically significant nephrotoxicity, is well recognized, but a few cases of hypophosphatemic osteomalacia (HO) caused by low-dose ADV therapy have recently been reported. Although HO induced by low-dose ADV therapy is rare, the presence of bone pain in patients treated with ADV should be monitored. Bone scintigraphy can be performed to confirm the occurrence of osteomalacia and to determine the disease extent. Bone scintigraphic and radiological image findings with a brief review of the literature are presented in this article. We report two cases of HO induced by low-dose ADV therapy that showed multifocal increased radiotracer uptakes in the bilateral bony ribs, spines, pelvic bones and lower extremities on whole-body bone scintigraphy. Bone pain gradually improved after phosphate supplementation and by changing the antiviral agent. Whole-body bone scintigraphy is a highly sensitive imaging tool and can show disease extent at once in the setting of the wide range of the clinical spectrum with nonspecific radiological findings. Furthermore, frequent involvement of the lower extremities, as a result of maximum weight bearing, could be an additional scintigraphic clue for the diagnosis of HO. These cases could be helpful for both clinicians prescribing ADV and nuclear physicians to prevent delayed diagnosis and plan further appropriate treatment.

  6. Low-Dose Adefovir-Induced Hypophosphatemic Osteomalacia on Whole-Body Bone Scintigraphy

    International Nuclear Information System (INIS)

    Kim, Sung Hoon; Won, Kyoung Sook; Song, Bongil; Jo, Il; Zeon, Seok Kil

    2013-01-01

    While adefovir dipivoxil (ADV) effectively suppresses the hepatitis B virus, it can cause proximal renal tubular dysfunction leading to phosphate wasting. The safety of low-dose ADV (a dose of 10 mg/day), which does not induce clinically significant nephrotoxicity, is well recognized, but a few cases of hypophosphatemic osteomalacia (HO) caused by low-dose ADV therapy have recently been reported. Although HO induced by low-dose ADV therapy is rare, the presence of bone pain in patients treated with ADV should be monitored. Bone scintigraphy can be performed to confirm the occurrence of osteomalacia and to determine the disease extent. Bone scintigraphic and radiological image findings with a brief review of the literature are presented in this article. We report two cases of HO induced by low-dose ADV therapy that showed multifocal increased radiotracer uptakes in the bilateral bony ribs, spines, pelvic bones and lower extremities on whole-body bone scintigraphy. Bone pain gradually improved after phosphate supplementation and by changing the antiviral agent. Whole-body bone scintigraphy is a highly sensitive imaging tool and can show disease extent at once in the setting of the wide range of the clinical spectrum with nonspecific radiological findings. Furthermore, frequent involvement of the lower extremities, as a result of maximum weight bearing, could be an additional scintigraphic clue for the diagnosis of HO. These cases could be helpful for both clinicians prescribing ADV and nuclear physicians to prevent delayed diagnosis and plan further appropriate treatment

  7. Radiation-Induced Leukemia at Doses Relevant to Radiation Therapy: Modeling Mechanisms and Estimating Risks

    Science.gov (United States)

    Shuryak, Igor; Sachs, Rainer K.; Hlatky, Lynn; Mark P. Little; Hahnfeldt, Philip; Brenner, David J.

    2006-01-01

    Because many cancer patients are diagnosed earlier and live longer than in the past, second cancers induced by radiation therapy have become a clinically significant issue. An earlier biologically based model that was designed to estimate risks of high-dose radiation induced solid cancers included initiation of stem cells to a premalignant state, inactivation of stem cells at high radiation doses, and proliferation of stem cells during cellular repopulation after inactivation. This earlier model predicted the risks of solid tumors induced by radiation therapy but overestimated the corresponding leukemia risks. Methods: To extend the model to radiation-induced leukemias, we analyzed in addition to cellular initiation, inactivation, and proliferation a repopulation mechanism specific to the hematopoietic system: long-range migration through the blood stream of hematopoietic stem cells (HSCs) from distant locations. Parameters for the model were derived from HSC biologic data in the literature and from leukemia risks among atomic bomb survivors v^ ho were subjected to much lower radiation doses. Results: Proliferating HSCs that migrate from sites distant from the high-dose region include few preleukemic HSCs, thus decreasing the high-dose leukemia risk. The extended model for leukemia provides risk estimates that are consistent with epidemiologic data for leukemia risk associated with radiation therapy over a wide dose range. For example, when applied to an earlier case-control study of 110000 women undergoing radiotherapy for uterine cancer, the model predicted an excess relative risk (ERR) of 1.9 for leukemia among women who received a large inhomogeneous fractionated external beam dose to the bone marrow (mean = 14.9 Gy), consistent with the measured ERR (2.0, 95% confidence interval [CI] = 0.2 to 6.4; from 3.6 cases expected and 11 cases observed). As a corresponding example for brachytherapy, the predicted ERR of 0.80 among women who received an inhomogeneous low-dose

  8. Relaxation behavior and dose dependence of radiation induced radicals in irradiated mango

    International Nuclear Information System (INIS)

    Kameya, Hiromi; Kakita, Daisuke; Kaimori, Yoshihiko; Ukai, Mitsuko; Kikuchi, Masahiro; Kobayashi, Yasuhiko; Shimoyama, Yuhei

    2010-01-01

    Mangoes are imported to Japan after treated with hot water. Recently, irradiated mangoes imported to U. S. are widely used. This paper reports on the ESR method for analyzing the radiation induced radicals of irradiated mangoes. Upon the γ ray irradiation, a strong single peak in the flesh and skin of mangoes was observed at g=2.004. This singlet peak may be attributed to organic free radicals. The ESR spectra of the flesh and skin of mangoes showed the radiation induced radicals due to cellulose by irradiation over 12 kGy. The relaxation times (T 1 and T 2 ) of the singlet signal were calculated. T 2 showed dose response according to increasing the irradiation dose levels, while T 1 was almost constant. The value of (T 1 T 2 ) 1/2 showed the dependence of irradiation dose level. (author)

  9. Clustered DNA damages induced in human hematopoietic cells by low doses of ionizing radiation

    Science.gov (United States)

    Sutherland, Betsy M.; Bennett, Paula V.; Cintron-Torres, Nela; Hada, Megumi; Trunk, John; Monteleone, Denise; Sutherland, John C.; Laval, Jacques; Stanislaus, Marisha; Gewirtz, Alan

    2002-01-01

    Ionizing radiation induces clusters of DNA damages--oxidized bases, abasic sites and strand breaks--on opposing strands within a few helical turns. Such damages have been postulated to be difficult to repair, as are double strand breaks (one type of cluster). We have shown that low doses of low and high linear energy transfer (LET) radiation induce such damage clusters in human cells. In human cells, DSB are about 30% of the total of complex damages, and the levels of DSBs and oxidized pyrimidine clusters are similar. The dose responses for cluster induction in cells can be described by a linear relationship, implying that even low doses of ionizing radiation can produce clustered damages. Studies are in progress to determine whether clusters can be produced by mechanisms other than ionizing radiation, as well as the levels of various cluster types formed by low and high LET radiation.

  10. Low dose radiation induced protein and its effect on expression of CD25 molecule in lymphocytes

    International Nuclear Information System (INIS)

    Lu Duicai; Su Liaoyuan

    2001-01-01

    Objective: To find the substantial basis for effects of low dose radiation, on development, extraction, and the biogical activity of the low-dose radiation-induced proteins, and the effects of LDR induced proteins on CD25 molecule expression of human lymphocytes. Methods: 1. Healthy Kumning male mice exposed to radiation of 226 Ra γ-rays at 5, 10 and 15 cGy respectively. The mice were killed 2 hours after exposure, the spleen cells were broken with ultrasonic energy and then ultra-centrifugalized at low temperature (4 degree C). The LDR-induced proteins were obtained in the supernatant solution. Then the changes of CD25 molecule was measured by flow cytometry (FCM) with immunofluorescence technique, which was used to reflect the effect of LDR induced proteins on CD25 molecule expression of human lymphocytes. Results: LDR induced proteins were obtained from spleen cells in mice exposed to 5-15 cGy whole body radiation. Conclusion: The expression of CD25 molecule of lymphocytes was increased significantly after use of LDR induced proteins. LDR induced proteins can enhance expression of CD25 molecule of lymphocytes slightly

  11. Low dose radiation induced protein and its experimental and ophthalmic clinical research

    International Nuclear Information System (INIS)

    Shen Wei; Su Liaoyuan; Liu Fenju; Ding Jie; Li Longbiao; Pan Chengsi

    2001-01-01

    The protective effects of low dose radiation (LDR) induced protein on cellular impairments caused by some harmful chemical and physical factors were studied. Male Kunming mice were irradiated with LDR, then the spleen cells of the mice were broken with ultrasonic energy and then ultracentrifugalized. The supernatant solution contained with LDR induced protein. The newly emerging protein was detected by gel filtration and its molecular weight was determined by gel electrophoresis. The content of newly emerging protein (LDR induced protein) was determined by Lowry's method. The method of isotope incorporation was used to observe the biological activity and its influence factors, the protective effects of LDR induced protein on the cells impaired by irradiating with ultraviolet (UV), high doses of 60 Co γ-rays and exposed to heat respectively, and the stimulative effects of LDR induced protein on human peripheral blood lymphocytes. Newly emerging protein has been observed in the experiment. The molecular weight of the protein is in the region 76.9 KD+- - 110.0 KD+-, the yield of the protein was 613.33 +- 213.42 μg per 3 x 10 7 spleen cells. DPM values (isotope were incorporated) of normal and injured mice spleen cells increased significantly after stimulating with the solution contained LDR induced protein. It is concluded that LDR induced protein could be obtained from mice spleen cells exposed to 5 - 15 cGy radiation for 2 - 16 h. The protein had biological activity and was able to stimulate the transformation of the spleen cells in vitro. It had obvious protective effects on some impaired cells caused by high dose radiation, UV radiation, heat and so on. It also had stimulative effects on the transformation of peripheral blood T and B lymphocytes of healthy individual and patients with eye diseases. It indicates that LDR induced protein increased immune function of human

  12. Tests of the linearity assumption in the dose-effect relationship for radiation-induced cancer

    International Nuclear Information System (INIS)

    Cohen, A.F.; Cohen, B.L.

    1978-01-01

    The validity of the BEIR linear extrapolation to low doses of the dose-effect relationship for radiation induced cancer is tested by use of natural radiation making use of selectivity on type of cancer, sex, age group, geographic area, and time period. For lung cancer, a linear interpolation between zero dose-zero effect and the data from radon-induced cancers in miners over-estimates the total number of observed lung cancers in many countries in the early years of this century; the discrepancy is substantially increased if the 30-44 year age range and/or if only females are considered, and by the fact that many other causes of lung cancer are shown to have been important at that time. The degree to which changes of diagnostic efficiency with time can influence the analysis is considered at some length. It is concluded that the linear relationship substantially over-estimates effects of low radiation doses. A similar analysis is applied to leukemia induced by natural radiation, applying selectivity by age, sex, natural background level, and date, and considering other causes. It is concluded that effects substantially larger than those obtained from linear extrapolation are excluded. The use of the selectivities mentioned above is justified by the fact that the incidence of cancer or leukemia is an upper limit on the rate at which it is caused by radiation effects; in determining upper limits it is justifiable to select situations which minimize it. (author)

  13. Dose-dependent effects of celecoxib on CB-1 agonist-induced antinociception in the mice

    Directory of Open Access Journals (Sweden)

    Mohammad Reza Zarrindast

    2009-04-01

    Full Text Available "nObjective: Endocannabinoid produce analgesia that is comparable which of opioids. The mechanism of antinociceptive effects of (∆ - 9 tetrahydrocannabinol (THC is suggested to be through cyclooxygenase (COX pathway. In the present work, the effect of two extreme dose ranges of celecoxib (mg/kg and ng/kg, a cyclooxygenase-2 (COX-2 antagonist, on arachidonylcyclopropylamide (ACPA, a selective CB1 agonist induced antinociception in mice was examined. "nMethods: We have investigated the interaction between celecoxib, at the doses of mg/kg (50, 100, 200 and 400 i.p.  and ultra low dose (ULD (25 and 50 ng/kg, i.p., on the antinociceptive effect of intracerebroventricular (i.c.v. administration of ACPA (0.004, 0.0625 and 1 μg/mice, using formalin test in mice. "nResults: I.C.V. administration of ACPA induced antinociception. Intraperitoneal administration of celecoxib (mg/kg and its ULD (ng/kg attenuated and potentiated, ACPA antinociceptive effects, respectively. "nConclusion: It is concluded that the mg/kg doses of COX-2 antagonist showed opposite effects compare to the ultra-low dose of the drug.

  14. Determination of dose ranges of gamma rays to induce specific changes in three ornamental species

    International Nuclear Information System (INIS)

    Gonzalez J, J.

    2011-11-01

    In order to confirming the possibility of to settle a dose range that takes place directly and not at random, a specific effect independently of the species that is were produced several similar organisms to three ornamental species took place via meristems cultivation: Petunia hybrid, Impatiens walleriana and Sprekelia formosissima, same that were irradiated in an irradiator Gamma cell 220, to different dose: 0, 3.5, 5.0, 7.5, 10, 12.5, 15, 17.5 and 20 Gy. Later on, of the plants treated via in vitro the subsequent generations were obtained until the M 4 . To determine the DL 50 and the possible good doses, the survival parameters, development, morphogenesis and height were evaluated during 8 weeks, interpreting based on them, the possible physiologic and genetic alterations induced by the radiation. The established DL 50 were: 7.5 Gy (Petunia), 19.0 Gy (Impatiens) and 12.0 Gy (Sprekelia). Based on the DL 50 of each species, a range of coincident dose settled down that produces a similar effect in the three species: a range of DL 23 to the DL 50 induces and alteration in the cytokinins production affecting directly in the leaves number, buds and plants taken place by meristem, also a range of DL 32 - DL 50 impacts in the auxins production altering to the radicule system. However, when being superimposed the dose is considered that the investigation should continue. (Author)

  15. Total dose induced latch in short channel NMOS/SOI transistors

    International Nuclear Information System (INIS)

    Ferlet-Cavrois, V.; Quoizola, S.; Musseau, O.; Flament, O.; Leray, J.L.; Pelloie, J.L.; Raynaud, C.; Faynot, O.

    1998-01-01

    A latch effect induced by total dose irradiation is observed in short channel SOI transistors. This effect appears on NMOS transistors with either a fully or a partially depleted structure. It is characterized by a hysteresis behavior of the Id-Vg characteristics at high drain bias for a given critical dose. Above this dose, the authors still observe a limited leakage current at low drain bias (0.1 V), but a high conduction current at high drain bias (2 V) as the transistor should be in the off-state. The critical dose above which the latch appears strongly depends on gate length, transistor structure (fully or partially depleted), buried oxide thickness and supply voltage. Two-dimensional (2D) numerical simulations indicate that the parasitic condition is due to the latch of the back gate transistor triggered by charge trapping in the buried oxide. To avoid the latch induced by the floating body effect, different techniques can be used: doping engineering, body contacts, etc. The study of the main parameters influencing the latch (gate length, supply voltage) shows that the scaling of technologies does not necessarily imply an increased latch sensitivity. Some technological parameters like the buried oxide hardness and thickness can be used to avoid latch, even at high cumulated dose, on highly integrated SOI technologies

  16. Tumor sterilization dose and radiation induced change of the brain tissue in radiotherapy of brain tumors

    International Nuclear Information System (INIS)

    Yoshii, Yoshihiko; Maki, Yutaka; Takano, Shingo

    1987-01-01

    Ninety-seven patients with brain tumors (38 gliomas, 26 brain metastases, 18 sellar tumors, 15 others) were treated by cobalt gamma ray or proton radiotherapy. In this study, normal brain injury due to radiation was analysed in terms of time-dose-fractionation (TDF), nominal standard dose (NSD) by the Ellis formula and NeuNSD by a modification in which the N exponent was -0.44 and the T exponent was -0.06. Their calculated doses were analysed in relationship to the normal brain radiation induced change (RIC) and the tumor sterilization dose. All brain tumors with an exception of many patients with brain metastases were received a surgical extirpation subtotally or partially prior to radiotherapy. And all patients with glioma and brain metastasis received also immuno-chemotherapy in the usual manner during radiotherapy. The calculated dose expressed by NeuNSD and TDF showed a significant relationship between a therapeutic dose and a postradiation time in terms of the appearance of RIC. It was suggested that RIC was caused by a dose over 800 in NeuNSD and a dose over 70 in TDF. Furthermore, it was suggested that an aged patient and a patient who had the vulnerable brain tissue to radiation exposure in the irradiated field had the high risk of RIC. On the other hand, our results suggested that the tumor sterilization dose should be over 1,536 NeuNSD and the irradiated method should be further considered in addition to the radiobiological concepts for various brain tumors. (author)

  17. Influence of dosing times on cisplatin-induced peripheral neuropathy in rats

    International Nuclear Information System (INIS)

    Seto, Yoshihiro; Okazaki, Fumiyasu; Horikawa, Keiji; Zhang, Jing; Sasaki, Hitoshi; To, Hideto

    2016-01-01

    Although cis-diamminedichloro-platinum (CDDP) exhibits strong therapeutic effects in cancer chemotherapy, its adverse effects such as peripheral neuropathy, nephropathy, and vomiting are dose-limiting factors. Previous studies reported that chronotherapy decreased CDDP-induced nephropathy and vomiting. In the present study, we investigated the influence of dosing times on CDDP-induced peripheral neuropathy in rats. CDDP (4 mg/kg) was administered intravenously at 5:00 or 17:00 every 7 days for 4 weeks to male Sprague–Dawley rats, and saline was given to the control group. To assess the dosing time dependency of peripheral neuropathy, von-Frey test and hot-plate test were performed. In order to estimate hypoalgesia, the hot-plate test was performed in rats administered CDDP weekly for 4 weeks. On day 28, the withdrawal latency to thermal stimulation was significantly prolonged in the 17:00-treated group than in the control and 5:00-treated groups. When the von-Frey test was performed to assess mechanical allodynia, the withdrawal threshold was significantly lower in the 5:00 and 17:00-treated groups than in the control group on day 6 after the first CDDP dose. The 5:00-treated group maintained allodynia throughout the experiment with the repeated administration of CDDP, whereas the 17:00-treated group deteriorated from allodynia to hypoalgesia. It was revealed that the severe of CDDP-induced peripheral neuropathy was inhibited in the 5:00-treated group, whereas CDDP-treated groups exhibited mechanical allodynia. These results suggested that the selection of an optimal dosing time ameliorated CDDP-induced peripheral neuropathy. The online version of this article (doi:10.1186/s12885-016-2777-0) contains supplementary material, which is available to authorized users

  18. Evaluation of the repeated-dose liver and gastrointestinal tract micronucleus assays with 22 chemicals using young adult rats: summary of the collaborative study by the Collaborative Study Group for the Micronucleus Test (CSGMT)/The Japanese Environmental Mutagen Society (JEMS) - Mammalian Mutagenicity Study Group (MMS).

    Science.gov (United States)

    Hamada, Shuichi; Ohyama, Wakako; Takashima, Rie; Shimada, Keisuke; Matsumoto, Kazumi; Kawakami, Satoru; Uno, Fuyumi; Sui, Hajime; Shimada, Yasushi; Imamura, Tadashi; Matsumura, Shoji; Sanada, Hisakazu; Inoue, Kenji; Muto, Shigeharu; Ogawa, Izumi; Hayashi, Aya; Takayanagi, Tomomi; Ogiwara, Yosuke; Maeda, Akihisa; Okada, Emiko; Terashima, Yukari; Takasawa, Hironao; Narumi, Kazunori; Wako, Yumi; Kawasako, Kazufumi; Sano, Masaki; Ohashi, Nobuyuki; Morita, Takeshi; Kojima, Hajime; Honma, Masamitsu; Hayashi, Makoto

    2015-03-01

    The repeated-dose liver micronucleus (RDLMN) assay using young adult rats has the potential to detect hepatocarcinogens. We conducted a collaborative study to assess the performance of this assay and to evaluate the possibility of integrating it into general toxicological studies. Twenty-four testing laboratories belonging to the Mammalian Mutagenicity Study Group, a subgroup of the Japanese Environmental Mutagen Society, participated in this trial. Twenty-two model chemicals, including some hepatocarcinogens, were tested in 14- and/or 28-day RDLMN assays. As a result, 14 out of the 16 hepatocarcinogens were positive, including 9 genotoxic hepatocarcinogens, which were reported negative in the bone marrow/peripheral blood micronucleus (MN) assay by a single treatment. These outcomes show the high sensitivity of the RDLMN assay to hepatocarcinogens. Regarding the specificity, 4 out of the 6 non-liver targeted genotoxic carcinogens gave negative responses. This shows the high organ specificity of the RDLMN assay. In addition to the RDLMN assay, we simultaneously conducted gastrointestinal tract MN assays using 6 of the above carcinogens as an optional trial of the collaborative study. The MN assay using the glandular stomach, which is the first contact site of the test chemical when administered by oral gavage, was able to detect chromosomal aberrations with 3 test chemicals including a stomach-targeted carcinogen. The treatment regime was the 14- and/or 28-day repeated-dose, and the regime is sufficiently promising to incorporate these methods into repeated-dose toxicological studies. The outcomes of our collaborative study indicated that the new techniques to detect chromosomal aberrations in vivo in several tissues worked successfully. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

  19. Immunologic mechanism of the suppressive effect of low dose radiation on thymic lymphoma induced by radiation

    International Nuclear Information System (INIS)

    Li Xiujuan; Yang Ying; Li Xiuyi; Liu Shuzheng

    1999-01-01

    To study immunologic mechanism of the suppressive effect of low dose radiation (LDR) on thymic lymphoma (TL) induced by high dose radiation (HDR). The authors adopted the model that C57BL/6J mice were administered whole body irradiation with 1.75 Gy X-rays one time every week for 4 weeks to induce TL. It was examined that splenic NK cytotoxic activity, IL-2 and γ-IFN secretion activity, peritoneal macrophage phagocytosis and its TNF-α secretion activity in mice with different dose 1 month after irradiation. The results showed that all the immunologic functions mentioned above in mice given 75 mGy 12 h before 1.75 Gy every time were higher than that in mice given only 1.75 Gy, and approached to the sham-irradiation mice. It suggested that the suppressive effect of LDR on TL induced by HDR may be related to the adaptive response induced by LDR and decreasing immunological functions damage caused by HDR

  20. Radiation-induced cell mutations as a function of dose rate

    International Nuclear Information System (INIS)

    Kiefer, J.

    1987-01-01

    A brief review of the data in the literature is presented and forms the background of the experimental data given by the author obtained with exponential long-term cultures of V79 hamster cells exposed over a period of up to 35 days to different dose rates of gamma radiation. The experimental results show that at a dose rate of 40 mGy/hour the number of induced mutations is reduced, - which is in agreement with literature data - , but a dose rate of less than 30 mGy/hour makes the induced mutations leap to a value clearly higher than those induced by acute irradiation. As in addition to the mutations recombination is a significant factor of the radiation risk, experiments with a heterozygotic yeast strain have been made, as there is to date no reliable mammalian cell system available for this kind of research. Long-term radiation exposure of the yeast cells over a period of six weeks drastically increased the rate of recombinations, to a value higher by a factor of about 4 than that induced by acute irradiation. (orig.) [de

  1. Induction of somatic mutations by low-dose X-rays: the challenge in recognizing radiation-induced events.

    Science.gov (United States)

    Nagashima, Haruki; Shiraishi, Kumiko; Ohkawa, Saori; Sakamoto, Yuki; Komatsu, Kenshi; Matsuura, Shinya; Tachibana, Akira; Tauchi, Hiroshi

    2017-10-19

    It is difficult to distinguish radiation-induced events from spontaneous events during induction of stochastic effects, especially in the case of low-dose or low-dose-rate exposures. By using a hypersensitive system for detecting somatic mutations at the HPRT1 locus, we investigated the frequency and spectrum of mutations induced by low-dose X-rays. The mutant frequencies induced by doses of >0.15 Gy were statistically significant when compared with the spontaneous frequency, and a clear dose dependency was also observed for mutant frequencies at doses of >0.15 Gy. In contrast, mutant frequencies at doses of 0.2 Gy. Our observations suggest that there could be a critical dose for mutation induction at between 0.1 Gy and 0.2 Gy, where mutagenic events are induced by multiple DNA double-strand breaks (DSBs). These observations also suggest that low-dose radiation delivered at doses of <0.1 Gy may not result in DSB-induced mutations but may enhance spontaneous mutagenesis events. © The Author 2017. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

  2. Dose-response study of the hematological toxicity induced by vectorized radionuclides in a mouse model

    International Nuclear Information System (INIS)

    Rousseau-Poivet, J.; Sas, N.; Nguyen, F.; Abadie, J.; Chouin, N.; Barbet, J.

    2015-01-01

    studied progenitor and blood cells. As compared to 0.8 Gy, one more week was necessary at 1.4 Gy. A mild anemia (21% erythrocyte depletion) was noticed only at this higher absorbed dose between D3 and D10. Conclusion: absorbed doses to the BM between 0.8 and 1.4 Gy induced hematological toxicity expressed by transient BM aplasia, neutropenia, thrombocytopenia and inconsistent anemia. These depletions and time to recovery were both dose-dependent. Higher absorbed doses will be achieved to better investigate the dose-response relationship and to further develop our compartmental model for platelets. Neutrophils and erythrocytes kinetics are also under investigation to generate satisfying simulations with the model. (authors)

  3. High doses of salicylate causes prepulse facilitation of onset-gap induced acoustic startle response.

    Science.gov (United States)

    Sun, Wei; Doolittle, Lauren; Flowers, Elizabeth; Zhang, Chao; Wang, Qiuju

    2014-01-01

    Prepulse inhibition of acoustic startle reflex (PPI), a well-established method for evaluating sensorimotor gating function, has been used to detect tinnitus in animal models. Reduced gap induced PPI (gap-PPI) was considered as a sign of tinnitus. The silent gap used in the test contains both onset and offset signals. Tinnitus may affect these cues differently. In this experiment, we studied the effects of a high dose of salicylate (250 mg/kg, i.p.), an inducer of reversible tinnitus and sensorineural hearing loss, on gap-PPI induced by three different gaps: an onset-gap with 0.1 ms onset and 25 ms offset time, an offset-gap with 25 ms onset and 0.1 ms offset time, and an onset-offset-gap with 0.1 ms onset and offset time. We found that the onset-gaps induced smaller inhibitions than the offset-gaps before salicylate treatment. The offset-gap induced PPI was significantly reduced 1-3h after salicylate treatment. However, the onset-gap caused a facilitation of startle response. These results suggest that salicylate induced reduction of gap-PPI was not only caused by the decrease of offset-gap induced PPI, but also by the facilitation induced by the onset-gap. Since the onset-gap induced PPI is caused by neural offset response, our results suggest that salicylate may cause a facilitation of neural response to an offset acoustical signal. Treatment of vigabatrin (60 mg/kg/day, 14 days), which elevates the GABA level in the brain, blocked the offset-gap induced PPI and onset-gap induced facilitation caused by salicylate. These results suggest that enhancing GABAergic activities can alleviate salicylate induced tinnitus. Published by Elsevier B.V.

  4. Irradiation induced aerosol formation in flue gas: experiments on low doses

    International Nuclear Information System (INIS)

    Maekelae, J.M.

    1992-01-01

    Laboratory experiments on irradiation induced aerosol formation from gaseous sulphur dioxide in humid air are presented. This work is connected to the aerosol particle formation process in the electron beam technique for cleaning flue gas. As a partial process of this method primary products of the radiolysis of water vapour convert sulphur dioxide into gaseous sulphuric acid which then nucleates with water vapour forming small acid droplets. This experimental work has been performed on relatively low absorbed doses. Aerosol particle formation is strongly dependent on dose. In the experiments, the first aerosol particles were detected already on absorbed doses of 0.1-10 mGy. The particle size in these cases is in the so-called ultrafine size range (1-20 nm). In this article three experimental set-ups with some characteristic results are presented. (Author)

  5. MAGIK: a Monte Carlo system for computing induced residual activation dose rates

    International Nuclear Information System (INIS)

    Barish, J.; Gabriel, T.A.; Alsmiller, R.G. Jr.

    1979-08-01

    The photon dose rate from the induced activity produced by sustained bombardment of materials by neutrons and charged particles may present a significant radiation hazard. To minimize this hazard, the material configuration must be so designed that the photon dose rate decays to an acceptable level soon after the source beam is turned off. MAGIK calculates the time-independent photon dose rates that result from activities produced by nucleon-nucleus and meson-nucleus collisions over a wide range of energies. The system has been used both for high-energy accelerator studies and for fusion reactor studies. In the MAGIK system the lengthy photon transport calculations are carried out independent of time, and the time dependence is introduced in the final program, thereby permitting study of various operating scenarios with a minimum computing cost

  6. Dose dependence of radiation-induced segregation in Ni-1 at% Si

    International Nuclear Information System (INIS)

    Rehn, L.E.; Okamoto, P.R.; Wiedersich, H.

    1979-01-01

    Measurements have been made of alloy composition as a function of depth from the external surface in Ni-1 at% Si specimens after irradiation with 3-MeV 58 Ni + ions to several different doses at nominal temperatures of 525 and 600 0 C. Very rapid segregation of Si toward the external surface ocurred during irradiation. Surface concentrations of Si in excess of the 10 at% solubility limit were found at both irradiation temperatures after a dose of only approximately 0.05 dpa. The rate of segregation decreased markedly in the dose range from approximately 1-10 dpa. Qualitative agreement was found between the experimental observations and calculations made using a modified Johnson-Lam segregation mode (1976). The present investigation suggests that radiation-induced segregation may significantly alter the mechanical behavior of irradiated alloys long before the onset of void swelling. (Auth.)

  7. High doses of bone morphogenetic protein 2 induce structurally abnormal bone and inflammation in vivo.

    Science.gov (United States)

    Zara, Janette N; Siu, Ronald K; Zhang, Xinli; Shen, Jia; Ngo, Richard; Lee, Min; Li, Weiming; Chiang, Michael; Chung, Jonguk; Kwak, Jinny; Wu, Benjamin M; Ting, Kang; Soo, Chia

    2011-05-01

    The major Food and Drug Association-approved osteoinductive factors in wide clinical use are bone morphogenetic proteins (BMPs). Although BMPs can promote robust bone formation, they also induce adverse clinical effects, including cyst-like bone formation and significant soft tissue swelling. In this study, we evaluated multiple BMP2 doses in a rat femoral segmental defect model and in a minimally traumatic rat femoral onlay model to determine its dose-dependent effects. Results of our femoral segmental defect model established a low BMP2 concentration range (5 and 10 μg/mL, total dose 0.375 and 0.75 μg in 75 μg total volume) unable to induce defect fusion, a mid-range BMP2 concentration range able to fuse the defect without adverse effects (30 μg/mL, total dose 2.25 μg in 75 μg total volume), and a high BMP2 concentration range (150, 300, and 600 μg/mL, total dose 11.25, 22.5, and 45 μg in 75 μg total volume) able to fuse the defect, but with formation of cyst-like bony shells filled with histologically confirmed adipose tissue. In addition, compared to control, 4 mg/mL BMP2 also induced significant tissue inflammatory infiltrates and exudates in the femoral onlay model that was accompanied by increased numbers of osteoclast-like cells at 3, 7, and 14 days. Overall, we consistently reproduced BMP2 side effects of cyst-like bone and soft tissue swelling using high BMP2 concentration approaching the typical human 1500 μg/mL.

  8. Search for the lowest irradiation dose from literatures on radiation-induced cancer in gastrointestinal tract

    International Nuclear Information System (INIS)

    Yoshizawa, Yasuo; Kusama, Tomoko

    1976-01-01

    A survey of past case reports about radiation-induced cancer in the gastrointestinal tract was carried out with the main object of finding the lowest irradiation dose. Search of the literature published since 1923 revealed 80 cases of radiation-induced large intestine cancer and one case of stomach cancer. The cases of radiation-induced cancer in the large intestine had received radiation for the treatment of non-malignant conditions, fibroma, ovarial cyste, myoma, endometritis and duodenal ulcer. The lowest irradiation dose was estimated at 460 rads. Adenocarcinoma was the histopathological finding in all cases of radiation-induced cancer in the caecum, colon and rectum, and squamous cell carcinoma in the cases of anal cancer. The latent period ranged from 1 to 31 years, with the average of 13.6 years. There were some reports of statistical studies of radiation-induced stomach cancer. Three groups were the subjects of these studies. The first group was composed of atomic bomb survivors, the second of patients who had undergone radiation treatment for ankylosing spondilitis, and the third of duodenal ulcer patients subjected to radiation treatment for the purpose of suppressing gastric acid secretion. These statistical studies showed no significant increase of the incidence of stomach cancer in the irradiated groups. (auth.)

  9. Search for the lowest irradiation dose from literatures on radiation-induced cancer in gastrointestinal tract

    Energy Technology Data Exchange (ETDEWEB)

    Yoshizawa, Y; Kusama, T [Tokyo Univ. (Japan). Faculty of Medicine

    1976-05-01

    A survey of past case reports about radiation-induced cancer in the gastrointestinal tract was carried out with the main object of finding the lowest irradiation dose. Search of the literature published since 1923 revealed 80 cases of radiation-induced large intestine cancer and one case of stomach cancer. The cases of radiation-induced cancer in the large intestine had received radiation for the treatment of non-malignant conditions, fibroma, ovarial cyste, myoma, endometritis and duodenal ulcer. The lowest irradiation dose was estimated at 460 rads. Adenocarcinoma was the histopathological finding in all cases of radiation-induced cancer in the caecum, colon and rectum, and squamous cell carcinoma in the cases of anal cancer. The latent period ranged from 1 to 31 years, with the average of 13.6 years. There were some reports of statistical studies of radiation-induced stomach cancer. Three groups were the subjects of these studies. The first group was composed of atomic bomb survivors, the second of patients who had undergone radiation treatment for ankylosing spondilitis, and the third of duodenal ulcer patients subjected to radiation treatment for the purpose of suppressing gastric acid secretion. These statistical studies showed no significant increase of the incidence of stomach cancer in the irradiated groups.

  10. High-dose radiation-induced meningioma following prophylactic cranial irradiation for acute lymphoblastic leukaemia

    International Nuclear Information System (INIS)

    Matsuda, Ryosuke; Nikaido, Yuji; Yamada, Tomonori; Mishima, Hideaki; Tamaki, Ryo

    2005-01-01

    A 12 year-old girl was treated with prophylactic cranial irradiation for acute lymphoblastic leukaemia (ALL). At the age of 39, she was admitted to our hospital for status epilepticus. Computed tomography demonstrated two, enhancing bilateral sided intracranial tumors. After surgery, this patient presented meningiomas which histologically, were of the meningothelial type. The high cure rate in childhood ALL, attributable to aggressive chemotherapy and prophylactic cranial irradiation, is capable of inducing secondary brain tumor. Twelve cases of high-dose radiation-induced meningioma following ALL are also reviewed. (author)

  11. High-dose radiation-induced meningioma following prophylactic cranial irradiation for acute lymphoblastic leukaemia

    Energy Technology Data Exchange (ETDEWEB)

    Matsuda, Ryosuke; Nikaido, Yuji; Yamada, Tomonori; Mishima, Hideaki; Tamaki, Ryo [National Hospital Organization Osaka Minami Medical Center, Kawachinagano (Japan)

    2005-03-01

    A 12 year-old girl was treated with prophylactic cranial irradiation for acute lymphoblastic leukaemia (ALL). At the age of 39, she was admitted to our hospital for status epilepticus. Computed tomography demonstrated two, enhancing bilateral sided intracranial tumors. After surgery, this patient presented meningiomas which histologically, were of the meningothelial type. The high cure rate in childhood ALL, attributable to aggressive chemotherapy and prophylactic cranial irradiation, is capable of inducing secondary brain tumor. Twelve cases of high-dose radiation-induced meningioma following ALL are also reviewed. (author)

  12. Single Low-Dose Radiation Induced Regulation of Keratinocyte Differentiation in Calcium-Induced HaCaT Cells

    Science.gov (United States)

    Hahn, Hyung Jin; Youn, Hae Jeong; Cha, Hwa Jun; Kim, Karam; An, Sungkwan

    2016-01-01

    Background We are continually exposed to low-dose radiation (LDR) in the range 0.1 Gy from natural sources, medical devices, nuclear energy plants, and other industrial sources of ionizing radiation. There are three models for the biological mechanism of LDR: the linear no-threshold model, the hormetic model, and the threshold model. Objective We used keratinocytes as a model system to investigate the molecular genetic effects of LDR on epidermal cell differentiation. Methods To identify keratinocyte differentiation, we performed western blots using a specific antibody for involucrin, which is a precursor protein of the keratinocyte cornified envelope and a marker for keratinocyte terminal differentiation. We also performed quantitative polymerase chain reaction. We examined whether LDR induces changes in involucrin messenger RNA (mRNA) and protein levels in calcium-induced keratinocyte differentiation. Results Exposure of HaCaT cells to LDR (0.1 Gy) induced p21 expression. p21 is a key regulator that induces growth arrest and represses stemness, which accelerates keratinocyte differentiation. We correlated involucrin expression with keratinocyte differentiation, and examined the effects of LDR on involucrin levels and keratinocyte development. LDR significantly increased involucrin mRNA and protein levels during calcium-induced keratinocyte differentiation. Conclusion These studies provide new evidence for the biological role of LDR, and identify the potential to utilize LDR to regulate or induce keratinocyte differentiation. PMID:27489424

  13. Sodium fusidate ameliorates the course of diabetes induced in mice by multiple low doses of streptozotocin

    DEFF Research Database (Denmark)

    Nicoletti, F; Di Marco, R; Conget, I

    2000-01-01

    We studied the effects of the immunosuppressant sodium fusidate (fusidin) on murine immunoinflammatory diabetes mellitus (DM) induced by multiple low doses of streptozotocin (SZ). Fusidin was given by gavage to three strains of mice (C57KsJ, C57BL/6, CD1) at doses 10 or 100 mg/kg body weight every...... induced in vivo by ConA, reducing the levels of IFN-gamma, IL-2 and TNF-alpha and augmenting the level of IL-6. However, only the inhibitory effect of the drug on the synthesis/release of IFN-gamma seemed to be causally related to its capacity to counteract the SZ-induced DM. In fact, the disease...... other day. The drug was administered as an early or late prophylactic regime starting either 1 day prior to the first or after the fifth and last injection of SZ. In both situations the largest dose of fusidin successfully reduced the clinical, chemical and histological signs of DM, the treated mice...

  14. Dose dependency of time of onset of radiation-induced growth hormone deficiency

    International Nuclear Information System (INIS)

    Clayton, P.E.; Shalet, S.M.

    1991-01-01

    Growth hormone (GH) secretion during insulin-induced hypoglycemia was assessed on 133 occasions in 82 survivors of childhood malignant disease. All had received cranial irradiation with a dose range to the hypothalamic-pituitary axis of 27 to 47.5 Gy (estimated by a schedule of 16 fractions over 3 weeks) and had been tested on one or more occasions between 0.2 and 18.9 years after treatment. Results of one third of the GH tests were defined as normal (GH peak response, greater than 15 mU/L) within the first 5 years, in comparison with 16% after 5 years. Stepwise multiple linear regression analysis showed that dose (p = 0.007) and time from irradiation (p = 0.03), but not age at therapy, had a significant influence on peak GH responses. The late incidence of GH deficiency was similar over the whole dose range (4 of 26 GH test results normal for less than 30 Gy and 4 of 25 normal for greater than or equal to 30 Gy after 5 years), but the speed of onset over the first years was dependent on dose. We conclude that the requirement for GH replacement therapy and the timing of its introduction will be influenced by the dose of irradiation received by the hypothalamic-pituitary axis

  15. Pretreatment of low dose radiation reduces radiation-induced apoptosis in mouse lymphoma (EL4) cells.

    Science.gov (United States)

    Kim, J H; Hyun, S J; Yoon, M Y; Ji, Y H; Cho, C K; Yoo, S Y

    1997-06-01

    Induction of an adaptive response to ionizing radiation in mouse lymphoma (EL4) cells was studied by using cell survival fraction and apoptotic nucleosomal DNA fragmentation as biological end points. Cells in early log phase were pre-exposed to low dose of gamma-rays (0.01 Gy) 4 or 20 hrs prior to high dose gamma-ray (4, 8 and 12 Gy for cell survival fraction analysis; 8 Gy for DNA fragmentation analysis) irradiation. Then cell survival fractions and the extent of DNA fragmentation were measured. Significant adaptive response, increase in cell survival fraction and decrease in the extent of DNA fragmentation were induced when low and high dose gamma-ray irradiation time interval was 4 hr. Addition of protein or RNA synthesis inhibitor, cycloheximide or 5,6-dichloro-1-beta-d-ribofuranosylbenzimidazole (DRFB), respectively during adaptation period, the period from low dose gamma-ray irradiation to high dose gamma-ray irradiation, was able to inhibit the induction of adaptive response, which is the reduction of the extent DNA fragmentation in irradiated EL4 cells. These data suggest that the induction of adaptive response to ionizing radiation in EL4 cells required both protein and RNA synthesis.

  16. Sodium selenosulfate at an innocuous dose markedly prevents cisplatin-induced gastrointestinal toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Li, Jun; Sun, Kang [School of Tea and Food Science, Anhui Agricultural University, Hefei 230036, Anhui (China); Ni, Lijuan; Wang, Xufang [School of Chemistry and Materials of Science, University of Science and Technology of China, Hefei 230052, Anhui (China); Wang, Dongxu [School of Tea and Food Science, Anhui Agricultural University, Hefei 230036, Anhui (China); Zhang, Jinsong, E-mail: zjs@ahau.edu.cn [School of Tea and Food Science, Anhui Agricultural University, Hefei 230036, Anhui (China)

    2012-02-01

    Our previous studies in mice revealed that two weeks short-term toxicity of sodium selenosulfate was significantly lower than that of sodium selenite, but selenium repletion efficacy of both compounds was equivalent. In addition, we showed that sodium selenosulfate reduced nephrotoxicity of cisplatin (CDDP) without compromising its anticancer activity, thus leading to a dramatic increase of cancer cure rate from 25% to 75%. Hydration has been used in clinical practice to reduce CDDP-induced nephrotoxicity, but it cannot mitigate CDDP-induced gastrointestinal toxicity. The present work investigated whether sodium selenosulfate is a potential preventive agent for the gastrointestinal toxicity. In tumor-bearing mice, sodium selenosulfate was administered at a dose of 9.5 μmol/kg daily for 11 days, CDDP alone resulted in diarrhea by 88% on day 12, whereas the co-administration of CDDP and sodium selenosulfate dramatically reduced diarrhea to 6% (p < 0.0001). Such a prominent protective effect promoted us to evaluate the safety potential of long-term sodium selenosulfate application. Mice were administered with sodium selenosulfate or sodium selenite for 55 days at the doses of 12.7 and 19 μmol/kg. The low-dose sodium selenite caused growth suppression and hepatotoxicity which were aggravated by the high-dose, leading to 40% mortality rate, but no toxic symptoms were observed in the two sodium selenosulfate groups. Altogether these results clearly show that sodium selenosulfate at an innocuous dose can markedly prevent CDDP-induced gastrointestinal toxicity. -- Highlights: ►Cisplatin resulted in diarrhea in mice by 88%. ►i.p. selenosulfate at 9.5 μmol/kg daily for 11 days reduced diarrhea to 6%. ►i.p. selenosulfate at 19 μmol/kg daily for 55 days was not toxic. ►i.p. selenite at 19 μmol/kg daily for 55 days was lethal. ►Innocuous dose of selenosulfate greatly prevents cisplatin-induced diarrhea.

  17. Sodium selenosulfate at an innocuous dose markedly prevents cisplatin-induced gastrointestinal toxicity

    International Nuclear Information System (INIS)

    Li, Jun; Sun, Kang; Ni, Lijuan; Wang, Xufang; Wang, Dongxu; Zhang, Jinsong

    2012-01-01

    Our previous studies in mice revealed that two weeks short-term toxicity of sodium selenosulfate was significantly lower than that of sodium selenite, but selenium repletion efficacy of both compounds was equivalent. In addition, we showed that sodium selenosulfate reduced nephrotoxicity of cisplatin (CDDP) without compromising its anticancer activity, thus leading to a dramatic increase of cancer cure rate from 25% to 75%. Hydration has been used in clinical practice to reduce CDDP-induced nephrotoxicity, but it cannot mitigate CDDP-induced gastrointestinal toxicity. The present work investigated whether sodium selenosulfate is a potential preventive agent for the gastrointestinal toxicity. In tumor-bearing mice, sodium selenosulfate was administered at a dose of 9.5 μmol/kg daily for 11 days, CDDP alone resulted in diarrhea by 88% on day 12, whereas the co-administration of CDDP and sodium selenosulfate dramatically reduced diarrhea to 6% (p < 0.0001). Such a prominent protective effect promoted us to evaluate the safety potential of long-term sodium selenosulfate application. Mice were administered with sodium selenosulfate or sodium selenite for 55 days at the doses of 12.7 and 19 μmol/kg. The low-dose sodium selenite caused growth suppression and hepatotoxicity which were aggravated by the high-dose, leading to 40% mortality rate, but no toxic symptoms were observed in the two sodium selenosulfate groups. Altogether these results clearly show that sodium selenosulfate at an innocuous dose can markedly prevent CDDP-induced gastrointestinal toxicity. -- Highlights: ►Cisplatin resulted in diarrhea in mice by 88%. ►i.p. selenosulfate at 9.5 μmol/kg daily for 11 days reduced diarrhea to 6%. ►i.p. selenosulfate at 19 μmol/kg daily for 55 days was not toxic. ►i.p. selenite at 19 μmol/kg daily for 55 days was lethal. ►Innocuous dose of selenosulfate greatly prevents cisplatin-induced diarrhea.

  18. Dose-response study of thimerosal-induced murine systemic autoimmunity

    International Nuclear Information System (INIS)

    Havarinasab, S.; Lambertsson, L.; Qvarnstroem, J.; Hultman, P.

    2004-01-01

    The organic compound ethylmercurithiosalicylate (thimerosal), which is primarily present in the tissues as ethylmercury, has caused illness and several deaths due to erroneous handling when used as a disinfectant or as a preservative in medical preparations. Lately, possible health effects of thimerosal in childhood vaccines have been much discussed. Thimerosal is a well-known sensitizing agent, although usually of no clinical relevance. In rare cases, thimerosal has caused systemic immune reactions including acrodynia. We have studied if thimerosal might induce the systemic autoimmune condition observed in genetically susceptible mice after exposure to inorganic mercury. A.SW mice were exposed to 1.25-40 mg thimerosal/l drinking water for 70 days. Antinucleolar antibodies, targeting the 34-kDa protein fibrillarin, developed in a dose-related pattern and first appeared after 10 days in the two highest dose groups. The lowest observed adverse effect level (LOAEL) for antifibrillarin antibodies was 2.5 mg thimerosal/l, corresponding to an absorbed dose of 147 μg Hg/kg bw and a concentration of 21 and 1.9 μg Hg/g in the kidney and lymph nodes, respectively. The same LOAEL was found for tissue immune-complex deposits. The total serum concentration of IgE, IgG1, and IgG2a showed a significant dose-related increase in thimerosal-treated mice, with a LOAEL of 5 mg thimerosal/l for IgG1 and IgE, and 20 mg thimerosal/l for IgG2a. The polyclonal B-cell activation showed a significant dose-response relationship with a LOAEL of 10 mg thimerosal/l. Therefore, thimerosal induces in genetically susceptible mice a systemic autoimmune syndrome very similar to that seen after treatment with inorganic mercury, although a higher absorbed dose of Hg is needed using thimerosal. The autoimmune syndrome induced by thimerosal is different from the weaker and more restricted autoimmune reaction observed after treatment with an equipotent dose of methylmercury

  19. Frequencies of aneuploidy and dominant lethal mutations in young female mice induced by low dose γ-rays

    International Nuclear Information System (INIS)

    Yao Suyan; Zhang Chaoyang; Dai Lianlian; Gao Changwen

    1991-01-01

    Relationship between aneuploidy, dominant lethal mutations and doses in young feral mice induced by low dose γ-rays was examined. The results suggest that the frequencies of aneuploidy of embryos increased at 0.15 Gy, but increases at over 0.50 Gy after irradiation in groups. The frequencies of aneuploidy and dominant lethal mutations increased with increasing doses and fitted linear relationship. This dose-response relationship of trisomic was not significant. The frequency of dominant lethal mutations induced by 60 Co γ irradiation is 5.59%. The effect of dominant lethal mutation is higher than that of the aneuploidy

  20. Search for the lowest irradiation dose from literatures on radiation-induced cancer in uterus

    International Nuclear Information System (INIS)

    Yoshizawa, Yasuo; Kusama, Tomoko

    1975-01-01

    A survey of past case reports on radiation-induced cancer of the uterus was carried out with the main object of finding the lowest irradiation dose. Search of literature published since 1912 revealed 548 cases of radiation-induced cancer of the uterus. All of these cases of radiation-induced cancer had received radiation for the treatment of non-malignant disease. The primary gynecological conditions which were the object of radiation therapy were functional bleeding, endometrial hyperplasia, myoma, endometritis, and polyps. The lowest irradiation dose was estimated at 1000-1450 rad in the case of external X-ray irradiation, and 100 mg.hr for intrauterine radium therapy, which corresponds to 100-1000 rad. It was noted that were more cases of corpus cancer than cervical cancer. Histopathological findings of radiation-induced uterine cancer were carcinoma, sarcoma, and mixed mesodermal tumors. The latent period was distributed in the range of 1 to 40 years, with the average of 10.1 years. (auth.)

  1. Search for the lowest irradiation dose from literatures on radiation-induced bone tumor

    Energy Technology Data Exchange (ETDEWEB)

    Yoshizawa, Y; Kusama, T; Morimoto, K [Tokyo Univ. (Japan). Faculty of Medicine

    1977-04-01

    A survey of past case reports of bone tumor induced by external radiation was carried out with the main object of finding the lowest irradiation dose. Search of the literature published since 1922 revealed 262 cases of radiation-induced bone tumor. These patients, except a patient with occupational exposure, had received radiation for treatment. The primary conditions as object of radiation therapy were nonmalignan bone diseases such as tuberclosis, giant cell tumor, fibrous dysplasia and bone cyst, and extra-skeletal diseases such as retinoblastoma, breast cancer and uterus cancer. The ratio of male to female patients with radiation-induced bone tumor was 1:1.3. The age of the patient ranged between 5 and 98 years, with an average of 37.6 years. Skeletal distribution of radiation-induced bone tumor was as follows: 20% the frontal and face bones, 17% the femur, 10% the humerus, 9% the vertebral column, and 44% other. The lowest absorbed dose reported was 800 rads in patients irradiated for the treatment of bone disease, but 1800 rads in patients with extra-skeletal disease. The latent period ranged between 2 and 42 years, with an average of 11.7 years. The histopathological findings were as follows: 60% osteosarcoma, 25% fibrosarcoma, 7% chondrosarcoma, and 8% other.

  2. Dose-rate effect of adaptive response of apoptosis and cell cycle progression induced by low-dose ionizing radiation in EL-4 lymphoma cells in vitro

    International Nuclear Information System (INIS)

    Liu Shuchun; Lu Zhe; Li Yanbo; Kang Shunai; Gong Shouliang; Zhao Wenju

    2008-01-01

    Objective: To observe the dose-rate effect of adaptive response of apoptosis and cell cycle progression induced by low-dose ionizing radiation in EL-4 lymphoma cells in vitro in order to reveal the possible mechanism of biological effect and adaptive response induced by low dose radiation. Methods: The experiment was divided into D2 (challenging dose), D1 (inductive dose) + D2 and sham-irradiation groups. EL-4 lymphoma cells were irradiated with D1 (75 mGy, 6.25-200.00 mGy·mm -1 ) and D2(1.5 Gy, 287 mGy·min -1 ), the time interval between D1 and D2 was 6 h. The percentage of apoptosis and each cell cycle phase were measured with flow cytometry. Results: When the dose rates of D1 were 6.25-50.00 mGy·min -1 , the percentages of apoptosis in the D1 + D2 group were significantly lower than those in the D2 group (P 0 /G 1 phase cells decreased significantly (P -1 , D2 is 1.5 Gy (287 mGy·min -1 ), and the time interval between D1 and D2 is 6 h, the adaptive response of apoptosis and cell cycle progression in EL-4 lymphoma cells in vitro could be induced. (authors)

  3. Diethylene glycol-induced toxicities show marked threshold dose response in rats

    Energy Technology Data Exchange (ETDEWEB)

    Landry, Greg M., E-mail: Landry.Greg@mayo.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Dunning, Cody L., E-mail: cdunni@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Abreo, Fleurette, E-mail: fabreo@lsuhsc.edu [Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Latimer, Brian, E-mail: blatim@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Orchard, Elysse, E-mail: eorcha@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Division of Animal Resources, Louisiana State University Health Sciences Center, Shreveport, LA (United States); McMartin, Kenneth E., E-mail: kmcmar@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States)

    2015-02-01

    Diethylene glycol (DEG) exposure poses risks to human health because of widespread industrial use and accidental exposures from contaminated products. To enhance the understanding of the mechanistic role of metabolites in DEG toxicity, this study used a dose response paradigm to determine a rat model that would best mimic DEG exposure in humans. Wistar and Fischer-344 (F-344) rats were treated by oral gavage with 0, 2, 5, or 10 g/kg DEG and blood, kidney and liver tissues were collected at 48 h. Both rat strains treated with 10 g/kg DEG had equivalent degrees of metabolic acidosis, renal toxicity (increased BUN and creatinine and cortical necrosis) and liver toxicity (increased serum enzyme levels, centrilobular necrosis and severe glycogen depletion). There was no liver or kidney toxicity at the lower DEG doses (2 and 5 g/kg) regardless of strain, demonstrating a steep threshold dose response. Kidney diglycolic acid (DGA), the presumed nephrotoxic metabolite of DEG, was markedly elevated in both rat strains administered 10 g/kg DEG, but no DGA was present at 2 or 5 g/kg, asserting its necessary role in DEG-induced toxicity. These results indicate that mechanistically in order to produce toxicity, metabolism to and significant target organ accumulation of DGA are required and that both strains would be useful for DEG risk assessments. - Highlights: • DEG produces a steep threshold dose response for kidney injury in rats. • Wistar and F-344 rats do not differ in response to DEG-induced renal injury. • The dose response for renal injury closely mirrors that for renal DGA accumulation. • Results demonstrate the importance of DGA accumulation in producing kidney injury.

  4. Dose-dependent neuroprotective effect of enoxaparin on cold-induced traumatic brain injury.

    Science.gov (United States)

    Keskin, Ilknur; Gunal, M Yalcin; Ayturk, Nilufer; Kilic, Ulkan; Ozansoy, Mehmet; Kilic, Ertugrul

    2017-05-01

    Recent evidence exists that enoxaparin can reduce brain injury because of its anticoagulant activity. To investigate the potential therapeutic effect of enoxaparin on cold-induced traumatic brain injury, at 20 minutes after modeling, male BALB/c mouse models of cold-induced traumatic brain injury were intraperitoneally administered 3 and 10 mg/kg enoxaparin or isotonic saline solution. Twenty-four hours later, enoxaparin at 10 mg/kg greatly reduced infarct volume, decreased cell apoptosis in the cortex and obviously increased serum level of total antioxidant status. By contrast, administration of enoxaparin at 3 mg/kg did not lead to these changes. These findings suggest that enoxaparin exhibits neuroprotective effect on cold-induced traumatic brain injury in a dose-dependent manner.

  5. Radiation-induced polymerization of water-saturated styrene in a wide range of dose rate

    International Nuclear Information System (INIS)

    Takezaki, J.; Okada, T.; Sakurada, I.

    1978-01-01

    Radiation-induced polymerization of water-saturated styrene (water content 3.5 x 10 -2 mole/liter) was carried out in a wide range of dose rate between 1.2 x 10 3 and 1.8 x 10 7 rad/sec, and compared with the polymerization of the moderately dried styrene (water content 3.2 x 10 -3 mole/liter). Molecular weight distribution curves of the polymerization products showed that they were generally consisted of four parts, namely, oligomers, radical, cationic, and super polymers. Contributions of the four constituents to the polymerization and the number average degrees of polymerization (DP) of the four kinds of polymers were calculated by the graphical analysis of the curves. The rate of radical polymerization and DP of radical polymers are independent of the water content; the dose rate dependences of the polymerization rate and DP agree with the well known square root and inverse square root laws, respectively, of the radical polymerization of styrene. The rate of ionic polymerization is directly proportional to the dose rate, but it decreases, at a given dose rate, inversely proportional to the water content of styrene. DP of ionic polymer is independent of the dose rate but decreases with increasing water content. The super polymer of DP about 10 4 is not formed in the case of the moderately dried styrene. G values for the initiating radical and ion formation are calculated to be independently of the dose rate and water content, 0.66 and 0.027, respectively. It was suggested that oligomer was formed in the early stage by the interaction of cation with anion and only those cations which had survived underwent polymerization. 10 figures, 4 tables

  6. The role of radiation types and dose in induced genomic instability

    International Nuclear Information System (INIS)

    Kadhim Munira, A.

    2007-01-01

    Complete text of publication follows. Genomic Instability (GI) is defined as long-term alterations induced by low-dose exposure to a variety of genotoxic agents in mammalian cells that act to increase the 'apparent' spontaneous mutation frequency.GI is a hallmark of tumorigenic progression and is observed in the progeny of irradiated and bystander cells as the delayed and stochastic appearance of de novo chromosomal aberrations, gene mutations and delayed lethal mutations both in vitro and in vivo. It occurs at a frequency several orders of magnitude greater than would be expected for mutation in a single gene, implying that GI is a multigenic phenomenon. The expression of GI can be influenced by genotype, cell type and radiation quality; however the underlying mechanisms are not fully understood. While several studies have demonstrated GI induction by high and low LET radiation, our work on human and mouse primary cell systems has shown significant differences in the capacity to induce GI and the spectrum of alterations depending on LET. These differences might be attributed to differences in radiation track structure, radiation dose and radiation exposure regime (distribution of hit and un hit cells). In this presentation I shall review the role of radiation quality; describe the possible mechanisms underlining the observed differences between radiation type and present results of experiments demonstrating that the dose of low LET radiation might be the most significant factor in determining the role of radiation type in the induction of GI.

  7. Benchmark studies of induced radioactivity and remanent dose rates produced in LHC materials

    International Nuclear Information System (INIS)

    Brugger, M.; Mayer, S.; Roesler, S.; Ulrici, L.; Khater, H.; Prinz, A.; Vincke, H.

    2005-01-01

    Samples of materials that will be used for elements of the LHC machine as well as for shielding and construction components were irradiated in the stray radiation field of the CERN-EU high-energy Reference Field facility. The materials included various types of steel, copper, titanium, concrete and marble as well as light materials such as carbon composites and boron nitride. Emphasis was put on an accurate recording of the irradiation conditions, such as irradiation profile and intensity, and on a detailed determination of the elemental composition of the samples. After the irradiation, the specific activity induced in the samples as well as the remanent dose rate were measured at different cooling times ranging from about 20 minutes to two months. Furthermore, the irradiation experiment was simulated using the FLUKA Monte Carlo code and specific activities. In addition, dose rates were calculated. The latter was based on a new method simulating the production of various isotopes and the electromagnetic cascade induced by radioactive decay at a certain cooling time. In general, solid agreement was found, which engenders confidence in the predictive power of the applied codes and tools for the estimation of the radioactive nuclide inventory of the LHC machine as well as the calculation of remanent doses to personnel during interventions. (authors)

  8. Bimodal cell death induced by high radiation doses in the radioresistant sf9 insect cell line

    International Nuclear Information System (INIS)

    Chandna, S.

    2003-01-01

    Full text: This study was conducted to investigate the mode(s) of cell death induced by high radiation doses in the highly radioresistant Sf9 insect ovarian cell line. Methods: Cells were exposed to γ-radiation doses 200Gy and 500Gy, harvested at various time intervals (6h-72h) following irradiation, and subjected to cell morphology assay, DNA agarose gel electrophoresis, single cell gel electrophoresis (SCGE; comet assay) and Annexin-V labeling for the detection of membrane phosphatidylserine externalization. Cell morphology was assessed in cells entrapped and fixed in agarose gel directly from the cell suspension, thus preventing the possible loss of fragments/ apoptotic bodies. Surviving fraction of Sf9 cells was 0.01 at 200Gy and 98%) undergoing extensive DNA fragmentation at 500Gy, whereas the frequency of cells with DNA fragmentation was considerably less (∼12%) at 200Gy. Conclusions: While the mode of cell death at 200Gy seems to be different from typical apoptosis, a dose of 500Gy induced bimodal cell death, with typical apoptotic as well as the atypical cell death observed at 200Gy

  9. Case study: an evaluation of the human relevance of the synthetic pyrethroid metofluthrin-induced liver tumors in rats based on mode of action.

    Science.gov (United States)

    Yamada, Tomoya; Uwagawa, Satoshi; Okuno, Yasuyoshi; Cohen, Samuel M; Kaneko, Hideo

    2009-03-01

    In recent years, mode of action (MOA) frameworks have been developed through the International Life Sciences Institute Risk Science Institute and the International Programme on Chemical Safety, including an evaluation of the human relevance of the animal MOA data. In the present paper, the MOA for rat liver tumors induced by Metofluthrin is first analyzed through this framework based on data from studies on Metofluthrin and information on related chemicals from the literature. The human relevance of the rat liver carcinogenic response is then discussed based upon the human relevance framework. Two-year treatment with high dose of Metofluthrin produced hepatocellular tumors in both sexes of the Wistar rats. Metofluthrin induced CYP2B (increased smooth endoplasmic reticulum), resulted in increased liver weights which were associated with centrilobular hepatocyte hypertrophy, and induction of increased hepatocellular DNA replications. The above parameters related to the key events in Metofluthrin-induced liver tumors were observed at or below tumorigenic dose levels. Furthermore, CYP2B induction by Metofluthrin was shown to involve activation of the constitutive androstane receptor in rat hepatocytes. Based on the evidence, including a comparison with the results with another chemical, phenobarbital, acting by a similar MOA, it is reasonable to conclude that Metofluthrin will not have any hepatocarcinogenic activity in humans.

  10. Low-dose acute vanillin is beneficial against harmaline-induced tremors in rats.

    Science.gov (United States)

    Abdulrahman, Al Asmari; Faisal, Kunnathodi; Meshref, Ali Al Amri; Arshaduddin, Mohammed

    2017-03-01

    To study the effect of pretreatment with low doses of vanillin, a flavoring agent used as a food additive, on harmaline-induced tremor in rats. Sprague Dawley rats (110 ± 5 g) were divided into groups of six animals each. Vanillin (6.25 mg, 12.5 mg, and 25 mg/kg) was administered by gavage to different groups of rats, 30 minutes before the induction of tremor. Harmaline (10 mg/kg, i.p.) was used for the induction of tremor. The latency of onset, duration, tremor intensity, tremor index, and spontaneous locomotor activity were recorded. A separate batch of animals was used for the determination of serotonin (5HT) and 5 hydroxyindole acetic acid (5HIAA) levels in the brain. Harmaline treatment resulted in characteristic tremor that lasted for more than 2 hours and decreased the locomotor activity of rats. Pre-treatment with vanillin significantly reduced the duration, intensity, and tremor index of harmaline-treated animals. Vanillin treatment also significantly attenuated harmaline-induced decrease in the locomotor activity. An increase in 5HT levels and the changes in 5HIAA/5HT ratio observed in harmaline treated rats were significantly corrected in vanillin pretreated animals. Vanillin in low doses reduces harmaline-induced tremor in rats, probably through its modulating effect on serotonin levels in the brain. These findings suggest a beneficial effect of vanillin in essential tremor.

  11. Low-dose cadmium exposure exacerbates polyhexamethylene guanidine-induced lung fibrosis in mice.

    Science.gov (United States)

    Kim, Min-Seok; Kim, Sung-Hwan; Jeon, Doin; Kim, Hyeon-Young; Han, Jin-Young; Kim, Bumseok; Lee, Kyuhong

    2018-01-01

    Cadmium (Cd) is a toxic metal present in tobacco smoke, air, food, and water. Inhalation is an important route of Cd exposure, and lungs are one of the main target organs for metal-induced toxicity. Cd inhalation is associated with an increased risk of pulmonary diseases. The present study aimed to assess the effects of repeated exposure to low-dose Cd in a mouse model of polyhexamethylene guanidine (PHMG)-induced lung fibrosis. Mice were grouped into the following groups: vehicle control (VC), PHMG, cadmium chloride (CdCl 2 ), and PHMG + CdCl 2 . Animals in the PHMG group exhibited increased numbers of total cells and inflammatory cells in the bronchoalveolar lavage fluid (BALF) accompanied by inflammation and fibrosis in lung tissues. These parameters were exacerbated in mice in the PHMG + CdCl 2 group. In contrast, mice in the CdCl 2 group alone displayed only minimal inflammation in pulmonary tissue. Expression of inflammatory cytokines and fibrogenic mediators was significantly elevated in lungs of mice in the PHMG group compared with that VC. Further, expression of these cytokines and mediators was enhanced in pulmonary tissue in mice administered PHMG + CdCl 2 . Data demonstrate that repeated exposure to low-dose Cd may enhance the development of PHMG-induced pulmonary fibrosis.

  12. Total-dose radiation-induced degradation of thin film ferroelectric capacitors

    International Nuclear Information System (INIS)

    Schwank, J.R.; Nasby, R.D.; Miller, S.L.; Rodgers, M.S.; Dressendorfer, P.V.

    1990-01-01

    Thin film PbZr y Ti 1-y O 3 (PZT) ferroelectric memories offer the potential for radiation-hardened, high-speed nonvolatile memories with good retention and fatigue properties. In this paper we explore in detail the radiation hardness of PZT ferroelectric capacitors. Ferroelectric capacitors were irradiated using x-ray and Co-60 sources to dose levels up to 16 Mrad(Si). The capacitors were characterized for their memory properties both before and after irradiation. The radiation hardness was process dependent. Three out of four processes resulted in capacitors that showed less than 30% radiation-induced degradation in retained polarization charge and remanent polarization after irradiating to 16 Mrad(Si). On the other hand, one of the processes showed significant radiation-induced degradation in retained polarization charge and remanent polarization at dose levels above 1 Mrad(Si). The decrease in retained polarization charge appears to be due to an alteration of the switching characteristics of the ferroelectric due to changes in the internal fields. The radiation-induced degradation is recoverable by a postirradiation biased anneal and can be prevented entirely if devices are cycled during irradiation. The authors have developed a model to simulate the observed degradation

  13. Evaluation of induced activity, decay heat and dose rate distribution after shutdown in ITER

    Energy Technology Data Exchange (ETDEWEB)

    Maki, Koichi [Hitachi Ltd., Ibaraki (Japan). Hitachi Research Lab.; Satoh, Satoshi; Hayashi, Katsumi; Yamada, Koubun; Takatsu, Hideyuki; Iida, Hiromasa

    1997-03-01

    Induced activity, decay heat and dose rate distributions after shutdown were estimated for 1MWa/m{sup 2} operation in ITER. The activity in the inboard blanket one day after shutdown is 1.5x10{sup 11}Bq/cm{sup 3}, and the average decay heating rate 0.01w/cm{sup 3}. The dose rate outside the 120cm thick concrete biological shield is two order higher than the design criterion of 5{mu}Sv/h. This indicates that the biological shield thickness should be enhanced by 50cm in concrete, that is, total thickness 170cm for workers to enter the reactor room and to perform maintenance. (author)

  14. Exacerbation of benign familial neonatal epilepsy induced by massive doses of phenobarbital and midazolam.

    Science.gov (United States)

    Maeda, Tomoki; Shimizu, Miki; Sekiguchi, Kazuhito; Ishii, Atsushi; Ihara, Yukiko; Hirose, Shinichi; Izumi, Tatsuro

    2014-08-01

    Barbiturates and benzodiazepines are the first-line anticonvulsants for neonatal seizures. However, in immature brains, those drugs may lead to paradoxical neuronal excitation. A patient with benign familial neonatal epilepsy developed epileptic encephalopathy after massive doses of phenobarbital that were followed by a continuous infusion of midazolam on postnatal day 3. Electroencephalography revealed rhythmic delta activity in clusters with migrating epileptic foci. After discontinuation of both drugs, the patient's consciousness promptly improved and her electroencephalography normalized on postnatal day 5. This baby developed persistent electroencephalographic seizures due to massive doses of phenobarbital and midazolam. Clinicians should be aware of this anticonvulsant-induced paradoxical neuronal excitation and the uncoupling phenomenon, especially in individuals with benign familial neonatal epilepsy, who have low seizure thresholds. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. Corticosteroid effects on ventilator-induced diaphragm dysfunction in anesthetized rats depend on the dose administered

    Directory of Open Access Journals (Sweden)

    Decramer Marc

    2010-12-01

    Full Text Available Abstract Background High dose of corticosteroids has been previously shown to protect against controlled mechanical ventilation (CMV-induced diaphragmatic dysfunction while inhibiting calpain activation. Because literature suggests that the calpain inhibiting effect of corticosteroid depends on the dose administered, we determined whether lower doses of corticosteroids would also provide protection of the diaphragm during CMV. This may be important for patients undergoing mechanical ventilation and receiving corticosteroids. Methods Rats were assigned to controls or to 24 hours of CMV while being treated at the start of mechanical ventilation with a single intramuscular administration of either saline, or 5 mg/kg (low MP or 30 mg/kg (high MP of methylprednisolone. Results Diaphragmatic force was decreased after CMV and this was exacerbated in the low MP group while high MP rescued this diaphragmatic dysfunction. Atrophy was more severe in the low MP group than after CMV while no atrophy was observed in the high MP group. A significant and similar increase in calpain activity was observed in both the low MP and CMV groups whereas the high dose prevented calpain activation. Expression of calpastatin, the endogenous inhibitor of calpain, was decreased in the CMV and low MP groups but its level was preserved to controls in the high MP group. Caspase-3 activity increased in all CMV groups but to a lesser extent in the low and high MP groups. The 20S proteasome activity was increased in CMV only. Conclusions Administration of 30 mg/kg methylprednisolone during CMV protected against CMV-induced diaphragm dysfunction while 5 mg/kg was more deleterious. The protective effect is due mainly to an inhibition of the calpain system through preservation of calpastatin levels and to a lesser extent to a caspase-3 inhibition.

  16. Evaluation of therapeutic effect of low dose naltrexone in experimentally-induced Crohn's disease in rats.

    Science.gov (United States)

    Tawfik, Dina Ibrahim; Osman, Afaf Sayed; Tolba, Hedayat Mahmoud; Khattab, Aida; Abdel-Salam, Lubna O; Kamel, Mahmoud M

    2016-10-01

    Crohn's disease is a relapsing inflammatory condition afflicting the digestive tract. Drugs used for treatment of Crohn's disease may be associated with serious side effects. Endogenous opioid peptides modulate inflammatory cytokine production. Opioid antagonists have been shown to play a role in healing and repair of tissues. This work was designed to detect the possible beneficial effects of opioid antagonist naltrexone in indomethacin-induced Crohn's disease in rats. Enteritis was induced in male albino rats by two subcutaneous injection of indomethacin in a dose of 7.5mg/kg 24h apart started on day one. Salfasalazine, naltrexone and their combination were administered orally from day one of induction of enteritis to day 10. Disease activity index, serum levels of C-reactive protein and tumor necrosis factor-α, macroscopic and microscopic pathological scores and in vitro motility studies were evaluated. Induction of enteritis resulted in significant increase of disease activity index, significant elevation of serum levels of C-reactive protein and tumor necrosis factor-α, significant deterioration of pathological scores and significant increase in the mean contractility response of the isolated ileal segments compared with normal untreated rats. Treatment with sulfasalazine, low dose of natrexone or their combination resulted in significant improvement of all measured parameters compared with enteritis group. The current finding could provide new interesting opportunity for developing new therapeutic approaches for treatment of Crohn's disease. Use of naltrexone, especially in small dose, has little side effects making it of interest for treatment of Crohn's disease. Also, it provides the possibility of reduced doses of other drugs if it is used as combined therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Effect of low doses of cannabidiolic acid and ondansetron on LiCl-induced conditioned gaping (a model of nausea-induced behaviour) in rats.

    Science.gov (United States)

    Rock, E M; Parker, L A

    2013-06-01

    To determine the minimally effective dose of cannabidiolic acid (CBDA) that effectively reduces lithium chloride (LiCl)-induced conditioned gaping reactions (nausea-induced behaviour) in rats and to determine if these low systemic doses of CBDA (5-0.1 μg·kg⁻¹) relative to those of CBD could potentiate the anti-nausea effects of the classic 5-hydroxytryptamine 3 (5-HT₃) receptor antagonist, ondansetron (OND). We investigated the efficacy of low doses of CBDA to suppress acute nausea, assessed by the establishment of conditioned gaping to a LiCl-paired flavour in rats. The potential of threshold and subthreshold doses of CBDA to enhance the reduction of nausea-induced conditioned gaping by OND were then determined. CBDA (at doses as low as 0.5 μg·kg⁻¹) suppressed nausea-induced conditioned gaping to a flavour. A low dose of OND (1.0 μg·kg⁻¹) alone reduced nausea-induced conditioned gaping, but when it was combined with a subthreshold dose of CBDA (0.1 μg·kg⁻¹) there was an enhancement in the suppression of LiCl-induced conditioned gaping. CBDA potently reduced conditioned gaping in rats, even at low doses and enhanced the anti-nausea effect of a low dose of OND. These findings suggest that combining low doses of CBDA and OND will more effectively treat acute nausea in chemotherapy patients. © 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society.

  18. Chronic low-dose ultraviolet-induced mutagenesis in nucleotide excision repair-deficient cells.

    Science.gov (United States)

    Haruta, Nami; Kubota, Yoshino; Hishida, Takashi

    2012-09-01

    UV radiation induces two major types of DNA lesions, cyclobutane pyrimidine dimers (CPDs) and 6-4 pyrimidine-pyrimidine photoproducts, which are both primarily repaired by nucleotide excision repair (NER). Here, we investigated how chronic low-dose UV (CLUV)-induced mutagenesis occurs in rad14Δ NER-deficient yeast cells, which lack the yeast orthologue of human xeroderma pigmentosum A (XPA). The results show that rad14Δ cells have a marked increase in CLUV-induced mutations, most of which are C→T transitions in the template strand for transcription. Unexpectedly, many of the CLUV-induced C→T mutations in rad14Δ cells are dependent on translesion synthesis (TLS) DNA polymerase η, encoded by RAD30, despite its previously established role in error-free TLS. Furthermore, we demonstrate that deamination of cytosine-containing CPDs contributes to CLUV-induced mutagenesis. Taken together, these results uncover a novel role for Polη in the induction of C→T transitions through deamination of cytosine-containing CPDs in CLUV-exposed NER deficient cells. More generally, our data suggest that Polη can act as both an error-free and a mutagenic DNA polymerase, depending on whether the NER pathway is available to efficiently repair damaged templates.

  19. Neutropenia induced by high-dose intravenous benzylpenicillin in treating neurosyphilis: Does it really matter?

    Directory of Open Access Journals (Sweden)

    Rui-Rui Peng

    2017-03-01

    Full Text Available Prompt therapy with high-dose intravenous benzylpenicillin for a prolonged period is critical for neurosyphilis patients to avoid irreversible sequelae. However, life-threatening neutropenia has been reported as a complication of prolonged therapy with high doses of benzylpenicillin when treating other diseases. This study aimed to investigate the incidence, presentation, management and prognosis of benzylpenicillin-induced neutropenia in treating neurosyphilis based on a large sample of syphilis patients in Shanghai.Between 1st January 2013 and 31st December 2015, 1367 patients with neurosyphilis were treated with benzylpenicillin, 578 of whom were eligible for recruitment to this study. Among patients without medical co-morbidities, the total incidence of benzylpenicillin-induced neutropenia and severe neutropenia was 2.42% (95% CI: 1.38-4.13% and 0.35% (95% CI: 0.06-1.39%, respectively. The treatment duration before onset of neutropenia ranged from 10 to 14 days, with a total cumulative dose of between 240 and 324 megaunits of benzylpenicillin. Neutropenia was accompanied by symptoms of chills and fever (5 patients, fatigue (2 patients, cough (1 patient, sore throat (1 patient, diarrhea (1 patient and erythematous rash (1 patient. The severity of neutropenia was not associated with age, gender or type of neurosyphilis (p>0.05. Neutropenia, even when severe, was often tolerated and normalized within one week. A more serious neutropenia did not occur when reinstituting benzylpenicillin in patients with mild or moderate neutropenia nor when ceftriaxone was used three months after patients had previously experienced severe neutropenia.Benzylpenicillin-induced neutropenia was uncommon in our cohort of patients. Continuation of therapy was possible with intensive surveillance for those with mild or moderate neutropenia. For severe neutropenia, it is not essential to aggressively use hematopoietic growth factors or broad-spectrum antibiotics for

  20. Tests of the linearity assumption in the dose-effect relationship for radiation-induced cancer

    International Nuclear Information System (INIS)

    Cohen, A.F.; Cohen, B.L.

    1980-01-01

    The validity of the BEIR linear extrapolation to low doses of the dose-effect relationship for radiation induced cancer is tested by use of natural radiation making use of selectivity on type of cancer, smoking habits, sex, age group, geographic area and/or time period. For lung cancer, a linear interpolation between zero dose-zero effect and the data from radon-induced cancers in miners implies that the majority of all lung cancers among non-smokers are due to radon; since lung cancers in miners are mostly small-cell undifferentiated (SCU), a rather rare type in general, linearity over predicts the frequency of SCU lung cancers among non smokers by a factor of 10, and among non-smoking females age 25-44 by a factor of 24. Similarly, linearity predicts that the majority of all lung cancers early in this century were due to radon even after due consideration is given to cases missed by poor diagnostic efficiency (this matter is considered in some detail). For the 30-40 age range, linearity over predicts the total lung cancer rate at that time by a factor of 3-6; for SCU lung cancer, the over-prediction is by at least a factor of 10. Other causes of lung cancer are considered which further enhance the degree to which the linearity assumption over-estimates the effects of low level radiation. A similar analysis is applied to leukemia induced by natural radiation. It is concluded that the upper limit for this is not higher than estimates from the linearity hypothesis. (author)

  1. Influence of irradiation dose on laser-induced surface nanostructures on silicon

    Energy Technology Data Exchange (ETDEWEB)

    Varlamova, Olga [Brandenburgische Technische Universität BTU Cottbus, Platz der Deutschen Einheit 1, 03046 Cottbus (Germany); Cottbus JointLab, Platz der Deutschen Einheit 1, 03046 Cottbus (Germany); Bounhalli, Mourad [Brandenburgische Technische Universität BTU Cottbus, Platz der Deutschen Einheit 1, 03046 Cottbus (Germany); Laboratoire Hubert Curien, Université St. Etienne, Bâtiment F 18 Rue du Professeur Benoît Lauras, 42000 Saint-Etienne (France); Reif, Juergen, E-mail: REIF@TU-COTTBUS.DE [Brandenburgische Technische Universität BTU Cottbus, Platz der Deutschen Einheit 1, 03046 Cottbus (Germany); Cottbus JointLab, Platz der Deutschen Einheit 1, 03046 Cottbus (Germany)

    2013-08-01

    We report on the dependence of femtosecond laser-induced periodic surface structures on an increase of incident pulse number. On silicon, the patterns evolve from linear, parallel sub-wavelength ripples, grossly perpendicular to the laser polarization, via coalesced wider features parallel to the polarization, to a crater with periodically structured, pillar-like walls. Closer inspection of the patterns indicates that the different features always continue to exhibit reminiscence to the preceding lower-dose patterns, suggesting that, indeed, all patterns can be created by ONE single GENERAL formation process, as in self-organized structure formation, and the different structures/feature sizes are NOT due to DIFFERENT mechanisms.

  2. Influence of irradiation dose on laser-induced surface nanostructures on silicon

    International Nuclear Information System (INIS)

    Varlamova, Olga; Bounhalli, Mourad; Reif, Juergen

    2013-01-01

    We report on the dependence of femtosecond laser-induced periodic surface structures on an increase of incident pulse number. On silicon, the patterns evolve from linear, parallel sub-wavelength ripples, grossly perpendicular to the laser polarization, via coalesced wider features parallel to the polarization, to a crater with periodically structured, pillar-like walls. Closer inspection of the patterns indicates that the different features always continue to exhibit reminiscence to the preceding lower-dose patterns, suggesting that, indeed, all patterns can be created by ONE single GENERAL formation process, as in self-organized structure formation, and the different structures/feature sizes are NOT due to DIFFERENT mechanisms.

  3. ACDOS2: a code for neutron-induced activities and dose rates

    International Nuclear Information System (INIS)

    Ruby, L.; Keney, G.S.; Lagache, J.C.

    1981-10-01

    In order to anticipate problems from the radioactivation of neutral beam sources as a result of testing, a code has been developed which calculates both the radioactivities produced and the dose rates resulting therefrom. The code ACDOS2 requires neutron source strength and spectral distribution as input, or alternately, the source strength can be calculated internally from an input of neutral beam source parameters. A variety of simple geometries can be specified, and up to 12 times of interest following the shutdown of the neutron source. Radiation attenuating and daughter radioactivities are treated accurately. ACDOS2 is also of use for neutron-induced radioactivation problems involving accelerators, fusion reactors, or fission reactors

  4. Ultraviolet Radiation Induces Dose-Dependent Pigment Dispersion in Crustacean Chromatophores

    OpenAIRE

    Gouveia, Glauce Ribeiro; Lopes, Thaís Martins; Neves, Carla Amorim; Nery, Luiz Eduardo Maia; Trindade, Gilma Santos

    2004-01-01

    Pigment dispersion in chromatophores as a response to UV radiation was investigated in two species of crustaceans, the crab Chasmagnathus granulata and the shrimp Palaemonetes argentinus. Eyestalkless crabs and shrimps maintained on either a black or a white background were irradiated with different UV bands. In eyestalkless crabs the significant minimal effective dose inducing pigment dispersion was 0.42 J/cm2 for UVA and 2.15 J/cm2 for UVB. Maximal response was achieved with 10.0 J/cm...

  5. Dose-response relationship of γ-ray-induced reciprocal translocations at low doses in spermatogonia of the crab-eating monkey (Macaca fascicularis)

    International Nuclear Information System (INIS)

    Matsuda, Yoichi; Tobari, Izuo; Yamagiwa, Junji; Utsugi, Toyoko; Okamoto, Masanori; Nakai, Sayaka

    1985-01-01

    The yield of translocations induced by acute γ-irradiation at low doses in the crab-eating monkey's (Macaca fascicularis) spermatogonia was examined. Over the low dose range from 0 to 1 Gy, the dose-response relationship for translocation yield was a linear one. To estimate the sensitivity to the induction of translocations in the crab-eating monkey's spermatogonia, the slope of the regression line was compared with those in other mammalian species. Consequently, over the low dose range below 1 Gy, the sensitivity of the crab-eating monkey's spermatogonia to translocation induction was similar to several mammalian species, the mouse, Chinese hamster, and the rabbit, but significantly higher than that of the rhesus monkey and lower than that of the marmoset. (Auth.)

  6. Suppression of alkylating agent induced cell transformation and gastric ulceration by low-dose alkylating agent pretreatment

    International Nuclear Information System (INIS)

    Onodera, Akira; Kawai, Yuichi; Kashimura, Asako; Ogita, Fumiya; Tsutsumi, Yasuo; Itoh, Norio

    2013-01-01

    Highlights: •Low-dose MNNG pretreatment suppresses high-dose MNNG induced in vitro transformation. •Gastric ulcers induced by high-dose MNNG decreased after low-dose MNNG pretreatment. •Efficacy of low-dose MNNG related to resistance of mutation and oxidative stress. -- Abstract: Exposure to mild stress by chemicals and radiation causes DNA damage and leads to acquired stress resistance. Although the linear no-threshold (LNT) model of safety assessment assumes risk from any dose, evidence from radiological research demonstrates a conflicting hormetic phenomenon known as the hormesis effect. However, the mechanisms underlying radiation hormesis have not yet been clarified, and little is known about the effects of low doses of chemical carcinogens. We analyzed the efficacy of pretreatment with low doses of the alkylating agent N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) on the subsequent induction of cell transformation and gastric ulceration by high-dose MNNG. We used an in vitro Balb/3T3 A31-1-1 cell transformation test and monitored the formation of gastric ulcers in 5-week-old male ICR mice that were administered MNNG in drinking water. The treatment concentrations of MNNG were determined by the cell survival rate and past reports. For low-dose in vitro and in vivo experiments, MNNG was used at 0.028 μM, and 2.8 μg/mL, respectively. The frequency of cell transformation induced by 10 μm MNNG was decreased by low-dose MNNG pretreatment to levels similar to that of spontaneous transformation. In addition, reactive oxygen species (ROS) and mutation frequencies induced by 10 μm MNNG were decreased by low-dose MNNG pretreatment. Importantly, low-dose MNNG pretreatment had no effect on cell proliferation. In vivo studies showed that the number of gastric ulcers induced by 1 mg/mL MNNG decreased after low-dose MNNG pretreatment. These data indicate that low-dose pretreatment with carcinogens may play a beneficial role in the prevention of chemical toxicity

  7. Suppression of alkylating agent induced cell transformation and gastric ulceration by low-dose alkylating agent pretreatment

    Energy Technology Data Exchange (ETDEWEB)

    Onodera, Akira, E-mail: onodera@pharm.kobegakuin.ac.jp [Department of Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871 (Japan); Department of Pharmaceutical Sciences, Kobegakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe 650-8586 (Japan); Kawai, Yuichi [Department of Pharmaceutical Sciences, Kobegakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe 650-8586 (Japan); Kashimura, Asako; Ogita, Fumiya; Tsutsumi, Yasuo; Itoh, Norio [Department of Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871 (Japan)

    2013-06-14

    Highlights: •Low-dose MNNG pretreatment suppresses high-dose MNNG induced in vitro transformation. •Gastric ulcers induced by high-dose MNNG decreased after low-dose MNNG pretreatment. •Efficacy of low-dose MNNG related to resistance of mutation and oxidative stress. -- Abstract: Exposure to mild stress by chemicals and radiation causes DNA damage and leads to acquired stress resistance. Although the linear no-threshold (LNT) model of safety assessment assumes risk from any dose, evidence from radiological research demonstrates a conflicting hormetic phenomenon known as the hormesis effect. However, the mechanisms underlying radiation hormesis have not yet been clarified, and little is known about the effects of low doses of chemical carcinogens. We analyzed the efficacy of pretreatment with low doses of the alkylating agent N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) on the subsequent induction of cell transformation and gastric ulceration by high-dose MNNG. We used an in vitro Balb/3T3 A31-1-1 cell transformation test and monitored the formation of gastric ulcers in 5-week-old male ICR mice that were administered MNNG in drinking water. The treatment concentrations of MNNG were determined by the cell survival rate and past reports. For low-dose in vitro and in vivo experiments, MNNG was used at 0.028 μM, and 2.8 μg/mL, respectively. The frequency of cell transformation induced by 10 μm MNNG was decreased by low-dose MNNG pretreatment to levels similar to that of spontaneous transformation. In addition, reactive oxygen species (ROS) and mutation frequencies induced by 10 μm MNNG were decreased by low-dose MNNG pretreatment. Importantly, low-dose MNNG pretreatment had no effect on cell proliferation. In vivo studies showed that the number of gastric ulcers induced by 1 mg/mL MNNG decreased after low-dose MNNG pretreatment. These data indicate that low-dose pretreatment with carcinogens may play a beneficial role in the prevention of chemical toxicity

  8. Adaptive response induced by low doses of ionizing radiation in human lymphocytes

    International Nuclear Information System (INIS)

    Frati, Diego Libkind; Bunge, Maria M.

    2001-01-01

    The term adaptive response (AR) applies to the phenomenon of protection or enhanced repair induced by a small dose of a mutagenic agent. In order to determine the existence of AR in human lymphocytes for two different irradiation schemes, microcultures of blood from 4 donors were irradiated. Samples were exposed 24 hours (hr) after phytohemagglutinin stimulation to an adapting dose of 0,01 Gy and to a challenging dose of 1,5 Gy either 6 or 24 hr later (irradiation scheme 24+30 or 24+48, respectively). Gamma radiation from a 2,5 MeV Linac was used in all experiments. A cytogenetic analysis of unstable chromosome aberrations was applied as the endpoint. High inter-individual variability was found for the first irradiation scheme: one expressed AR, two did not and the last showed an apparent synergistic response. For the second irradiation scheme, low mitotic indices (MI) were found, suggesting a G2 arrest. When a series of harvesting times were applied for the last donor, normal MI were obtained only harvesting after 58 hr. An AR was found when harvesting at 72 hr but not at 58 hr. (author)

  9. Lansoprazole induces sensitivity to suboptimal doses of paclitaxel in human melanoma.

    Science.gov (United States)

    Azzarito, Tommaso; Venturi, Giulietta; Cesolini, Albino; Fais, Stefano

    2015-01-28

    Tumor acidity is now considered an important determinant of drug-resistance and tumor progression, and anti-acidic approaches, such as Proton Pump inhibitors (PPIs), have demonstrated promising antitumor and chemo-sensitizing efficacy. The main purpose of the present study was to evaluate the possible PPI-induced sensitization of human melanoma cells to Paclitaxel (PTX). Our results show that PTX and the PPI Lansoprazole (LAN) combination was extremely efficient against metastatic melanoma cells, as compared to the single treatments, both in vitro and in vivo. We also showed that acidity plays an important role on the anti-tumor activity of these drugs, being detrimental for PTX activity, while crucial for the synergistic effect of PTX following pretreatment with LAN, due to its nature of pro-drug needing protonation for a full activation. We obtained straightforward results in a human melanoma xenograft model combining well tolerated LAN doses with suboptimal and poorly toxic doses of PTX. With this study we provide a clear evidence that the PPI LAN may be included in new combined therapy of human melanoma together with low doses of PTX. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  10. Age and dose as determinants of times of appearance of radium-induced osteosarcomas in humans

    International Nuclear Information System (INIS)

    Stebbings, J.H.; Lucas, H.F.

    1983-01-01

    Determinants of time-until-tumor for bone sarcomas in US radium cases have been reevaluated. For the 57 measured female bone sarcoma cases exposed to 226 Ra and/or 228 Ra, ages at appearance of tumor are more strongly correlated with radium intake doses than are latency periods. Ages at appearance of tumor increase as initial radium intakes decrease. As many lower dose cases were iatrogenic cases exposed in mid-adult life, rather than about age 22 as for the dial worker cases, these results may be artifactual, resulting from an increased susceptability to sarcoma induction at older ages. Alternatively the time of appearance of a sarcoma may be in part directly determined by age. Both explanations find support in the literature. These results suggest that 226 228 Ra-induced bone sarcomas do have an expression period. The downturn in sarcoma incidence at very high doses may result from truncation of the expression period on its early side by the minimum induction period

  11. Induced terpene accumulation in Norway spruce inhibits bark beetle colonization in a dose-dependent manner.

    Directory of Open Access Journals (Sweden)

    Tao Zhao

    Full Text Available Tree-killing bark beetles (Coleoptera, Scolytinae are among the most economically and ecologically important forest pests in the northern hemisphere. Induction of terpenoid-based oleoresin has long been considered important in conifer defense against bark beetles, but it has been difficult to demonstrate a direct correlation between terpene levels and resistance to bark beetle colonization.To test for inhibitory effects of induced terpenes on colonization by the spruce bark beetle Ips typographus (L. we inoculated 20 mature Norway spruce Picea abies (L. Karsten trees with a virulent fungus associated with the beetle, Ceratocystis polonica (Siem. C. Moreau, and investigated induced terpene levels and beetle colonization in the bark.Fungal inoculation induced very strong and highly variable terpene accumulation 35 days after inoculation. Trees with high induced terpene levels (n = 7 had only 4.9% as many beetle attacks (5.1 vs. 103.5 attacks m(-2 and 2.6% as much gallery length (0.029 m m(-2 vs. 1.11 m m(-2 as trees with low terpene levels (n = 6. There was a highly significant rank correlation between terpene levels at day 35 and beetle colonization in individual trees. The relationship between induced terpene levels and beetle colonization was not linear but thresholded: above a low threshold concentration of ∼100 mg terpene g(-1 dry phloem trees suffered only moderate beetle colonization, and above a high threshold of ∼200 mg terpene g(-1 dry phloem trees were virtually unattacked.This is the first study demonstrating a dose-dependent relationship between induced terpenes and tree resistance to bark beetle colonization under field conditions, indicating that terpene induction may be instrumental in tree resistance. This knowledge could be useful for developing management strategies that decrease the impact of tree-killing bark beetles.

  12. Mechanisms of Low Dose Radiation-induced T helper Cell Function

    International Nuclear Information System (INIS)

    Gridley, Daila S.

    2008-01-01

    Exposure to radiation above levels normally encountered on Earth can occur during wartime, accidents such as those at Three Mile Island and Chernobyl, and detonation of 'dirty bombs' by terrorists. Relatively high levels of radiation exposure can also occur in certain occupations (low-level waste sites, nuclear power plants, nuclear medicine facilities, airline industry, and space agencies). Depression or dysfunction of the highly radiosensitive cells of the immune system can lead to serious consequences, including increased risk for infections, cancer, hypersensitivity reactions, poor wound healing, and other pathologies. The focus of this research was on the T helper (Th) subset of lymphocytes that secrete cytokines (proteins), and thus control many actions and interactions of other cell types that make up what is collectively known as the immune system. The Department of Energy (DOE) Low Dose Radiation Program is concerned with mechanisms altered by exposure to high energy photons (x- and gamma-rays), protons and electrons. This study compared, for the first time, the low-dose effects of two of these radiation forms, photons and protons, on the response of Th cells, as well as other cell types with which they communicate. The research provided insights regarding gene expression patterns and capacity to secrete potent immunostimulatory and immunosuppressive cytokines, some of which are implicated in pathophysiological processes. Furthermore, the photon versus proton comparison was important not only to healthy individuals who may be exposed, but also to patients undergoing radiotherapy, since many medical centers in the United States, as well as worldwide, are now building proton accelerators. The overall hypothesis of this study was that whole-body exposure to low-dose photons (gamma-rays) will alter CD4+ Th cell function. We further proposed that exposure to low-dose proton radiation will induce a different pattern of gene and functional changes compared to

  13. Pretreatment with mixed-function oxidase inducers increases the sensitivity of the hepatocyte/DNA repair assay

    International Nuclear Information System (INIS)

    Shaddock, J.G.; Heflich, R.H.; McMillan, D.C.; Hinson, J.A.; Casciano, D.A.

    1989-01-01

    A recent National Toxicology Program evaluation indicates that the rat hepatocyte/DNA repair assay has a high false-negative rate and that it is insensitive to some genotoxic hepatocarcinogens as well as other species and organ-specific carcinogens. In this study, the authors examined whether the sensitivity of the hepatocyte/DNA repair assay might be increased through animal pretreatment with various hepatic mixed-function oxidase inducers, i.e., Aroclor 1254, phenobarbital, and 3,3',4,4'-tetrachloroazobenzene (TCAB). The effects on unscheduled DNA synthesis (UDS), a measured of DNA damage and repair, were studied in cultures exposed to known and/or potential carcinogens that had been evaluated as negative or questionable or that produced conflicting results with hepatocytes isolated from uninduced animals. 4,4'-Oxydianiline, 1-nitropy-rene, and TCAB produced concentration-dependent increases in UDS in hepatocytes from rats pretreated with Aroclor 1254. 4,4'-Oxydianiline and TCAB also induced a dose-dependent increase in DNA repair in hepatocytes from rats pretreated with phenobarbital, whereas 1-nitropyrene was negative. These data indicate that the limited sensitivity to chemical carcinogens displayed by the hepatocyte/DNA repair assay may be increased by using hepatocytes isolated from animals exposed to hepatic mixed-function oxidase inducers

  14. Pretreatment with mixed-function oxidase inducers increases the sensitivity of the hepatocyte/DNA repair assay

    Energy Technology Data Exchange (ETDEWEB)

    Shaddock, J.G.; Heflich, R.H.; McMillan, D.C.; Hinson, J.A.; Casciano, D.A. (National Center for Toxicological Research, Jefferson, AK (USA) Univ. of Arkansas for Medical Sciences, Little Rock (USA))

    1989-01-01

    A recent National Toxicology Program evaluation indicates that the rat hepatocyte/DNA repair assay has a high false-negative rate and that it is insensitive to some genotoxic hepatocarcinogens as well as other species and organ-specific carcinogens. In this study, the authors examined whether the sensitivity of the hepatocyte/DNA repair assay might be increased through animal pretreatment with various hepatic mixed-function oxidase inducers, i.e., Aroclor 1254, phenobarbital, and 3,3{prime},4,4{prime}-tetrachloroazobenzene (TCAB). The effects on unscheduled DNA synthesis (UDS), a measured of DNA damage and repair, were studied in cultures exposed to known and/or potential carcinogens that had been evaluated as negative or questionable or that produced conflicting results with hepatocytes isolated from uninduced animals. 4,4{prime}-Oxydianiline, 1-nitropy-rene, and TCAB produced concentration-dependent increases in UDS in hepatocytes from rats pretreated with Aroclor 1254. 4,4{prime}-Oxydianiline and TCAB also induced a dose-dependent increase in DNA repair in hepatocytes from rats pretreated with phenobarbital, whereas 1-nitropyrene was negative. These data indicate that the limited sensitivity to chemical carcinogens displayed by the hepatocyte/DNA repair assay may be increased by using hepatocytes isolated from animals exposed to hepatic mixed-function oxidase inducers.

  15. Protective and Therapeutic Role of Low Dose Gamma Radiation on Streptozotocin Induced Diabetes in Rats

    International Nuclear Information System (INIS)

    Mansour, H.H.; Hafez, H.F.; Shouman, S.A.

    2011-01-01

    Diabetes mellitus is a multi-factorial disease which is characterized by vascular and renal complication. This study was initiated to investigate the protective and the therapeutic effect of low dose of gamma radiation (LDR) on diabetic complications. A total of 30 adult male rats were divided into 5 groups: Group I: served as control and injected intraperitoneally with 0.2 ml of 0.1 mol/l citrate buffer (ph 4.5), group II: rats became diabetic via intraperitoneal injection with 60 mg/kg streptozotocin (STZ) dissolved in 0.2 ml of 0.1 mol/l citrate buffer (ph 4.5), group III irradiated rats (IRR): submitted to fractionated dose of whole body gamma rays; 0.25 Gy for 2 consecutive days (whole dose 0.5 Gy), group IV diabetic irradiated rats (STZ + IRR): rats became diabetic as group II then four weeks after diabetes induction (day 28), rats were submitted to 2 fractions of whole body gamma rays as in group III, and group V irradiated diabetic rats (IRR + STZ): rats were injected intraperitoneally with 0.2 ml of 0.1 mol/l citrate buffer then submitted to whole body gamma rays; 0.25 Gy for 2 consecutive days then one hour after the last IRR dose, rats were made diabetic as group II. In pre and post-irradiation of STZ rats, significant changes were observed in serum lipid profiles, hepatic and cardiac serum enzymes. Significant decrease in hepatic and cardiac malondialdehyde (MDA) and total nitrate/nitrite (NO(x)) levels, and significant increase in superoxide dismutase (SOD) and glutathione (GSH) levels were observed as compared to diabetic group. The study suggests that LDR may provide useful protective and therapeutic option in the reversal of oxidative stress induced in diabetic rats

  16. Characterization of hepatic DNA damage induced in rats by the pyrrolizidine alkaloid monocrotaline

    Energy Technology Data Exchange (ETDEWEB)

    Petry, T.W.; Bowden, G.T.; Huxtable, R.J.; Sipes, I.G.

    1984-04-01

    Hepatic DNA damage induced by the pyrrolizidine alkaloid monocrotaline was evaluated following i.p. administration to adult male Sprague-Dawley rats. Animals were treated with various doses ranging upward from 5 mg/kg, and hepatic nuclei were isolated 4 hr later. Hepatic nuclei were used as the DNA source in all experiments. DNA damage was characterized by the alkaline elution technique. A mixture of DNA-DNA interstrand cross-links and DNA-protein cross-links was induced. Following an injection of monocrotaline, 30 mg/kg i.p., DNA-DNA interstrand cross-linking reached a maximum within 12 hr or less and thereafter decreased over a protracted period of time. By 96 hr postadministration, the calculated cross-linking factor was no longer statistically different from zero. No evidence for the induction of DNA single-strand breaks was observed, although the presence of small numbers of DNA single-strand breaks could have been masked by the overwhelming predominance of DNA cross-links. These DNA cross-links may be related to the hepatocarcinogenic, hepatotoxic, and/or antimitotic effects of monocrotaline.

  17. High-dose irradiation induces cell cycle arrest, apoptosis, and developmental defects during Drosophila oogenesis.

    Directory of Open Access Journals (Sweden)

    Hee Jin Shim

    Full Text Available Ionizing radiation (IR treatment induces a DNA damage response, including cell cycle arrest, DNA repair, and apoptosis in metazoan somatic cells. Because little has been reported in germline cells, we performed a temporal analysis of the DNA damage response utilizing Drosophila oogenesis as a model system. Oogenesis in the adult Drosophila female begins with the generation of 16-cell cyst by four mitotic divisions of a cystoblast derived from the germline stem cells. We found that high-dose irradiation induced S and G2 arrests in these mitotically dividing germline cells in a grp/Chk1- and mnk/Chk2-dependent manner. However, the upstream kinase mei-41, Drosophila ATR ortholog, was required for the S-phase checkpoint but not for the G2 arrest. As in somatic cells, mnk/Chk2 and dp53 were required for the major cell death observed in early oogenesis when oocyte selection and meiotic recombination occurs. Similar to the unscheduled DNA double-strand breaks (DSBs generated from defective repair during meiotic recombination, IR-induced DSBs produced developmental defects affecting the spherical morphology of meiotic chromosomes and dorsal-ventral patterning. Moreover, various morphological abnormalities in the ovary were detected after irradiation. Most of the IR-induced defects observed in oogenesis were reversible and were restored between 24 and 96 h after irradiation. These defects in oogenesis severely reduced daily egg production and the hatch rate of the embryos of irradiated female. In summary, irradiated germline cells induced DSBs, cell cycle arrest, apoptosis, and developmental defects resulting in reduction of egg production and defective embryogenesis.

  18. Comments on 'Reconsidering the definition of a dose-volume histogram'-dose-mass histogram (DMH) versus dose-volume histogram (DVH) for predicting radiation-induced pneumonitis

    International Nuclear Information System (INIS)

    Mavroidis, Panayiotis; Plataniotis, Georgios A; Gorka, Magdalena Adamus; Lind, Bengt K

    2006-01-01

    In a recently published paper (Nioutsikou et al 2005 Phys. Med. Biol. 50 L17) the authors showed that the use of the dose-mass histogram (DMH) concept is a more accurate descriptor of the dose delivered to lung than the traditionally used dose-volume histogram (DVH) concept. Furthermore, they state that if a functional imaging modality could also be registered to the anatomical imaging modality providing a functional weighting across the organ (functional mass) then the more general and realistic concept of the dose-functioning mass histogram (D[F]MH) could be an even more appropriate descriptor. The comments of the present letter to the editor are in line with the basic arguments of that work since their general conclusions appear to be supported by the comparison of the DMH and DVH concepts using radiobiological measures. In this study, it is examined whether the dose-mass histogram (DMH) concept deviated significantly from the widely used dose-volume histogram (DVH) concept regarding the expected lung complications and if there are clinical indications supporting these results. The problem was investigated theoretically by applying two hypothetical dose distributions (Gaussian and semi-Gaussian shaped) on two lungs of uniform and varying densities. The influence of the deviation between DVHs and DMHs on the treatment outcome was estimated by using the relative seriality and LKB models using the Gagliardi et al (2000 Int. J. Radiat. Oncol. Biol. Phys. 46 373) and Seppenwoolde et al (2003 Int. J. Radiat. Oncol. Biol. Phys. 55 724) parameter sets for radiation pneumonitis, respectively. Furthermore, the biological equivalent of their difference was estimated by the biologically effective uniform dose (D-bar) and equivalent uniform dose (EUD) concepts, respectively. It is shown that the relation between the DVHs and DMHs varies depending on the underlying cell density distribution and the applied dose distribution. However, the range of their deviation in terms of

  19. Characterization of the adaptive response to ionizing radiation induced by low doses of X-rays to Vibrio cholerae cells

    International Nuclear Information System (INIS)

    Basak, Jayasri

    1996-01-01

    Pretreatment with sublethal doses of X-rays induced an adaptive response in Vibrio cholerae cells as indicated by their greater resistance to the subsequent challenging doses of X-irradiation. The adaptive response was maximum following a pre-exposure dose of 1.7 Gy X-rays and an optimum incubation period of 40 min at 37C. Pre-exposure to a sublethal dose of 1.7 Gy X-rays made the Vibrio cholerae cells 3.38-fold more resistant to the subsequent challenge by X-rays. Pretreatment with a sublethal dose of hydrogen peroxide offered a similar degree of protection to the bacterial cells against subsequent treatment with challenging doses of X-ray radiation. However, exposure of Vibrio cholerae cells to mild heat (42C for 10 min) before X-ray irradiation decreased their survival following X-irradiation

  20. Elevated sodium chloride concentrations enhance the bystander effects induced by low dose alpha-particle irradiation

    International Nuclear Information System (INIS)

    Han Wei; Zhu Lingyan; Jiang Erkang; Wang Jun; Chen Shaopeng; Bao Linzhi; Zhao Ye; Xu An; Yu Zengliang; Wu Lijun

    2007-01-01

    Previous studies have shown that high NaCl can be genotoxic, either alone or combined with irradiation. However, little is known about the relationship between environmental NaCl at elevated conditions and radiation-induced bystander effects (RIBE). RIBE, which has been considered as non-targeted bystander responses, has been demonstrated to occur widely in various cell lines. In the present study, RIBE under the elevated NaCl culture condition was assessed in AG 1522 cells by both the induction of γ-H2AX, a reliable marker of DNA double-strand break (DSB) for the early process ( G -methyl-L-arginine, an inhibitor of nitric oxide synthase, the induced fraction of foci-positive cells was effectively inhibited both in 0.2 cGy α-particle irradiated and adjacent non-irradiated regions under either normal or elevated NaCl conditions. These results suggested that the cultures with elevated NaCl medium magnified the damage effects induced by the low dose α-particle irradiation and nitric oxide generated by irradiation was also very important in this process

  1. Computational model of dose response for low-LET-induced complex chromosomal aberrations

    International Nuclear Information System (INIS)

    Eidelman, Y.A.; Andreev, S.G.

    2015-01-01

    Experiments with full-colour mFISH chromosome painting have revealed high yield of radiation-induced complex chromosomal aberrations (CAs). The ratio of complex to simple aberrations is dependent on cell type and linear energy transfer. Theoretical analysis has demonstrated that the mechanism of CA formation as a result of interaction between lesions at a surface of chromosome territories does not explain high complexes-to-simples ratio in human lymphocytes. The possible origin of high yields of γ-induced complex CAs was investigated in the present work by computer simulation. CAs were studied on the basis of chromosome structure and dynamics modelling and the hypothesis of CA formation on nuclear centres. The spatial organisation of all chromosomes in a human interphase nucleus was predicted by simulation of mitosis-to-interphase chromosome structure transition. Two scenarios of CA formation were analysed, 'static' (existing in a nucleus prior to irradiation) centres and 'dynamic' (formed in response to irradiation) centres. The modelling results reveal that under certain conditions, both scenarios explain quantitatively the dose-response relationships for both simple and complex γ-induced inter-chromosomal exchanges observed by mFISH chromosome painting in the first post-irradiation mitosis in human lymphocytes. (authors)

  2. Carbon dioxide inhalation induces dose-dependent and age-related negative affectivity.

    Directory of Open Access Journals (Sweden)

    Eric J Griez

    Full Text Available BACKGROUND: Carbon dioxide inhalation is known to induce an emotion similar to spontaneous panic in Panic Disorder patients. The affective response to carbon dioxide in healthy subjects was not clearly characterized yet. METHODOLOGY/PRINCIPAL FINDINGS: Sixty-four healthy subjects underwent a double inhalation of four mixtures containing respectively 0, 9, 17.5 and 35% CO(2 in compressed air, following a double blind, cross-over, randomized design. Affective responses were assessed according to DSM IV criteria for panic, using an Electronic Visual Analogue Scale and the Panic Symptom List. It was demonstrated that carbon dioxide challenges induced a dose dependent negative affect (p<0.0001. This affect was semantically identical to the DSM IV definition of panic. Older individuals were subjectively less sensitive to Carbon Dioxide (p<0.05. CONCLUSIONS/SIGNIFICANCE: CO(2 induced affectivity may lay on a continuum with pathological panic attacks. Consistent with earlier suggestions that panic is a false biological alarm, the affective response to CO(2 may be part of a protective system triggered by suffocation and acute metabolic distress.

  3. Ultraviolet radiation induces dose-dependent pigment dispersion in crustacean chromatophores.

    Science.gov (United States)

    Gouveia, Glauce Ribeiro; Lopes, Thaís Martins; Neves, Carla Amorim; Nery, Luiz Eduardo Maia; Trindade, Gilma Santos

    2004-10-01

    Pigment dispersion in chromatophores as a response to UV radiation was investigated in two species of crustaceans, the crab Chasmagnathus granulata and the shrimp Palaemonetes argentinus. Eyestalkless crabs and shrimps maintained on either a black or a white background were irradiated with different UV bands. In eyestalkless crabs the significant minimal effective dose inducing pigment dispersion was 0.42 J/cm(2) for UVA and 2.15 J/cm(2) for UVB. Maximal response was achieved with 10.0 J/cm(2) UVA and 8.6 J/cm(2) UVB. UVA was more effective than UVB in inducing pigment dispersion. Soon after UV exposure, melanophores once again reached the initial stage of pigment aggregation after 45 min. Aggregated erythrophores of shrimps adapted to a white background showed significant pigment dispersion with 2.5 J/cm(2) UVA and 0.29 J/cm(2) UVC. Dispersed erythrophores of shrimps adapted to a black background did not show any significant response to UVA, UVB or UVC radiation. UVB did not induce any significant pigment dispersion in shrimps adapted to either a white or a black background. As opposed to the tanning response, which only protects against future UV exposure, the pigment dispersion response could be an important agent protecting against the harmful effects of UV radiation exposure.

  4. Low-dose radiation (LDR) induces hematopoietic hormesis: LDR-induced mobilization of hematopoietic progenitor cells into peripheral blood circulation.

    Science.gov (United States)

    Li, Wei; Wang, Guanjun; Cui, Jiuwei; Xue, Lu; Cai, Lu

    2004-11-01

    The aim of this study was to investigate the stimulating effect of low-dose radiation (LDR) on bone marrow hematopoietic progenitor cell (HPC) proliferation and peripheral blood mobilization. Mice were exposed to 25- to 100-mGy x-rays. Bone marrow and peripheral blood HPCs (BFU-E, CFU-GM, and c-kit+ cells) were measured, and GM-CSF, G-CSF, and IL-3 protein and mRNA expression were detected using ELISA, slot blot hybridization, and Northern blot methods. To functionally evaluate LDR-stimulated and -mobilized HPCs, repopulation of peripheral blood cells in lethally irradiated recipients after transplantation of LDR-treated donor HPCs was examined by WBC counts, animal survival, and colony-forming units in the recipient spleens (CFUs-S). 75-mGy x-rays induced a maximal stimulation for bone marrow HPC proliferation (CFU-GM and BFU-E formation) 48 hours postirradiation, along with a significant increase in HPC mobilization into peripheral blood 48 to 72 hours postradiation, as shown by increases in CFU-GM formation and proportion of c-kit+ cells in the peripheral mononuclear cells. 75-mGy x-rays also maximally induced increases in G-CSF and GM-CSF mRNA expression in splenocytes and levels of serum GM-CSF. To define the critical role of these hematopoietic-stimulating factors in HPC peripheral mobilization, direct administration of G-CSF at a dose of 300 microg/kg/day or 150 microg/kg/day was applied and found to significantly stimulate GM-CFU formation and increase c-kit+ cells in the peripheral mononuclear cells. More importantly, 75-mGy x-rays plus 150 microg/kg/day G-CSF (LDR/150-G-CSF) produced a similar effect to that of 300 microg/kg/day G-CSF alone. Furthermore, the capability of LDR-mobilized donor HPCs to repopulate blood cells was confirmed in lethally irradiated recipient mice by counting peripheral WBC and CFUs-S. These results suggest that LDR induces hematopoietic hormesis, as demonstrated by HPC proliferation and peripheral mobilization, providing a

  5. A Voxel-Based Approach to Explore Local Dose Differences Associated With Radiation-Induced Lung Damage

    Energy Technology Data Exchange (ETDEWEB)

    Palma, Giuseppe [Institute of Biostructure and Bioimaging, National Research Council, Naples (Italy); Monti, Serena [IRCCS SDN, Naples (Italy); D' Avino, Vittoria [Institute of Biostructure and Bioimaging, National Research Council, Naples (Italy); Conson, Manuel [Institute of Biostructure and Bioimaging, National Research Council, Naples (Italy); Department of Advanced Biomedical Sciences, Federico II University School of Medicine, Naples (Italy); Liuzzi, Raffaele [Institute of Biostructure and Bioimaging, National Research Council, Naples (Italy); Pressello, Maria Cristina [Department of Health Physics, S. Camillo-Forlanini Hospital, Rome (Italy); Donato, Vittorio [Department of Radiation Oncology, S. Camillo-Forlanini Hospital, Rome (Italy); Deasy, Joseph O. [Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY (United States); Quarantelli, Mario [Institute of Biostructure and Bioimaging, National Research Council, Naples (Italy); Pacelli, Roberto [Institute of Biostructure and Bioimaging, National Research Council, Naples (Italy); Department of Advanced Biomedical Sciences, Federico II University School of Medicine, Naples (Italy); Cella, Laura, E-mail: laura.cella@cnr.it [Institute of Biostructure and Bioimaging, National Research Council, Naples (Italy)

    2016-09-01

    Purpose: To apply a voxel-based (VB) approach aimed at exploring local dose differences associated with late radiation-induced lung damage (RILD). Methods and Materials: An interinstitutional database of 98 patients who were Hodgkin lymphoma (HL) survivors treated with postchemotherapy supradiaphragmatic radiation therapy was analyzed in the study. Eighteen patients experienced late RILD, classified according to the Radiation Therapy Oncology Group scoring system. Each patient's computed tomographic (CT) scan was normalized to a single reference case anatomy (common coordinate system, CCS) through a log-diffeomorphic approach. The obtained deformation fields were used to map the dose of each patient into the CCS. The coregistration robustness and the dose mapping accuracy were evaluated by geometric and dose scores. Two different statistical mapping schemes for nonparametric multiple permutation inference on dose maps were applied, and the corresponding P<.05 significance lung subregions were generated. A receiver operating characteristic (ROC)-based test was performed on the mean dose extracted from each subregion. Results: The coregistration process resulted in a geometrically robust and accurate dose warping. A significantly higher dose was consistently delivered to RILD patients in voxel clusters near the peripheral medial-basal portion of the lungs. The area under the ROC curves (AUC) from the mean dose of the voxel clusters was higher than the corresponding AUC derived from the total lung mean dose. Conclusions: We implemented a framework including a robust registration process and a VB approach accounting for the multiple comparison problem in dose-response modeling, and applied it to a cohort of HL survivors to explore a local dose–RILD relationship in the lungs. Patients with RILD received a significantly greater dose in parenchymal regions where low doses (∼6 Gy) were delivered. Interestingly, the relation between differences in the high-dose

  6. Low-Dose Ribavirin Treatments Attenuate Neuroinflammatory Activation of BV-2 Cells by Interfering with Inducible Nitric Oxide Synthase

    Directory of Open Access Journals (Sweden)

    Iva Bozic

    2015-01-01

    Full Text Available Microglia play a key role in defending central nervous system from various internal and external threats. However, their excessive and/or chronic activation is associated with deleterious effects in a variety of neurodegenerative diseases. Previously, we have shown that ribavirin when applied in clinically relevant dosage (10 μM modulates activated microglia in complex fashion inducing both anti- and proinflammatory effects, simultaneously causing cytotoxicity. Here, we examined potential of low-dose ribavirin (0.1 and 1 μM to modulate activated BV-2 microglia. Morphological and functional activation of BV-2 cells was achieved with lipopolysaccharide (LPS stimulation. Our results demonstrated that low-dose ribavirin did not induce cell death, while 10 μM ribavirin promoted LPS induced apoptosis. We determined that 1 μM ribavirin was equally efficient in deactivation of LPS induced morphological changes as 10 μM ribavirin treatment. Ribavirin showed halfway success in reducing markers of functional activation of microglia. Namely, none of the doses had effect on LPS triggered production of proinflammatory cytokine tumor necrosis factor alpha. On the other hand, low-dose ribavirin proved its effectiveness in reduction of another inflammatory mediator, nitric oxide, by inhibiting inducible form of nitric oxide synthase. Our results imply that low-dose ribavirin may alleviate nitrosative stress during neuroinflammation.

  7. Low-Dose Ribavirin Treatments Attenuate Neuroinflammatory Activation of BV-2 Cells by Interfering with Inducible Nitric Oxide Synthase

    Science.gov (United States)

    Bozic, Iva; Savic, Danijela; Jovanovic, Marija; Bjelobaba, Ivana; Laketa, Danijela; Nedeljkovic, Nadezda; Stojiljkovic, Mirjana; Pekovic, Sanja; Lavrnja, Irena

    2015-01-01

    Microglia play a key role in defending central nervous system from various internal and external threats. However, their excessive and/or chronic activation is associated with deleterious effects in a variety of neurodegenerative diseases. Previously, we have shown that ribavirin when applied in clinically relevant dosage (10 μM) modulates activated microglia in complex fashion inducing both anti- and proinflammatory effects, simultaneously causing cytotoxicity. Here, we examined potential of low-dose ribavirin (0.1 and 1 μM) to modulate activated BV-2 microglia. Morphological and functional activation of BV-2 cells was achieved with lipopolysaccharide (LPS) stimulation. Our results demonstrated that low-dose ribavirin did not induce cell death, while 10 μM ribavirin promoted LPS induced apoptosis. We determined that 1 μM ribavirin was equally efficient in deactivation of LPS induced morphological changes as 10 μM ribavirin treatment. Ribavirin showed halfway success in reducing markers of functional activation of microglia. Namely, none of the doses had effect on LPS triggered production of proinflammatory cytokine tumor necrosis factor alpha. On the other hand, low-dose ribavirin proved its effectiveness in reduction of another inflammatory mediator, nitric oxide, by inhibiting inducible form of nitric oxide synthase. Our results imply that low-dose ribavirin may alleviate nitrosative stress during neuroinflammation. PMID:26413464

  8. Low-dose ionizing radiation alleviates Aβ42-induced defective phenotypes in Drosophila Alzheimer's disease models

    Energy Technology Data Exchange (ETDEWEB)

    Hwang, SooJin; Jeong, Hae Min; Nam, Seon Young [Low-dose Radiation Research Team, Radiation Health Institute, Korea Hydro & Nuclear Power Co. Ltd., Daejeon (Korea, Republic of)

    2017-04-15

    Alzheimer's disease (AD) is the most common neurodegenerative disease that is characterized by amyloid plaques, progressive neuronal loss, and gradual deterioration of memory. Amyloid imaging using positron emission tomography (PET) radiotracers have been developed and approved for clinical use in the evaluation of suspected neurodegenerative disease, including AD. Particularly, previous studies involving low-dose ionizing radiation on Aβ 42-treated mouse hippocampal neurons have suggested a potential role for low-dose ionizing radiation in the treatment of AD. However, associated in vivo studies involving the therapy effects of low-dose ionizing radiation on AD are still insufficient. As a powerful cell biological system, Drosophila AD models have been generated and established a useful model organism for study on the etiology of human AD. In this study, we investigated the hormesis effects of low-dose ionizing radiation on Drosophila AD models. Our results suggest that low-dose ionizing radiation have the beneficial effects on not only the Aβ42-induced developmental defective phenotypes but also motor defects in Drosophila AD models. These results might be due to a regulation of apoptosis, and provide insight into the hormesis effects of low-dose ionizing radiation. Our results suggest that low-dose ionizing radiation have the beneficial effects on not only the Aβ42-induced developmental defective phenotypes but also motor defects in Drosophila AD models. These results might be due to a regulation of apoptosis, and provide insight into the hormesis effects of low-dose ionizing radiation.

  9. Hesperidin and low dose gamma irradiation alleviate rosiglitazone -induced cardiotoxicity in type 2 diabetic rats

    International Nuclear Information System (INIS)

    Morcos, N.Y.; Abdel-Ghaffar, A.B.; Osman, S.A.; Mohamed, M.Kh.; Arbid, M.S.; El-Eraky, W.I.

    2012-01-01

    Aim: The present study was designed to investigate the cardio protective effect of hesperidin and low dose γ- irradiation (LDR) against rosiglitazone cardiotoxicity. Experiment: Type 2 diabetes mellitus (T2DM) was induced in rats by single intraperitoneal injection of streptozotocin (STZ) followed by nicotinamide (NIC) (65 and 110 mg/kg b.wt, respectively). The diabetic rats were divided into 5 groups: untreated, LDR, LDR+ rosiglitazone, LDR + Hesperidin, LDR+ rosiglitazone + Hesperidin for one month, and blood and tissue samples were collected. Results: The diabetic rats showed elevated serum creatine kinase (CK-MB), lactate dehydrogenase (LDH), C-reactive protein (CRP), hyaluronidase activity, and reduced serum nitric oxide (NO) level, hematocrit % as well as final body weight, and pathological alterations in myocardial tissue. Treatment with LDR + rosiglitazone + Hesperidin ameliorated all these abnormalities approaching control levels. Conclusion: Results indicate the possible cardio protective role of hesperidin and LDR against rosiglitazone cardiotoxicity.

  10. Natural radioactivity contents in tobacco and radiation dose induced from smoking

    International Nuclear Information System (INIS)

    Shousha, H. A.; Ahmad, F.

    2012-01-01

    One of the causative factors for cancer-inducing mechanisms in humans is radioactive elements present in tobacco leaves used in the manufacture of cigarettes. Smoking of tobacco and its products increases the internal intake and radiation dose due to naturally occurring radionuclides that are considered to be one of the most significant causes of lung cancer. In this work, different commercial types of cigarettes, cigar and moassel were collected from market. Naturally occurring radionuclides 226 Ra and 214 Bi ( 238 U series), 228 Ac and 228 Ra ( 232 Th series), 40 K and man-made 137 Cs were measured in tobacco using gamma-ray spectrometer. Results show that the average concentrations of 238 U, 232 Th and 40 K were 4.564, 3.940 and 1289.53 Bq kg -1 , respectively. This reflects their origin from the soil by root uptake and fertilisers used in the cultivation of tobacco plants. Concentration of 137 Cs was 0.348 Bq kg -1 due to root uptake or deposition onto the leaf foliage. For smokers, the annual effective dose due to inhalation of 238 U varied from 49.35 to 139.40 μSv -1 (average 104.27 μSv y -1 ), while of 232 Th from 23.86 to 111.06 μSv y -1 (average 65.52 μSv y -1 ). The annual effective dose resulting from 137 Cs was varied from 10.96 to 24.01 nSv y -1 (average 19.41 nSv y -1 ). (authors)

  11. Enrofloxacin in therapeutic doses alters cytokine production by porcine PBMCs induced by lipopolysaccharide.

    Science.gov (United States)

    Pomorska-Mól, Małgorzata; Czyżewska-Dors, Ewelina; Kwit, Krzysztof; Pejsak, Zygmunt

    2017-07-01

    The effect of enrofloxacin on cytokine secretion by porcine peripheral blood mononuclear cells (PBMCs) was studied. Twenty 8-20-week-old pigs were randomly divided into two groups: control (C, n = 10) and experimental (E, n = 10) were used. Pigs from group E received enrofloxacin at therapeutic dose for 5 consecutive days. Blood samples were collected at 0 (before antibiotic administration), 2, 4 (during antibiotic therapy) 6, 9, 14 21, 35, 49, and 63 d of study (after treatment). PBMCs of pigs from both groups were incubated with or without lipopolysaccharide (LPS). Ex vivo production on interleukin (IL)-4, IL-6, IL-10, INF-γ, and TNF-α were analyzed using ELISA assay. Intramuscular administration of enrofloxacin to healthy pigs for 5 consecutive days induced a transitory reduction of the ex vivo response of PBMCs to LPS in terms of IL-6 and TNF-α secretion. The level of IL-6 returned to day 0 level shortly after end of treatment, while the TNF-α production remained reduced 10 d after the end of treatment. Our results indicate that enrofloxacin given in vivo in therapeutic doses has an immunomodulatory effect through its capacity to inhibit ex vivo secretion of IL-6 and TNF-α by porcine PBMC after LPS stimulation.

  12. Effect of different doses of oxytocin on cardiac electrophysiology and arrhythmias induced by ischemia.

    Science.gov (United States)

    Houshmand, Fariba; Faghihi, Mahdieh; Imani, Alireza; Kheiri, Soleiman

    2017-01-01

    The onset of acute myocardial ischemia (MI) is accompanied by a rapid increase in electrical instability and often fatal ventricular arrhythmias. This study investigated that whether oxytocin (OT) can modulate ischemia-induced arrhythmias and considered relationships between the severity of arrhythmia and the electrocardiogram parameters during ischemia. OT (0.0001-1 μg) was administrated intraperitoneally 30 min before ischemia. To examine receptor involved, a selective OT-receptor antagonist, atosiban (ATO), was infused 10 min before OT. OT caused a significant and biphasic dose-dependent reduction in ectopic heart activity and arrhythmia score. OT doses that reduced ventricular arrhythmia elicited significant increase in QT interval. OT attenuated the electrophysiological changes associated with MI and there was significant direct relationship between QRS duration and arrhythmia score. ATO treatment reduced beneficial effects of OT on arrhythmogenesis. Nevertheless, ATO failed to alter OT effects on premature ventricular contractions. We assume that the ability of OT to modulate the electrical activity of the heart may play an important role in the antiarrhythmic actions of OT.

  13. Effect of different doses of oxytocin on cardiac electrophysiology and arrhythmias induced by ischemia

    Directory of Open Access Journals (Sweden)

    Fariba Houshmand

    2017-01-01

    Full Text Available The onset of acute myocardial ischemia (MI is accompanied by a rapid increase in electrical instability and often fatal ventricular arrhythmias. This study investigated that whether oxytocin (OT can modulate ischemia-induced arrhythmias and considered relationships between the severity of arrhythmia and the electrocardiogram parameters during ischemia. OT (0.0001–1 μg was administrated intraperitoneally 30 min before ischemia. To examine receptor involved, a selective OT-receptor antagonist, atosiban (ATO, was infused 10 min before OT. OT caused a significant and biphasic dose-dependent reduction in ectopic heart activity and arrhythmia score. OT doses that reduced ventricular arrhythmia elicited significant increase in QT interval. OT attenuated the electrophysiological changes associated with MI and there was significant direct relationship between QRS duration and arrhythmia score. ATO treatment reduced beneficial effects of OT on arrhythmogenesis. Nevertheless, ATO failed to alter OT effects on premature ventricular contractions. We assume that the ability of OT to modulate the electrical activity of the heart may play an important role in the antiarrhythmic actions of OT.

  14. Low-dose tryptophan depletion in recovered depressed women induces impairments in autobiographical memory specificity.

    Science.gov (United States)

    Haddad, Anneke D M; Williams, J Mark G; McTavish, Sarah F B; Harmer, Catherine J

    2009-12-01

    Depressed patients perform poorly on tests of autobiographical memory specificity (AMS); this may have negative consequences for other important cognitive abilities, delays recovery from mood episodes, and, in recovered patients, may mediate vulnerability to future episodes. Although the cognitive mechanisms underlying AMS deficits are beginning to be understood, the neurobiological mechanisms remain unclear. Serotonin is implicated in both depression and long-term memory; therefore, temporary lowering of brain serotonin function via acute tryptophan depletion (ATD) offers a means of studying the role of serotonin in autobiographical memory specificity. In this study, 24 previously depressed women underwent low-dose ATD or sham depletion and completed tests of initial and delayed memory, recollection- and familiarity-based recognition, and AMS. ATD did not differentially affect state mood. Compared with sham depletion, ATD impaired immediate recall on the Auditory Verbal Learning Test. Although ATD did not differentially impair recollection- and familiarity-based recognition, it did slow recognition of positive words. ATD also reduced autobiographical memory specificity in response to negative cue words. The results confirm previous findings that low-dose ATD can reinstate depression-congruent biases in cognition without causing depressive mood in vulnerable populations. The ATD-induced reduction in memory specificity suggests that serotonergic dysfunction may mediate depressive deficits in autobiographical memory; the interaction of cognitive and neurobiological vulnerability mechanisms is discussed.

  15. Resolution of methylphenidate osmotic release oral system-induced hair loss in two siblings after dose escalation.

    Science.gov (United States)

    Ardic, Ulku Akyol; Ercan, Eyup Sabri

    2017-11-01

    This report describes the cases of two siblings who experienced hair loss after treatment with methylphenidate (MPH) osmotic release oral system (OROS). Hair loss was resolved after discontinuation of the drug, but the children re-initiated treatment, after which hair loss again occurred, but they continued the treatment. After dose escalation, the hair loss resolved. This is the first report to describe resolution of OROS-MPH-induced hair loss after dose escalation. © 2017 Japan Pediatric Society.

  16. New way of dosing sugammadex for termination of vecuronium induced neuromuscular block

    Directory of Open Access Journals (Sweden)

    Blaž Peček

    2015-06-01

    Full Text Available Background and Goal of Study: Sugammadex is a selective binding agent that bindsaminosteroid muscle relaxants. Each molecule of sugammadex binds one molecule of musclerelaxant. To produce the same depth of the neuromuscular block (NMB much less molecules ofvecuronium are needed than molecules of rocuronium. In theory less sugammadex would beneeded to neutralise the neuromuscular block if vecuronium was used to produce the neuromuscular block. Our aim was to compare reversal of vecuronium induced muscle relaxation between a new way of dosing sugammadex, which takes into account TOF value at the end of the surgery and the amount of vecuronium given during the surgery with neostigmine atropine combination. We also wanted to know how much this dosage regime can save compared to standard per kg dosage.Materials and Methods: 20 adult patients requiring a general anesthesia for surgery were analysed. The first group of 11 patients (SUG received sugammadex at the end of the surgery according to the table one for NMB reversal. The second group of 9 patients (NEO received neostigmine and atropine. Train of four (TOF value was recorded at the end of the surgery and then continuously until the TOF value reached more than 0.9 and the patient was extubated. The time required for the TOF value reaching 0.9 was compared between the groups. For economical evaluation we compared the amount of sugammadex used in the SUG group to standard sugammadex per kg dosage.Results and Discussion: Mean time to recovery to a TOF ratio of 0.9 with sugammadex was 5.12min versus 12.6 min with neostigmine atropine (P < 0.05. No sign of postoperative residual curarisation was observed in the SUG group. For patients in our study 530 mg of sugammadex were used to neutralise the NMB. If standard per kg sugammadex dosing had been used we would have used 2420 mg for the NMB reversal.Conclusion(s: New dosing for sugammadex was successful in neutralising the NMB regardlessof the TOF value

  17. Blood pressure reduction induced by low dose of epinephrine via different routes in rats.

    Science.gov (United States)

    Wu, Jing; Ji, Mu-Huo; Wang, Zhong-Yun; Zhu, Wei; Yang, Jian-Jun; Peng, Yong G

    2013-09-01

    Epinephrine was recently shown to induce a hypotension episode. Activation of β₂-adrenoceptors with smooth muscle relaxation may be the underlying mechanism. This study investigated the effects of ICI 118551, a β₂-adrenoceptors antagonist, on epinephrine-induced blood pressure reduction via different administration routes in rats. A total of 144 Sprague Dawley rats were equally randomized into 3 groups (intranasal, intravenous, and intra-arterial administration), each with 4 subgroups: saline + saline, ICI 118551 + saline, saline + epinephrine, and ICI 118551 + epinephrine. All rats were anesthetized while spontaneously breathing. Epinephrine was administered at doses of 5 μg/kg via nose, 0.25 μg/kg via femoral vein, and 0.1 μg/kg via aorta. Mean arterial pressure and heart rate were monitored. Mean arterial pressure decreased in all 3 saline + epinephrine subgroups after administration (P blood pressure reduction can be prevented by ICI 118551 in rats, suggesting that the activation of β₂-adrenoceptors contributes to blood pressure reduction.

  18. Taenia crassiceps Infection Attenuates Multiple Low-Dose Streptozotocin-Induced Diabetes

    Directory of Open Access Journals (Sweden)

    Arlett Espinoza-Jiménez

    2010-01-01

    Full Text Available Taenia crassiceps, like other helminths, can exert regulatory effects on the immune system of its host. This study investigates the effect of chronic T. crassiceps infection on the outcome of Multiple Low Dose Streptozotocin-Induced Diabetes (MLDS. Healthy or previously T. crassiceps-infected mice received MLDS and type 1 diabetes (T1D symptoms were evaluated for 6 weeks following the induction of MLDS. T. crassiceps-infected mice displayed lower blood glucose levels throughout the study. A significantly lower percentage of T. crassiceps-infected mice (40% developed T1D compared to the uninfected group (100%. Insulitis was remarkably absent in T. crassiceps-infected mice, which had normal pancreatic insulin content, whereas uninfected mice showed a dramatic reduction in pancreatic insulin. Infected mice that received MLDS did not show an increase in their regulatory T cell population, however, they had a greater number of alternatively activated macrophages, higher levels of the cytokine IL-4, and lower levels of TNF-α. Therefore, infection with T. crassiceps causes an immunomodulation that modifies the incidence and development of MLDS-induced autoimmune diabetes.

  19. Single Low-Dose Ionizing Radiation Induces Genotoxicity in Adult Zebrafish and its Non-Irradiated Progeny.

    Science.gov (United States)

    Lemos, J; Neuparth, T; Trigo, M; Costa, P; Vieira, D; Cunha, L; Ponte, F; Costa, P S; Metello, L F; Carvalho, A P

    2017-02-01

    This study investigated to what extent a single exposure to low doses of ionizing radiation can induce genotoxic damage in irradiated adult zebrafish (Danio rerio) and its non-irradiated F1 progeny. Four groups of adult zebrafish were irradiated with a single dose of X-rays at 0 (control), 100, 500 and 1000 mGy, respectively, and couples of each group were allowed to reproduce following irradiation. Blood of parental fish and whole-body offspring were analysed by the comet assay for detection of DNA damage. The level of DNA damage in irradiated parental fish increased in a radiation dose-dependent manner at day 1 post-irradiation, but returned to the control level thereafter. The level of DNA damage in the progeny was directly correlated with the parental irradiation dose. Results highlight the genotoxic risk of a single exposure to low-dose ionizing radiation in irradiated individuals and also in its non-irradiated progeny.

  20. LET and dose rate effect on radiation-induced copolymerization of maleimide with styrene in 2-propanol solution

    Energy Technology Data Exchange (ETDEWEB)

    Nakagawa, Seiko, E-mail: Nakagawa.Seiko@iri-tokyo.jp [Tokyo Metropolitan Industrial Technology Research Institute, 2-4-10 Aoumi, Koto-ku, Tokyo 135-0064 (Japan); Taguchi, Mitsumasa; Kimura, Atsushi [Environmental Radiation Processing Group, Environment and Industrial Materials Research Division, Quantum Beam Science Directorate, Japan Atomic Energy Agency, 1233 Watanuki, Takasaki, Gunma 370-1292 (Japan)

    2011-11-15

    N{sub 2}-saturated 2-propanol solutions containing styrene and maleimide were irradiated by electron, proton, He and C-ion beams. The styrene-maleimide copolymer was produced by radical polymerization induced during irradiation. The effects of the radical distribution, which depends on the LET or dose rate, on the molecular weight and the polymer yield were discussed. - Highlights: > Maleimide with styrene in N{sub 2}-saturated 2-propanol was irradiated by electron and heavy ions. > LET and dose rate effects of radical polymerization induced by irradiation were studied. > Results have shown the relation between radical distribution and efficiency of polymerization.

  1. Therapeutic Effect of Low Doses of Acenocoumarol in the Course of Ischemia/Reperfusion-Induced Acute Pancreatitis in Rats

    Directory of Open Access Journals (Sweden)

    Zygmunt Warzecha

    2017-04-01

    Full Text Available Intravascular activation of coagulation is observed in acute pancreatitis and is related to the severity of this inflammation. The aim of our study was to evaluate the impact of acenocoumarol therapy on the course of acute pancreatitis induced in male rats by pancreatic ischemia followed by reperfusion. Acenocoumarol at a dose of 50, 100, or 150 µg/kg/dose was administered intragastrically once a day, starting the first dose 24 h after the initiation of pancreatic reperfusion. Results: Histological examination showed that treatment with acenocoumarol reduces pancreatic edema, necrosis, and hemorrhages in rats with pancreatitis. Moreover, the administration of acenocoumarol decreased pancreatic inflammatory infiltration and vacuolization of pancreatic acinar cells. These findings were accompanied with a reduction in the serum activity of lipase and amylase, concentration of interleukin-1β, and plasma d-Dimer concentration. Moreover, the administration of acenocoumarol improved pancreatic blood flow and pancreatic DNA synthesis. Acenocoumarol given at a dose of 150 µg/kg/dose was the most effective in the treatment of early phase acute pancreatitis. However later, acenocoumarol given at the highest dose failed to exhibit any therapeutic effect; whereas lower doses of acenocoumarol were still effective in the treatment of acute pancreatitis. Conclusion: Treatment with acenocoumarol accelerates the recovery of ischemia/reperfusion-induced acute pancreatitis in rats.

  2. Elevated sodium chloride concentrations enhance the bystander effects induced by low dose alpha-particle irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Han Wei; Zhu Lingyan; Jiang Erkang; Wang Jun; Chen Shaopeng; Bao Linzhi; Zhao Ye; Xu An; Yu Zengliang [Key Laboratory of Ion Beam Bioengineering, Institute of Plasma Physics, Chinese Academy of Sciences, Hefei 230031 (China); Wu Lijun [Key Laboratory of Ion Beam Bioengineering, Institute of Plasma Physics, Chinese Academy of Sciences, Hefei 230031 (China)], E-mail: ljw@ipp.ac.cn

    2007-11-01

    Previous studies have shown that high NaCl can be genotoxic, either alone or combined with irradiation. However, little is known about the relationship between environmental NaCl at elevated conditions and radiation-induced bystander effects (RIBE). RIBE, which has been considered as non-targeted bystander responses, has been demonstrated to occur widely in various cell lines. In the present study, RIBE under the elevated NaCl culture condition was assessed in AG 1522 cells by both the induction of {gamma}-H2AX, a reliable marker of DNA double-strand break (DSB) for the early process (<1 h post irradiation), and the generation of micronuclei (MN), a sensitive marker for relative long process of RIBE. Our results showed that in the absence of irradiation, NaCl at elevated concentration such as 8.0, 9.0 and 10.0 g/L did not significantly increase the frequency of {gamma}-H2AX foci-positive cells and the number of foci per positive cell comparing with that NaCl at a normal concentration (6.8 g/L). However, with 0.2 cGy {alpha}-particle irradiation, the induced fraction of {gamma}-H2AX foci-positive cells and the number of induced {gamma}-H2AX foci per positive cell were significantly increased in both irradiated and adjacent non-irradiated regions. Similarly, the induction of MN by 0.2 cGy {alpha}-particle irradiation also increased with the elevated NaCl concentrations. With N{sup G}-methyl-L-arginine, an inhibitor of nitric oxide synthase, the induced fraction of foci-positive cells was effectively inhibited both in 0.2 cGy {alpha}-particle irradiated and adjacent non-irradiated regions under either normal or elevated NaCl conditions. These results suggested that the cultures with elevated NaCl medium magnified the damage effects induced by the low dose {alpha}-particle irradiation and nitric oxide generated by irradiation was also very important in this process.

  3. Dose response of micronuclei induced by combination radiation of α-particles and γ-rays in human lymphoblast cells

    Energy Technology Data Exchange (ETDEWEB)

    Ren, Ruiping; He, Mingyuan; Dong, Chen; Xie, Yuexia; Ye, Shuang; Yuan, Dexiao [Institute of Radiation Medicine, Fudan University, No. 2094 Xie-Tu Road, Shanghai 200032 (China); Shao, Chunlin, E-mail: clshao@shmu.edu.cn [Institute of Radiation Medicine, Fudan University, No. 2094 Xie-Tu Road, Shanghai 200032 (China)

    2013-01-15

    Highlights: ► α-Particle induced MN had a biphasic dose–response followed by a bystander model. ► MN dose–response of α- and γ-combination IR was similar to that of α-particle. ► α-Particles followed by γ-rays yielded a synergistic effect on MN induction. ► Low dose γ-rays triggered antagonistic and adaptive responses against α-particle. - Abstract: Combination radiation is a real situation of both nuclear accident exposure and space radiation environment, but its biological dosimetry is still not established. This study investigated the dose–response of micronuclei (MN) induction in lymphocyte by irradiating HMy2.CIR lymphoblast cells with α-particles, γ-rays, and their combinations. Results showed that the dose–response of MN induced by γ-rays was well-fitted with the linear-quadratic model. But for α-particle irradiation, the MN induction had a biphasic phenomenon containing a low dose hypersensitivity characteristic and its dose response could be well-stimulated with a state vector model where radiation-induced bystander effect (RIBE) was involved. For the combination exposure, the dose response of MN was similar to that of α-irradiation. However, the yield of MN was closely related to the sequence of irradiations. When the cells were irradiated with α-particles at first and then γ-rays, a synergistic effect of MN induction was observed. But when the cells were irradiated with γ-rays followed by α-particles, an antagonistic effect of MN was observed in the low dose range although this combination radiation also yielded a synergistic effect at high doses. When the interval between two irradiations was extended to 4 h, a cross-adaptive response against the other irradiation was induced by a low dose of γ-rays but not α-particles.

  4. Chronic UVA (365-nm) irradiation induced scratching in hairless mice: dose-time dependency and the effect of ketanserin

    International Nuclear Information System (INIS)

    Laat, J.M.T. de; Groenendijk, M.; Vloten, W.A. van; Gruijl, F.R. de; Seite, S.

    1997-01-01

    In a study on the dose-response relationship for longwave UVA (UVA1; 340-400 nm) carcinogenesis in hairless mice scratch marks appeared after months of daily exposure as an unwanted side effect. Tumor induction in the highest of the 4 tested dose groups (receiving a daily dose of 430 kJ/m 2 of 365-nm radiation) could not be determined because extensive scarification occurred prior to the development of any tumors. The induction of scratch marks could be scored and quantified in all 4 dose groups tested. The UVA1 dose-dependencies for the induction of tumors and scratch marks were compared. We found that the induction of scratch marks depended mainly on the cumulative UVA1 exposure, whereas tumor induction showed a lesser dose-dependency. An attempt was made to prevent the apparent pruritogenic effect of UVA1 irradiation and to understand its mechanism. The influence of ketanserin, a serotonin/histamine antagonist, on the UVA1 induction of scratch marks was tested in groups of 8 mice daily irradiated with 430 kJ/m 2 . No difference was found between treated and untreated animals. Histological examination of skin biopsies from irradiated mice from the 430-kJ/m 2 dose group from the UVA1 carcinogenic experiment, showed no changes in numbers of mast cells or other inflammatory features when compared to skin biopsies from unirradiated control mice. This indicated that UVA1-induced scratching is not mediated through mast cell release of serotonin and/or histamine. An adequate therapeutic treatment which can prevent UVA1-induced scratching would enable us to test tumor induction with UVA1 over a larger dose range, and may provide additional insight in how this radiation damages the skin. It remains conjectural whether there exists and analogous UVA-induced pruritus in human skin. (au)

  5. Hepatoprotection and neuroprotection induced by low doses of IGF-II in aging rats

    Directory of Open Access Journals (Sweden)

    Barhoum Rima

    2011-07-01

    Full Text Available Abstract Background GH and IGFs serum levels decline with age. Age-related changes appear to be associated to decreases in these anabolic hormones. We have previously demonstrated that IGF-I replacement therapy improves insulin resistance, lipid metabolism and reduces oxidative damage (in brain and liver in aging rats. Using the same experimental model, the aim of this work was to study whether the exogenous administration of IGF-II, at low doses, acts analogous to IGF-I in aging rats. Methods Three experimental groups were included in this study: young healthy controls (yCO, 17 weeks old; untreated old rats (O, 103 weeks old; and aging rats treated with IGF-II (O+IGF-II, 2 μg * 100 g body weight-1 * day-1 for 30 days. Analytical parameters were determined in serum by routine laboratory methods using an autoanalyzer (Cobas Mira; Roche Diagnostic System, Basel, Switzerland. Serum levels of hormones (testosterone, IGF-I and insulin were assessed by RIA. Serum Total Antioxidant Status was evaluated using a colorimetric assay. Mitochondrial membrane potential was evaluated using rhodamine 123 dye (adding different substrates to determine the different states. ATP synthesis in isolated mitochondria was determined by an enzymatic method. Results Compared with young controls, untreated old rats showed a reduction of IGF-I and testosterone levels with a decrease of serum total antioxidant status (TAS. IGF-II therapy improved serum antioxidant capability without modifying testosterone and IGF-I circulating concentrations. In addition, IGF-II treatment reduced oxidative damage in brain and liver, improving antioxidant enzyme activities and mitochondrial function. IGF-II was also able to reduce cholesterol and triglycerides levels increasing free fatty acids concentrations. Conclusions We demonstrate that low doses of IGF-II induce hepatoprotective, neuroprotective and metabolic effects, improving mitochondrial function, without affecting testosterone and

  6. "Interaction of different doses of Aspartame with Morphine-induced antinociception in the presence of MK-801, a NMDA antagonist "

    Directory of Open Access Journals (Sweden)

    Abdollahi M

    2002-07-01

    Full Text Available This study was designed to investigate the relative role of sweetness and comparative effects of different taste sensation of the non - caloric sweetener , aspartame on pain and its interaction with MK - 80] as a non - selective MMDA antagonist by formalin - test in mice. The formalin - test was chosen because it measures the response to a long - lasting nociceptive stimulus and closely resembles to the clinical pain. Morphine induced a dose dependent antinociception in the early and late phases of formalin test. Twelve days pretreatment of animals by aspartame ( 0.08% , 0.16% , 0.32% significantly potentiated morphine - induced (1.5-9 mg/kg analgesia in the early phase but significantly antagonized its analgesic effect in the late phase, dose dependently. Aspartame (0.16% alone showed a reduction in pain response . Naloxone (0.4 mg/kg significantly antagonized the antinociceptive effect of morphine in the presence of aspartame (0-0.32% in the early phase. Increasing the dose of aspartame decreased effects of naloxone. MK-801 (0.1 mg/kg as an N- Methyl - D - Aspartate (NMDA antagonist significantly potentiated the effect of aspartame on morphine - induced antinociception in the early phase. In the late phase, naloxone (0.4 mg/kg increased pain response but MK- 801 (0.1 mg/kg induced anti-inflammatory effect significantly. Treatment of animals with MK- 801 alone, significantly induced analgesia in both phases of formalin - test. This effect was potentiated with aspartame dose - dependently. Possible interaction of aspartame with NMDA receptors and its role to facilitate endogenous opioid system are proposed mechanisms of aspartame in modulating morphine - induced antinociception. Furthermore, the resulting association between morphine and aspartame chronic consumption may be explained as an interactive action rather than simple dose combination of both drugs.

  7. Increased interleukin-1β levels following low dose MDMA induces tolerance against the 5-HT neurotoxicity produced by challenge MDMA

    Science.gov (United States)

    2011-01-01

    Background Preconditioning is a phenomenon by which tolerance develops to injury by previous exposure to a stressor of mild severity. Previous studies have shown that single or repeated low dose MDMA can attenuate 5-HT transporter loss produced by a subsequent neurotoxic dose of the drug. We have explored the mechanism of delayed preconditioning by low dose MDMA. Methods Male Dark Agouti rats were given low dose MDMA (3 mg/kg, i.p.) 96 h before receiving neurotoxic MDMA (12.5 mg/kg, i.p.). IL-1β and IL1ra levels and 5-HT transporter density in frontal cortex were quantified at 1 h, 3 h or 7 days. IL-1β, IL-1ra and IL-1RI were determined between 3 h and 96 h after low dose MDMA. sIL-1RI combined with low dose MDMA or IL-1β were given 96 h before neurotoxic MDMA and toxicity assessed 7 days later. Results Pretreatment with low dose MDMA attenuated both the 5-HT transporter loss and elevated IL-1β levels induced by neurotoxic MDMA while producing an increase in IL-1ra levels. Low dose MDMA produced an increase in IL-1β at 3 h and in IL-1ra at 96 h. sIL-1RI expression was also increased after low dose MDMA. Coadministration of sIL-1RI (3 μg, i.c.v.) prevented the protection against neurotoxic MDMA provided by low dose MDMA. Furthermore, IL-1β (2.5 pg, intracortical) given 96 h before neurotoxic MDMA protected against the 5-HT neurotoxicity produced by the drug, thus mimicking preconditioning. Conclusions These results suggest that IL-1β plays an important role in the development of delayed preconditioning by low dose MDMA. PMID:22114930

  8. Increased interleukin-1β levels following low dose MDMA induces tolerance against the 5-HT neurotoxicity produced by challenge MDMA

    Directory of Open Access Journals (Sweden)

    Mayado Andrea

    2011-11-01

    Full Text Available Abstract Background Preconditioning is a phenomenon by which tolerance develops to injury by previous exposure to a stressor of mild severity. Previous studies have shown that single or repeated low dose MDMA can attenuate 5-HT transporter loss produced by a subsequent neurotoxic dose of the drug. We have explored the mechanism of delayed preconditioning by low dose MDMA. Methods Male Dark Agouti rats were given low dose MDMA (3 mg/kg, i.p. 96 h before receiving neurotoxic MDMA (12.5 mg/kg, i.p.. IL-1β and IL1ra levels and 5-HT transporter density in frontal cortex were quantified at 1 h, 3 h or 7 days. IL-1β, IL-1ra and IL-1RI were determined between 3 h and 96 h after low dose MDMA. sIL-1RI combined with low dose MDMA or IL-1β were given 96 h before neurotoxic MDMA and toxicity assessed 7 days later. Results Pretreatment with low dose MDMA attenuated both the 5-HT transporter loss and elevated IL-1β levels induced by neurotoxic MDMA while producing an increase in IL-1ra levels. Low dose MDMA produced an increase in IL-1β at 3 h and in IL-1ra at 96 h. sIL-1RI expression was also increased after low dose MDMA. Coadministration of sIL-1RI (3 μg, i.c.v. prevented the protection against neurotoxic MDMA provided by low dose MDMA. Furthermore, IL-1β (2.5 pg, intracortical given 96 h before neurotoxic MDMA protected against the 5-HT neurotoxicity produced by the drug, thus mimicking preconditioning. Conclusions These results suggest that IL-1β plays an important role in the development of delayed preconditioning by low dose MDMA.

  9. Therapeutic doses of irradiation activate viral transcription and induce apoptosis in HIV-1 infected cells

    International Nuclear Information System (INIS)

    Iordanskiy, Sergey; Van Duyne, Rachel; Sampey, Gavin C; Woodson, Caitlin M; Fry, Kelsi; Saifuddin, Mohammed; Guo, Jia; Wu, Yuntao; Romerio, Fabio; Kashanchi, Fatah

    2015-01-01

    The highly active antiretroviral therapy reduces HIV-1 RNA in plasma to undetectable levels. However, the virus continues to persist in the long-lived resting CD4"+ T cells, macrophages and astrocytes which form a viral reservoir in infected individuals. Reactivation of viral transcription is critical since the host immune response in combination with antiretroviral therapy may eradicate the virus. Using the chronically HIV-1 infected T lymphoblastoid and monocytic cell lines, primary quiescent CD4"+ T cells and humanized mice infected with dual-tropic HIV-1 89.6, we examined the effect of various X-ray irradiation (IR) doses (used for HIV-related lymphoma treatment and lower doses) on HIV-1 transcription and viability of infected cells. Treatment of both T cells and monocytes with IR, a well-defined stress signal, led to increase of HIV-1 transcription, as evidenced by the presence of RNA polymerase II and reduction of HDAC1 and methyl transferase SUV39H1 on the HIV-1 promoter. This correlated with the increased GFP signal and elevated level of intracellular HIV-1 RNA in the IR-treated quiescent CD4"+ T cells infected with GFP-encoding HIV-1. Exposition of latently HIV-1infected monocytes treated with PKC agonist bryostatin 1 to IR enhanced transcription activation effect of this latency-reversing agent. Increased HIV-1 replication after IR correlated with higher cell death: the level of phosphorylated Ser46 in p53, responsible for apoptosis induction, was markedly higher in the HIV-1 infected cells following IR treatment. Exposure of HIV-1 infected humanized mice with undetectable viral RNA level to IR resulted in a significant increase of HIV-1 RNA in plasma, lung and brain tissues. Collectively, these data point to the use of low to moderate dose of IR alone or in combination with HIV-1 transcription activators as a potential application for the “Shock and Kill” strategy for latently HIV-1 infected cells. - Highlights: • X-ray irradiation (IR) increases

  10. Modelling the dynamics of ambient dose rates induced by radiocaesium in the Fukushima terrestrial environment

    Science.gov (United States)

    Gonze, Marc-André; Mourlon, Christophe; Calmon, Philippe; Manach, Erwan; Debayle, Christophe; Baccou, Jean

    2017-09-01

    Since the Fukushima accident, Japanese scientists have been intensively monitoring ambient radiations in the highly contaminated territories situated within 80 km of the nuclear site. The surveys that were conducted through mainly carborne, airborne and in situ gamma-ray measurement devices, enabled to efficiently characterize the spatial distribution and temporal evolution of air dose rates induced by Caesium-134 and Caesium-137 in the terrestrial systems. These measurements revealed that radiation levels decreased at rates greater than expected from physical decay in 2011-2012 (up to a factor of 2), and dependent on the type of environment (i.e. urban, agricultural or forest). Unlike carborne measurements that may have been strongly influenced by the depuration of road surfaces, no obvious reason can be invoked for airborne measurements, especially above forests that are known to efficiently retain and recycle radiocaesium. The purpose of our research project is to develop a comprehensive understanding of the data acquired by Japanese, and identify the environmental mechanisms or factors that may explain such decays. The methodology relies on the use of a process-based and spatially-distributed dynamic model that predicts radiocaesium transfer and associated air dose rates inside/above a terrestrial environment (e.g., forests, croplands, meadows, bare soils and urban areas). Despite the lack of site-specific data, our numerical study predicts decrease rates that are globally consistent with both aerial and in situ observations. The simulation at a flying altitude of 200 m indicated that ambient radiation levels decreased over the first 12 months by about 45% over dense urban areas, 15% above evergreen coniferous forests and between 2 and 12% above agricultural lands, owing to environmental processes that are identified and discussed. In particular, we demonstrate that the decrease over evergreen coniferous regions might be due the combined effects of canopy

  11. Therapeutic doses of irradiation activate viral transcription and induce apoptosis in HIV-1 infected cells

    Energy Technology Data Exchange (ETDEWEB)

    Iordanskiy, Sergey [School of Systems Biology, Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110 (United States); Van Duyne, Rachel [School of Systems Biology, Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110 (United States); Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702 (United States); Sampey, Gavin C; Woodson, Caitlin M; Fry, Kelsi; Saifuddin, Mohammed; Guo, Jia; Wu, Yuntao [School of Systems Biology, Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110 (United States); Romerio, Fabio [Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201 (United States); Kashanchi, Fatah, E-mail: fkashanc@gmu.edu [School of Systems Biology, Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110 (United States)

    2015-11-15

    The highly active antiretroviral therapy reduces HIV-1 RNA in plasma to undetectable levels. However, the virus continues to persist in the long-lived resting CD4{sup +} T cells, macrophages and astrocytes which form a viral reservoir in infected individuals. Reactivation of viral transcription is critical since the host immune response in combination with antiretroviral therapy may eradicate the virus. Using the chronically HIV-1 infected T lymphoblastoid and monocytic cell lines, primary quiescent CD4{sup +} T cells and humanized mice infected with dual-tropic HIV-1 89.6, we examined the effect of various X-ray irradiation (IR) doses (used for HIV-related lymphoma treatment and lower doses) on HIV-1 transcription and viability of infected cells. Treatment of both T cells and monocytes with IR, a well-defined stress signal, led to increase of HIV-1 transcription, as evidenced by the presence of RNA polymerase II and reduction of HDAC1 and methyl transferase SUV39H1 on the HIV-1 promoter. This correlated with the increased GFP signal and elevated level of intracellular HIV-1 RNA in the IR-treated quiescent CD4{sup +} T cells infected with GFP-encoding HIV-1. Exposition of latently HIV-1infected monocytes treated with PKC agonist bryostatin 1 to IR enhanced transcription activation effect of this latency-reversing agent. Increased HIV-1 replication after IR correlated with higher cell death: the level of phosphorylated Ser46 in p53, responsible for apoptosis induction, was markedly higher in the HIV-1 infected cells following IR treatment. Exposure of HIV-1 infected humanized mice with undetectable viral RNA level to IR resulted in a significant increase of HIV-1 RNA in plasma, lung and brain tissues. Collectively, these data point to the use of low to moderate dose of IR alone or in combination with HIV-1 transcription activators as a potential application for the “Shock and Kill” strategy for latently HIV-1 infected cells. - Highlights: • X-ray irradiation

  12. Adaptive response to ionizing radiation induced by low doses of gamma rays in human cell lines

    International Nuclear Information System (INIS)

    Seong, Jinsil; Chang, Ok Suh; Gwi, Eon Kim

    1995-01-01

    Purpose: The aim of this study was to investigate whether the adaptive response could be induced in human lymphoblastoid cell lines and human tumor cell lines. The time necessary for the expression of the adaptive response was also investigated. Materials and Methods: Three lymphoblastoid cell lines from ataxia telangiectasia (AT) homozygote (GM 1526), AT heterozygote (GM 3382), and normal individual (3402p) and two hepatoma cell lines, Hep G2 and Hep 3B, were used in this study. Experiments were carried out by delivering 0.01 Gy followed by 0.5 Gy of gamma radiation to the exponentially growing cells. The time necessary for the expression of the adaptive response was determined by varying the time interval between the two doses from 1 to 72 h. In some experiments, 3-aminobenzamide, a potent inhibitor of poly (ADP-ribose) polymerase, was added immediately after the 0.5 Gy exposure. The cultures were fixed 30 min (for the G 2 chromatid) and 6 h (for the S chromatid) after the 0.5 Gy exposure. Metaphase chromosome assay was carried out to score chromatid breaks as an end point. Results: A prior exposure to 0.01 Gy of gamma rays significantly reduced the number of chromatid breaks induced by subsequent higher doses (0.5 Gy) in all the tested cell lines. The magnitude of the adaptive response was similar among the cell lines despite their different radiosensitivities. In the G 2 chromatids, the adaptive response was observed both at short-time intervals, as early as 1 h, and at long-time intervals. In the S chromatids, however, the adaptive response was shown only at long-time intervals. When 3-aminobenzamide was added after the 0.5 Gy, the adaptive responses were abolished in all the experimental groups. Conclusion: The adaptive response was observed in human lymphoblastoid cell lines and hepatoma cell lines. The magnitude of the adaptive response did not seem to be related to the radiosensitivity of the cells. The elimination of the adaptive response with 3

  13. Dose-response relationship for chromosomal aberrations induced in human lymphocytes by 18 MeV electron beam irradiation

    International Nuclear Information System (INIS)

    Lashin, E.A.; Elaasar, E.M.; Moustafa, H.F.; Bakir, Y.Y.; Al Zenki, S.D.

    1990-01-01

    Dose response curves for lymphocyte chromosome aberration frequencies using X- and gamma radiation became an important and reliable indicator as biological dosimeter especially in radiation accidents and occupational over exposures. Nowadays electron beam therapy is frequently used for their advantages in cases of tumours under or near to the body surface. Dose-response curves for these electron beams are rarely published. Human peripheral blood lymphocytes were in vitro irradiated with various low and high doses (0.1 Gy to 4.9 Gy) of 18 MeV electron beams to utilize such a dose-response curve using chromosomal aberration frequencies as a biological indicator. Then we compared the biological curve with physically obtained curves normally used in planning for radiotherapy treatment. It is interesting to find a significant difference between both of them. The biological curve is generally higher in value and the aberrations induced by 93% of a dose is significantly higher and deeper in site than those aberrations induced by the 100% dose calculated physically. If the above observation is confirmed by detailed studies, it would be of importance to the radiotherapist to plan for isodose curves according to biological determinations. (author)

  14. Low dose transdermal estradiol induces breast density and heterogeneity changes comparable to those of raloxifene

    DEFF Research Database (Denmark)

    Nielsen, Mads; Raundahl, Jakob; Pettersen, Paola

    2009-01-01

    Objective: To investigate whether transdermal low dose estradiol treatment induces changes in mammographic density or heterogeneity compared to raloxifene. Secondarily, if these changes relate to changes in bone formation/resorption markers, and if these findings indicate elevation of breast canc...

  15. Low submetamorphic doses of dexamethasone and thyroxine induce complete metamorphosis in the axolotl (Ambystoma mexicanum) when injected together.

    Science.gov (United States)

    Kühn, Eduard R; De Groef, Bert; Grommen, Sylvia V H; Van der Geyten, Serge; Darras, Veerle M

    2004-06-01

    Entanglement of functions between the adrenal (or interrenal) and thyroid axis has been well described for all vertebrates and can be tracked down up to the level of gene expression. Both thyroid hormones and corticosteroids may induce morphological changes leading to metamorphosis climax in the neotenic Mexican axolotl (Ambystoma mexicanum). In a first series of experiments, metamorphosis was induced with an injection of 25 microg T(4) on three alternate days as judged by a decrease in body weight and tail height together with complete gill resorption. This injection also resulted in elevated plasma concentrations of T(3) and corticosterone. Previous results have indicated that the same dose of dexamethasone (DEX) is ineffective in this regard (Gen. Comp. Endocrinol. 127 (2002) 157). In a second series of experiments low doses of T(4) (0.5 microg) or DEX (5 microg) were ineffective to induce morphological changes. However, when these submetamorphic doses were injected together, morphological changes were observed within one week leading to complete metamorphosis. It is concluded that thyroid hormones combined with corticosteroids are essential for metamorphosis in the axolotl and that only high doses of either thyroid hormone or corticosteroid can induce morphological changes when injected separately.

  16. Exposure to low infective doses of HCV induces cellular immune responses without consistently detectable viremia or seroconversion in chimpanzees

    International Nuclear Information System (INIS)

    Shata, Mohamed Tarek; Tricoche, Nancy; Perkus, Marion; Tom, Darley; Brotman, Betsy; McCormack, Patricia; Pfahler, Wolfram; Lee, Dong-Hun; Tobler, Leslie H.; Busch, Michael; Prince, Alfred M.

    2003-01-01

    In hepatitis C virus (HCV) infection, there is accumulating data suggesting the presence of cellular immune responses to HCV in exposed but seemingly uninfected populations. Some studies have suggested cross-reactive antigens rather than prior HCV exposure as the main reason for the immune responses. In this study we address this question by analyzing the immune response of chimpanzees that have been sequentially exposed to increasing doses of HCV virions. The level of viremia, as well as the immune responses to HCV at different times after virus inoculation, were examined. Our data indicate that HCV infective doses as low as 1-10 RNA (+) virions induce detectable cellular immune responses in chimpanzees without consistently detectable viremia or persistent seroconversion. However, increasing the infective doses of HCV to 100 RNA (+) virions overcame the low-inoculum-induced immune response and produced high-level viremia followed by seroconversion

  17. Dose-response relationship of cadmium or radiation-induced embryotoxicity in mouse whole embryo culture

    International Nuclear Information System (INIS)

    Nakashima, Kiyohito; Kawamata, Akitoshi; Matsuoka, Masato; Wakisaka, Takashi; Fujiki, Yoshishige

    1988-01-01

    Mouse embryos of B6C3F 1 strain were exposed in vitro to 1.2 to 2.2 μM cadmium chloride (Cd) or to 100 to 320 R x-rays, and the effects of the exposure on development were examined after 39 h of culture. Development of embryos was assessed from lethality, formation of the neural tube defect, diameter and protein of yolk sac, crown-rump and head lengths, embryonic protein, and number of somites. Incidence of the neural tube defect increased from 3.4 to 100% by 1.2 to 2.0 μM Cd, while embryo deaths increased from 13.8 to 93.3% by 2.0 to 2.2 μM Cd. Embryonic protein was significantly reduced at the teratogenic range, but the number of somites was only affected by 1.6 to 2.0 μM Cd. X-irradiation at 100 to 320 R induced the neural tube defect in 2.9 to 72.7% of the embryos. An embryolethal effect was observed only at the 320 R dose. Crown-rump and head lengths and embryonic protein were significantly affected at the teratogenic range, but the diameter and protein of yolk sac and number of somites were hardly affected. Cadmium- or radiation-induced response data of both teratogenicity and endpoints indicating inhibition of embryonic development were acceptably fitted to a linear log-probit regression. These regressions suggest that as an estimation of interference in development of embryos, embryonic protein and head length are sensitive endpoints while the number of somites is an insensitive criterion. (author)

  18. SU-F-J-221: Adjusted Dose and Its Relation to Radiation Induced Liver Disease During Hepatocellular Carcinoma Radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Huang, P; Gang, Y; Qin, S; Li, D [Shandong Province Key Laboratory of Medical Physics and Image Processing Technology, School of Physics and Electronics, Shandong Normal University (China); Li, H; Chen, J; Ma, C; Yin, Y [Department of Radiation Oncology, Shandong Cancer Hospital and Institute (China)

    2016-06-15

    Purpose: Many patients with hepatocellular carcinoma (HCC) had hepatic anatomy variations as a result of inter-fraction deformation during fractionated radiotherapy, which may result in difference from the planned dose. This study aimed to investigate the relationship between adjusted dose and radiation induced liver disease (RILD) in HCC patients receiving three dimensional conformal radiotherapy (3DCRT). Methods: Twenty-three HCC patients received conventional fractionated 3DCRT were enrolled in this retrospective investigation. Among them, seven patients had been diagnosed of RILD post-radiotherapy, including 4 cases of grade 2, 3 cases of grade 3 according to the CTCAE Version 3.0. Daily cone-beam CT (CBCT) scans were acquired throughout the whole treatment course for each patient. To reconstruct the daily dose to a patient considering the interfraction anatomy variations, the planned beams from each patient’s treatment plan were firstly applied to each daily modified CBCT (mCBCT). The daily doses were then summed together with the help of deformable image registration (DIR) to obtain the adjusted dose (Dadjusted) of the patient. Finally, the dose changes in normal liver between planned dose (Dplan) and Dadjusted were evaluated by V20, V30, V40 and the mean dose to normal liver (MDTNL). Univariate analysis was performed to identify the significant dose changes. Results: Among the twenty-three patients, the adjusted liver V20, V30, V40 and MDTNL showed significant changes from the planned ones (p<0.05) and averagely increased by 4.1%, 4.7%, 4.5% and 3.9Gy, respectively. And the adjusted liver dose in twenty-one patients (91%) were higher than planned value, the adjusted dose of patients with RILD (6/7) exceeds to the hepatic radiation tolerance. Conclusion: The adjusted dose of all the studied patients significantly differs from planned dose, and mCBCT-based dose reconstruction can aid in evaluating the robustness of the planning solutions, and adjusted dose

  19. Low-Dose Radiation-Induced Adaptive Response in Polychromatic Mice Erythrocyte as Measured by Acridine Orange Stained Micronuleus Assay

    International Nuclear Information System (INIS)

    Hee-Sun, K.; Kwang-Hee, Y.; Cha-Soom, K.; Jung-Mi, C.; Gu-Choul, S.; Suk-Young, P.; Kyoung-H, C.; Chong-Soom, K.; Young-Khi, L.; Jae-Ho, W.

    2004-01-01

    The effect of conditioning pretreatment with 0.01Gy of gamma rays on micronucleated polychromatic erythrocyte (MN-PCE) induction by 2Gy of g-rays was determined in peripheral blood of C3H/He mice. The timing of their administration of challenge doses was 6hr. The response was determined by scoring of Acridine orange dye stained MN-PCEs. The results indicate that low dose gamma ray pretreatment does protect against MN-PCE induction by the challenge g-ray dose. Introduction: An adaptive response induced by low doses of ionizing radiation in vivo reported. Some research team reports that a reduction on MN-PCE of mice caused by the pretreatment was observed [1- 4]. However, there was variability in the amount of the response depending on the time and adaptive dose [3]. This is important because the variation of MN-PCE frequency with time could lead to differences in the interpretation. In this study, differences in the biological effects within the priming dose ranges are discussed. Materials and Methods: Specific pathogen free 5-week-old C3H/He mice, purchased from Shizuoka Laboratory Center (Japan), were kept in clean and conventional environment. When 6 weeks old, the animal were whole body irradiated using irradiator of IBL-437 (137Cs, 0.8Gy/min). After various time intervals, the two groups were administrated to adaptation dose and challenge dose of 0.01Gy and 2Gy, respectively. For experiments, sham-irradiated, only adaptive and challenge dose irradiated groups were run concurrently. Smears were stained and scored using Acridine orange dye method [2]. Statistically significant differences in MN-PCE frequency were determined by comparing tie individual values at each group with the respective control values (challenge dose irradiated group) by using the paired ttest. Results and Discussions: Induced MN by the challenge dose (2Gy) after the pretreatment with 0.01Gy is low to the one induced by the challenge dose alone. In the present study, this estimation for the

  20. Effect of dose of gamma-rays and ethylmethane sulphonate on the germination and survival of induced mutations in pigeonpea

    Energy Technology Data Exchange (ETDEWEB)

    Premsekar, S [Central Inst. for Cotton Research, Coimbatore (India). Regional Station; Appadurai, R [Tamil Nadu Agricultural Univ., Coimbatore (India)

    1981-06-01

    The LD/sub 50/ values for germination and survival of the induced mutants (M/sub 1/) of pigeonpea (Cajanus cajan (Linn.) Millsp.) were attained with 20 and 15 krad when gamma-rays were used, and 30 and 40 mM concentration when EMS was used. In the combination treatments the half-kill dose for germination and survival was reached even at the low dose combination of 5 krad gamma-ray + 20 mM EMS. Higher doses resulted in lower pollen and seed fertility. The sterility was much enhanced in the combined treatments. The number of pods, seed yield and weight of seeds could be stimulated with 10 and 15 krad doses of gamma-rays and 20 mM of EMS. In combination treatments such a stimulatory effect was noticed in seed weight only.

  1. Reduction of aspirin-induced fecal blood loss with low-dose misoprostol tablets in man

    International Nuclear Information System (INIS)

    Cohen, M.M.; Clark, L.; Armstrong, L.; D'Souza, J.

    1985-01-01

    Misoprostol (SC-29333), a synthetic prostaglandin E1 methyl ester analog, was given simultaneously with acetylsalicylic acid in a double-blind, placebo-controlled randomized prospective study of 32 healthy human male subjects. Fecal blood loss was measured for eight days using the 51 Cr-labeled red blood cell technique. Aspirin (650 mg qid) and misoprostol (25 micrograms qid) or placebo were given during days 3, 4, and 5. There was a significant (P less than 0.05) increase in median blood loss (modified Friedman test) from 0.81 to 6.05 ml/day in the aspirin with placebo group (N = 16). Median blood loss was increased (from 0.75 to 3.75 ml/day) in the aspirin with misoprostol group (N = 16), but this was significantly less (Mann-Whitney U test, P less than 0.01) than the placebo group. Mean serum salicylate concentrations in the placebo and misoprostol groups were similar (7.8 and 6.8 micrograms/ml, respectively). There were no significant changes in laboratory values in any of the subjects studied, nor were any major side-effects encountered. This study demonstrates that oral misoprostol reduces aspirin-induced gastrointestinal bleeding even when administered simultaneously and at a dose level below its threshold for significant acid inhibition. This indicates a potential role for misoprostol in the prevention of gastric mucosal damage in selected patients

  2. Gamma radiation-induced Impairment of hippocampal neurogenesis, comparison of single and fractionated dose regimens

    International Nuclear Information System (INIS)

    Khoshbin khoshnazar, A. R; Jahanshahi, M; Azami, N. S

    2012-01-01

    Radiation therapy of the brain is associated with many consequences, including cognitive disorders. Pathogenesis of radiation induced cognitive disorder is not clear, but reduction of neurogenesis in hippocampus may be an underlying reason. 24 adult male rats entered to study. Radiation absorbed dose to midbrain was 10 Gy, delivered by routine cobalt radiotherapy machine which its output was measured 115.24 cGy/min. The rats were divided in four groups of sixes, including groups of control, single fraction 10 Gy, fractionated 10 Gy and finally anaesthesia sham group. Number of pyramidal nerve cells was counted in two regions of hippocampus formation (CA1 and CA3). The radiation could reduce the number of cells in two regions of hippocampus significantly (p=0.000). It seems fractionated 10 Gy irradiation to more efficient than single fraction, while role of anaesthesia drug should be cautiously assessed. Moreover the rate of neurogenesis reduction was determined the same in these regions of hippocampus meaning the same radiosensitivity of cells

  3. Electron beam induced graft-polymerization of methyl methacrylate onto polyethylene films at high dose rates

    International Nuclear Information System (INIS)

    Mori, Koji; Koshiishi, Kenji; Masuhara, Ken-ichi

    1991-01-01

    Electron beam induced graft-polymerization by the mutual irradiation technique of methyl methacrylate on the surface of low density polyethylene films (LD) and high density polyethylene films (HD) was investigated at high dose rates over 10 Mrad per second. Graft-polymerization mechanisms were discussed on the basis of O 2 permeability, tensile strength, elongation at break, and surface tension of the grafted films. As the degree of grafting increased, the O 2 permeability of LD decreased, while that of HD little changed at the grafting up to 4 ∼ 5 %. This indicates that the grafting occurred in the amorphous regions for LD and occurred in the amorphous regions in the neighborhood of crystalline regions for HD. For HD, when the degree of the grafting surpassed 4 ∼ 5 %, the O 2 permeability, tensile strength, elongation at break, and surface tension decreased with an increase in the degree of grafting. It was assumed that rapid grafting in the amorphous regions in the neighborhood of crystalline regions caused the increase in local temperature by the heat of polymerization, and the viscosity of polyethylene in the amorphous regions decreased with an increase in temperature. As a result, the graft chains, which formed micro domain structure, condensed in the amorphous regions and the domain increased in size. (author)

  4. Long-term biological effects induced by ionizing radiation--implications for dose mediated risk.

    Science.gov (United States)

    Miron, S D; Astărăstoae, V

    2014-01-01

    Ionizing radiations are considered to be risk agents that are responsible for the effects on interaction with living matter. The occurring biological effects are due to various factors such as: dose, type of radiation, exposure time, type of biological tissue, health condition and the age of the person exposed. The mechanisms involved in the direct modifications of nuclear DNA and mitochondrial DNA are reviewed. Classical target theory of energy deposition in the nucleus that causes DNA damages, in particular DNA double-strand breaks and that explanation of the biological consequences of ionizing radiation exposure is a paradigm in radiobiology. Recent experimental evidences have demonstrated the existence of a molecular mechanism that explains the non-targeted effects of ionizing radiation exposure. Among these novel data, genomic instability and a variety of bystander effects are discussed here. Those bystander effects of ionizing radiation are fulfilled by cellular communication systems that give rise to non-targeted effects in the neighboring non irradiated cells. This paper provides also a commentary on the synergistic effects induced by the co-exposures to ionizing radiation and various physical agents such as electromagnetic fields and the co-exposures to ionizing radiation and chemical environmental contaminants such as metals. The biological effects of multiple stressors on genomic instability and bystander effects are also discussed. Moreover, a brief presentation of the methods used to characterize cyto- and genotoxic damages is offered.

  5. Sun-Induced Changes in Stratum Corneum Function Are Gender and Dose Dependent in a Chinese Population

    Science.gov (United States)

    Liu, Z.; Fluhr, J.W.; Song, S.P.; Sun, Z.; Wang, H.; Shi, Y.J.; Elias, P.M.; Man, M.-Q.

    2010-01-01

    Previous studies have demonstrated that UVB radiation changes the epidermal permeability barrier and stratum corneum (SC) hydration. It is well known that sun exposure causes erythema, sunburn and melanoma. However, whether daily sun exposure alters SC integrity and epidermal permeability barrier function is largely unknown, especially in Chinese subjects. In the present study, we assess the SC integrity, SC hydration and epidermal permeability barrier function following various doses of sun exposure. A total of 258 subjects (124 males and 134 females) aged 18–50 years were enrolled. A multifunctional skin physiology monitor (Courage & Khazaka MPA5) was used to measure SC hydration and transepidermal water loss (TEWL) on the forearms. In males, basal TEWL was higher with higher doses of sun exposure than with lower doses and control, whereas in females, basal TEWL was higher with lower doses of sun exposure than with higher doses and control. In the group with higher doses of sun exposure, TEWL in females was significantly lower than that in males. The barrier recovery was faster in females than in males in both control and lower-dose groups. In both males and females, barrier recovery was delayed with higher doses of sun exposure. In males, sun exposure did not alter SC hydration, while in females SC hydration was lower with lower doses of sun exposure as compared with control and higher doses of sun exposure. These results demonstrated that sun-induced changes in SC function and SC hydration vary with gender and the extent of sun exposure. PMID:20571289

  6. Possible Protective Effect of Low-dose Gamma Irradiation and Certain Natural Products on Chemically Induced Hepatotoxicity in Rats

    International Nuclear Information System (INIS)

    Rashed, R.R.A.

    2015-01-01

    Liver, the largest organ in the human body, is a vital organ that performs more than 500 vital metabolic functions. More than a 1000 drugs of the modern pharmacopoeia can induce liver injury with different clinical presentations. In the most severe cases, drug-induced liver injury may require liver transplantation or lead to death of the patient. Acetaminophen (acetyl-para-amino-phenol, paracetamol, APAP) is safe at therapeutic doses, but accidental or intentional overdose can induce severe hepatotoxicity in both humans and experimental animals. APAP-induced hepatotoxicity is dose related and reproducible in animals, and is thus widely used as a model for experimentally induced hepatotoxicity. Many herbs have been used as natural remedies for the prevention and/or treatment of liver diseases. Herbal drugs gained importance and popularity in recent years because of their safety, efficacy and cost effectiveness. Interestingly, exposure to a small dose or dose rate of radiation was reported to induce stress, perturbing homeostasis. Organisms respond adaptively to such disturbances. The mechanisms by which low-dose radiation (LDR) protects the cells or tissue against subsequent radiation- or drug-induced toxicities have been attributed to its stimulation of various protective molecules such as antioxidants and anti apoptotic. In the light of the above mentioned information, this study was constructed in order to investigate the mechanism(s) of the hepato protective effects offered by each of garlic oil (GO), black seed oil (BO) and sesame oil (SO) each alone or combined with low dose total body gamma (γ)-irradiation against APAP-induced hepatotoxicity in male albino Wistar rats. Preliminary pilot studies were performed prior to the main experimental work; in order to select the effective irradiation dose, the hepato protective natural products and the duration of their administration to be used in the main study. To carry out the main study, 96 rats were randomly

  7. Sustained Low-Dose Treatment with the Histone Deacetylase Inhibitor LBH589 Induces Terminal Differentiation of Osteosarcoma Cells

    Directory of Open Access Journals (Sweden)

    Jason E. Cain

    2013-01-01

    Full Text Available Histone deacetylase inhibitors (HDACi were identified nearly four decades ago based on their ability to induce cellular differentiation. However, the clinical development of these compounds as cancer therapies has focused on their capacity to induce apoptosis in hematologic and lymphoid malignancies, often in combination with conventional cytotoxic agents. In many cases, HDACi doses necessary to induce these effects result in significant toxicity. Since osteosarcoma cells express markers of terminal osteoblast differentiation in response to DNA methyltransferase inhibitors, we reasoned that the epigenetic reprogramming capacity of HDACi might be exploited for therapeutic benefit. Here, we show that continuous exposure of osteosarcoma cells to low concentrations of HDACi LBH589 (Panobinostat over a three-week period induces terminal osteoblast differentiation and irreversible senescence without inducing cell death. Remarkably, transcriptional profiling revealed that HDACi therapy initiated gene signatures characteristic of chondrocyte and adipocyte lineages in addition to marked upregulation of mature osteoblast markers. In a mouse xenograft model, continuous low dose treatment with LBH589 induced a sustained cytostatic response accompanied by induction of mature osteoblast gene expression. These data suggest that the remarkable capacity of osteosarcoma cells to differentiate in response to HDACi therapy could be exploited for therapeutic benefit without inducing systemic toxicity.

  8. Effects of subanesthetic doses of ketamine in cats with induced experimental endotoxemia

    Directory of Open Access Journals (Sweden)

    Felipe Hertzing Farias

    2015-12-01

    Full Text Available ABSTRACT. Farias F.H., Gehrcke M.I., Padilha V.S., Volpato J., Tochetto R., Comassetto F. & Oleskovicz N. [Effects of subanesthetic doses of ketamine in cats with induced experimental endotoxemia.] Efeitos da cetamina em doses subanestésicas em gatos submetidos à endotoxemia experimental. Revista Brasileira de Medicina Veterinária, 37(4:297-302, 2015. Programa de Pós-Graduação em Ciência Animal, Centro de Ciências Agroveterinárias, Universidade do Estado de Santa Catarina, Avenida Luís de Camões, 2090, Bairro Conta Dinheiro, Lages, SC 88520-000, Brasil. E-mail: noleskovicz@yahoo.com.br The clinical endotoxemia is difficult to diagnosis and treatment because of the involvement of multiple organs. This study aimed to evaluate the clinical effects of subanesthetic doses of ketamine, before or after the induction of endotoxemia in cats. Were used nine healthy cats, with 4.3±0.59 kg, autocontroles, placed into three groups: lipopolysaccharide (LPS, n=9 received a bolus of NaCl 0,9 % followed by a continuous infusion (CI of LPS for two hours and; bolus of NaCl 0,9 % followed by CI of LPS for two hours; ketamine/LPS (C/ LPS, n=9 received a bolus of ketamine followed by ketamine CI and LPS for two hours and, after, bolus of saline followed by CI of LPS for another two hours; LPS/ketamine (LPS/C, n=9 received bolus of saline followed by a CI LPS for two hours and then after bolus of ketamine followed by the same CI associated with LPS for two hours. The heart rate was higher for 5 to 120 minutes after initiation of the CI LPS in C/LPS and less than 150 to 240 minutes and from 600 to 720 minutes in LPS compared to the other groups. Five minutes after CI LPS initiation in C/LPS, 60 minutes in LPS/C and 90 minutes to 720 minutes in LPS, FC was higher than at baseline. The PAS was lower in all groups from 360 to 720 minutes compared to baseline. All treatments showed increased TR from 60 to 600 minutes compared to baseline. The levels of glucose

  9. Radiation-induced rectal complications are not influenced by age: a dose fractionation study in the rat.

    Science.gov (United States)

    van den Aardweg, Gerard J M J; Olofsen-van Acht, Manouk J J; van Hooije, Christel M C; Levendag, Peter C

    2003-05-01

    Radiation-induced complications of the rectum are an important dose-limiting factor in radiotherapy of pelvic malignancies. In general, animal studies demonstrated no differences in acute and late normal tissue toxicity with age, but little is known about rectal complications in relation to age. For this purpose, an extensive histological and dose fractionation study was carried out on the rectum of young (12 weeks) and older (77-80 weeks) rats. In this paper, the results of dose fractionation are presented in relation to age at the time of irradiation. Young and older animals were irradiated with single and fractionated doses. After irradiation, rectal complications could lead to occlusion and stenosis, eventually resulting in the clinical symptoms of a megacolon and a possible fistula. For each dose group, cumulative survival rates were obtained with Kaplan-Meier analysis, from which dose-effect curves and the associated LD(50) values for a megacolon/fistula were calculated. The majority of responders died between 8 and 24 weeks after irradiation, irrespective of age. For both age groups, only the fractionation data showed a reduction in the mean latency with increasing dose. In the older age group, 39% of the responders developed a fistula compared to 26% for the younger animals. The LD(50) values increased from around 30 Gy after single doses to nearly 65 Gy after 10 fractions. The increases in LD(50) values with the number of fractions were independent of the age of the rats. For each of the dose fractionation schedules, log-rank testing indicated no significant differences in cumulative survival rates between younger and older animals (P > 0.10). The high alpha/beta ratios obtained for both the young and older animals strongly suggested that the late rectal complications were a consequence of early epithelial injury. Associated histological findings indicated that blood vessel damage, which was already evident at a high incidence at 4 weeks after irradiation

  10. The evolutionary reserve cell concept and model of cellular response induced by low doses of radiation

    International Nuclear Information System (INIS)

    Spitkovsky, D.M.; Talyzina, T.A.

    1995-01-01

    The model is based on the concept of programmed initiation of genetic damage in sub-populations of specific evolutionary reserve cells (ERC). The model quantitatively predicts a dose response of genetic lesions at low dose range and furnishes an explanation of the minimum observed in the dose-response curve at doses corresponding to one (on the average) event of energy deposition per ERC. The complex shape of the dose-response curve is demonstrated to result from superposition of processes in different sub-populations within the exposed cell population (at low doses mainly in ERC). Programmed initiation of genetic lesions in ERC requires two hits to cell membrane and probably, at the same time, to the cell nucleus. The equation for dicentric yield in human lymphocytes as a function of dose describes the experimental observations rather well. (Author)

  11. A UV-Induced Genetic Network Links the RSC Complex to Nucleotide Excision Repair and Shows Dose-Dependent Rewiring

    Directory of Open Access Journals (Sweden)

    Rohith Srivas

    2013-12-01

    Full Text Available Efficient repair of UV-induced DNA damage requires the precise coordination of nucleotide excision repair (NER with numerous other biological processes. To map this crosstalk, we generated a differential genetic interaction map centered on quantitative growth measurements of >45,000 double mutants before and after different doses of UV radiation. Integration of genetic data with physical interaction networks identified a global map of 89 UV-induced functional interactions among 62 protein complexes, including a number of links between the RSC complex and several NER factors. We show that RSC is recruited to both silenced and transcribed loci following UV damage where it facilitates efficient repair by promoting nucleosome remodeling. Finally, a comparison of the response to high versus low levels of UV shows that the degree of genetic rewiring correlates with dose of UV and reveals a network of dose-specific interactions. This study makes available a large resource of UV-induced interactions, and it illustrates a methodology for identifying dose-dependent interactions based on quantitative shifts in genetic networks.

  12. Inhibitory effects of prior low-dose X-ray irradiation on carbon tetrachloride-induced hepatopathy in acatalasemic mice

    International Nuclear Information System (INIS)

    Yamaoka, Kiyonori; Kataoka, Takahiro; Taguchi, Takehito; Wang, Da-Hong; Mori, Shuji; Hanamoto, Katsumi; Kira, Shohei; Nomura, Takaharu

    2004-01-01

    The catalase activities in blood and organs of the acatalasemic (C3H/AnLCs b Cs b ) mouse of C3H strain are lower than those of the normal (C3H/AnLCs a Cs a ) mouse. We examined the effects of prior low-dose (0.5 Gy) X-ray irradiation, which reduced the oxidative damage under carbon tetrachloride-induced hepatopathy in the acatalasemic or normal mice. The acatalasemic mice showed a significantly lower catalase activity and a significantly higher glutathione peroxidase activity compared with those in the normal mice. Moreover, low-dose irradiation increased the catalase activity in the acatalasemic mouse liver to a level similar to that of the normal mouse liver. Pathological examinations and analyses of blood glutamic oxaloacetic and glutamic pyruvic transaminase activity and lipid peroxide levels showed that carbon tetrachloride induced hepatopathy was inhibited by low-dose irradiation. These findings may indicate that the free radical reaction induced by the lack of catalase and the administration of carbon tetrachloride is more properly neutralized by high glutathione peroxidase activity and low-dose irradiation in the acatalasemic mouse liver. (author)

  13. Adaptive response of spermatogenic cell apoptosis selectively induced by low dose X-ray irradiation in mice

    International Nuclear Information System (INIS)

    Liu Guangwei; Dong Lihua; Liu Yang; Lv Zhe; Liu Shuchun; Gong Shouliang

    2003-01-01

    Objective: The adaptive response of spermatogenic cell apoptosis induced by whole-body X-ray irradiation at low doses was studied in mice. Methods: Kunming male mice were irradiated with an inductive dose (D1:75 mGy) and/or a challenging dose (D2:1.0, 2.0 or 3.0 Gy). Different kinds of spermatogenic cells were separated using density gradient centrifugation and their apoptotic percentages were analysed using flow cytometry (FCM). Results: When the mice were irradiated with D1 6 h before irradiation with D2, the apoptotic percentages of the spermatogonia and spermatocytes declined rapidly as compared with those in the groups irradiated with D2 only, and those of spermatids and spermatozoa showed no significant changes. When the interval times between D1 and D2 was 3, 6, 12 or 24 h, the apoptotic percentages in spermatogonia and spermatocytes reduced early, significantly and continued for a longer duration after smaller D2(1.0 and 2.0 Gy) irradiation, while the apoptotic percentages did not change after larger D2(3.0 Gy) irradiation. Conclusion: The adaptive response of apoptosis in spermatogonia and spermatocytes could be selectively induced by low dose X-ray irradiation. The adaptive response could be closely related to the D2 dose and interval time between D1 and D2

  14. The Effects of Pretreatment with Various Doses of L-Arginine on Cisplatin-Induced Nephropathy of Male Rats

    Directory of Open Access Journals (Sweden)

    B Rasoulian

    2016-09-01

    Full Text Available Introduction: Cisplatin is a widely used anti-cancer drug, which its application is limited by nephrotoxicity. In this study, the effect of pretreatment with different l-arginine doses on Cisplatin-induced renal functional injury was investigated. Methods: 63 male rats were divided into 7 groups: In groups 3, 4, 5 and 6, 60 min before the Cisplatin injection (5mg/kg; L-Arginine with doses of 50,100,200 or 400mg/kg was injected, respectively. In group7, normal saline was injected before Cisplatin administration. In groups 1 and 2, normal saline was injected instead of Cisplatin. In group 2, 60min before normal saline injection, 400mg/kg L-Arginine was administered and in group1, instead of L-arginine, normal saline was injected too. Injections were intraperitoneal. 72h after Cisplatin injection, blood sampling and plasma separation were done. Urine sample was collected 24 hours before blood sampling by metabolic cage. The mean of plasma urea and creatinine levels and creatinine clearance (ml/day.kg and fractional excretion of Na (FENa, % were compared among different groups as renal functional parameters. Results: In comparison to group 7, L-arginine injection in a dose of 400mg/kg led to significant amelioration of all parameters. 200 mg/kg L-arginine administration led to significant decrease in plasma urea level and FENa. 100mg/kg L-arginine caused significant improvement in fractional excretion of sodium. L-arginine injection with 50mg/kg dose, significantly ameliorate all renal function tests instead of creatinine clearance. Conclusion: Pretreatment with L-arginine administration with 400 or 50 mg/kg doses, respectively, had the highest effect on reducing Cisplatin-induced nephropathy. L-arginine injection with intermediate doses i.e. 200 or 100 mg/kg had less effect in reducing Cisplatin-induced nephropathy and it needs more investigations.

  15. Comparative transcriptome analysis of rice seedlings induced by different doses of heavy ion radiation

    Science.gov (United States)

    Zhao, Qian; Sun, Yeqing; Wang, Wei

    2016-07-01

    Highly ionizing radiation (HZE) in space is considered as a main factor causing biological effects on plant seeds. To investigate the different effects on genome-wide gene expression of low-dose and high-dose ion radiation, we carried out ground-base carbon particle HZE experiments with different cumulative doses (0Gy, 0.2Gy, 2Gy) to rice seeds and then performed comparative transcriptome analysis of the rice seedlings. We identified a total of 2551 and 1464 differentially expressed genes (DEGs) in low-dose and high-dose radiation groups, respectively. Gene ontology analyses indicated that low-dose and high-dose ion radiation both led to multiple physiological and biochemical activities changes in rice. By Gene Ontology analyses, the results showed that only one process-oxidation reduction process was enriched in the biological process category after high-dose ion radiation, while more processes such as response to biotic stimulus, heme binding, tetrapyrrole binding, oxidoreductase activity, catalytic activity and oxidoreductase activity were significantly enriched after low-dose ion radiation. The results indicated that the rice plants only focused on the process of oxidation reduction to response to high-dose ion radiation, whereas it was a coordination of multiple biological processes to response to low-dose ion radiation. To elucidate the transcriptional regulation of radiation stress-responsive genes, we identified several DEGs-encoding TFs. AP2/EREBP, bHLH, C2H2, MYB and WRKY TF families were altered significantly in response to ion radiation. Mapman analysis speculated that the biological effects on rice seedlings caused by the radiation stress might share similar mechanisms with the biotic stress. Our findings highlight important alterations in the expression of radiation response genes, metabolic pathways, and TF-encoding genes in rice seedlings exposed to low-dose and high-dose ion radiation.

  16. Clustered DNA damages induced in isolated DNA and in human cells by low doses of ionizing radiation

    Science.gov (United States)

    Sutherland, B. M.; Bennett, P. V.; Sidorkina, O.; Laval, J.; Lowenstein, D. I. (Principal Investigator)

    2000-01-01

    Clustered DNA damages-two or more closely spaced damages (strand breaks, abasic sites, or oxidized bases) on opposing strands-are suspects as critical lesions producing lethal and mutagenic effects of ionizing radiation. However, as a result of the lack of methods for measuring damage clusters induced by ionizing radiation in genomic DNA, neither the frequencies of their production by physiological doses of radiation, nor their repairability, nor their biological effects are known. On the basis of methods that we developed for quantitating damages in large DNAs, we have devised and validated a way of measuring ionizing radiation-induced clustered lesions in genomic DNA, including DNA from human cells. DNA is treated with an endonuclease that induces a single-strand cleavage at an oxidized base or abasic site. If there are two closely spaced damages on opposing strands, such cleavage will reduce the size of the DNA on a nondenaturing gel. We show that ionizing radiation does induce clustered DNA damages containing abasic sites, oxidized purines, or oxidized pyrimidines. Further, the frequency of each of these cluster classes is comparable to that of frank double-strand breaks; among all complex damages induced by ionizing radiation, double-strand breaks are only about 20%, with other clustered damage constituting some 80%. We also show that even low doses (0.1-1 Gy) of high linear energy transfer ionizing radiation induce clustered damages in human cells.

  17. Possibilities of the reduction of a dose of metronidazole during irradiation of tumor with subsequent induced hyperglycemia

    International Nuclear Information System (INIS)

    Vinskaya, N.P.; Voloshina, E.A.; Kozin, S.V.

    1989-01-01

    The therapeutic efficacy of a scheme of polyradiomodification with metronidazole (MZ) administration was investigated in experiments on mice with Ehrlich carcinoma before local irradiation of tumors and with subsequent induced hyperglycemia (IH) depending on a MZ dose. For equally effective potentiation of the effect of radiation on a tumor during a combined use of MZ and postradiation IH a 4-fold lower dose of the drug was required as combined to MZ used alone. The combined effect of the modifiers was superadditive. The use of IH in this scheme not only potentiated skin radiation reactions on a tumor growth zone but also slighly weakened their expression

  18. 90Y/90 Sr electron induced damages in an essential eucalyptus oil related to the absorbed dose

    International Nuclear Information System (INIS)

    Heredia Cardona, J.A.; Diaz Rizo, O.; Martinez Luzardo, F.; Quert, R.

    2007-01-01

    A good irradiation geometry was achieved in order to carry out the irradiation of an essential eucalyptus oil with a 90 Y/ 90 Sr electron source. The Monte Carlo simulation code MCNP-4C was employed to determine the absorbed doses in this particular experimental configuration. It also helped us to understand which electrons (from an energetic point of view) were responsible for the damages. In order to identify the induced damages, the irradiated samples were studied by mass spectrometry. The obtained results were related to the absorbed doses determined by the computational simulation

  19. Drug–drug interaction of microdose and regular-dose omeprazole with a CYP2C19 inhibitor and inducer

    Science.gov (United States)

    Park, Gab-jin; Bae, Soo Hyeon; Park, Wan-Su; Han, Seunghoon; Park, Min-Ho; Shin, Seok-Ho; Shin, Young G; Yim, Dong-Seok

    2017-01-01

    Purpose A microdose drug–drug interaction (DDI) study may be a valuable tool for anticipating drug interaction at therapeutic doses. This study aimed to compare the magnitude of DDIs at microdoses and regular doses to explore the applicability of a microdose DDI study. Patients and methods Six healthy male volunteer subjects were enrolled into each DDI study of omeprazole (victim) and known perpetrators: fluconazole (inhibitor) and rifampin (inducer). For both studies, the microdose (100 μg, cold compound) and the regular dose (20 mg) of omeprazole were given at days 0 and 1, respectively. On days 2–9, the inhibitor or inducer was given daily, and the microdose and regular dose of omeprazole were repeated at days 8 and 9, respectively. Full omeprazole pharmacokinetic samplings were performed at days 0, 1, 8, and 9 of both studies for noncompartmental analysis. Results The magnitude of the DDI, the geometric mean ratios (with perpetrator/omeprazole only) of maximum concentration (Cmax) and area under the curve to the last measurement (AUCt) of the microdose and the regular dose were compared. The geometric mean ratios in the inhibition study were: 2.17 (micro) and 2.68 (regular) for Cmax, and 4.07 (micro), 4.33 (regular) for AUCt. For the induction study, they were 0.26 (micro) and 0.21 (regular) for Cmax, and 0.16 (micro) and 0.15 (regular) for AUCt. There were no significant statistical differences in the magnitudes of DDIs between microdose and regular-dose conditions, regardless of induction or inhibition. Conclusion Our results may be used as partial evidence that microdose DDI studies may replace regular-dose studies, or at least be used for DDI-screening purposes. PMID:28408803

  20. Drug-drug interaction of microdose and regular-dose omeprazole with a CYP2C19 inhibitor and inducer.

    Science.gov (United States)

    Park, Gab-Jin; Bae, Soo Hyeon; Park, Wan-Su; Han, Seunghoon; Park, Min-Ho; Shin, Seok-Ho; Shin, Young G; Yim, Dong-Seok

    2017-01-01

    A microdose drug-drug interaction (DDI) study may be a valuable tool for anticipating drug interaction at therapeutic doses. This study aimed to compare the magnitude of DDIs at microdoses and regular doses to explore the applicability of a microdose DDI study. Six healthy male volunteer subjects were enrolled into each DDI study of omeprazole (victim) and known perpetrators: fluconazole (inhibitor) and rifampin (inducer). For both studies, the microdose (100 μg, cold compound) and the regular dose (20 mg) of omeprazole were given at days 0 and 1, respectively. On days 2-9, the inhibitor or inducer was given daily, and the microdose and regular dose of omeprazole were repeated at days 8 and 9, respectively. Full omeprazole pharmacokinetic samplings were performed at days 0, 1, 8, and 9 of both studies for noncompartmental analysis. The magnitude of the DDI, the geometric mean ratios (with perpetrator/omeprazole only) of maximum concentration (C max ) and area under the curve to the last measurement (AUC t ) of the microdose and the regular dose were compared. The geometric mean ratios in the inhibition study were: 2.17 (micro) and 2.68 (regular) for C max , and 4.07 (micro), 4.33 (regular) for AUC t . For the induction study, they were 0.26 (micro) and 0.21 (regular) for C max , and 0.16 (micro) and 0.15 (regular) for AUC t . There were no significant statistical differences in the magnitudes of DDIs between microdose and regular-dose conditions, regardless of induction or inhibition. Our results may be used as partial evidence that microdose DDI studies may replace regular-dose studies, or at least be used for DDI-screening purposes.

  1. Dose- dependent ameliorative effects of quercetin and l-Carnitine against atrazine- induced reproductive toxicity in adult male Albino rats.

    Science.gov (United States)

    Abdel Aziz, Rabie L; Abdel-Wahab, Ahmed; Abo El-Ela, Fatma I; Hassan, Nour El-Houda Y; El-Nahass, El-Shaymaa; Ibrahim, Marwa A; Khalil, Abdel-Tawab A Y

    2018-06-01

    This study aimed to determine the protective effects of co-administration of Quercetin (QT) or l-Carnitine (LC) against the oxidative stress induced by Atrazine (ATZ) in the reproductive system of intact male Albino rats. 36 rats were divided equally into 6 groups. Rats in the control negative "CNT" group received 1.5 ml distilled water for 21 days. All rats in the other groups received ATZ (120 mg/kg bw) through gavage. Groups 3 and 4 were co-administered with either low or high dose of QT (10 "ATZLQT" and 50 "ATZHQT" mg/kg bw, respectively). Groups 5 and 6 were co-administered with either low or high dose of LC (200 "ATZLLC" and 400 "ATZHLC" mg/kg bw, respectively). At the end of the experiment, animals were sacrificed and all samples were collected. ATZ significantly increased serum level of malondialdehyde (MDA) and decreased total antioxidant capacity (TAC). Also, ATZ increased significantly the sperm cell abnormalities and reduced both testicular IgA and serum testosterone levels. Testicular DNA laddering % and CYP17A1 mRNA expression were significantly reduced in ATZ group. Interestingly, co-administration with low dose QT or different doses of LC succeeded to counteract the negative toxic effects of ATZ on serum oxidative stress indicators, serum testosterone levels, testicular IgA level and improved testicular CYP17A1 mRNA expression. In conclusion, QT in low dose and LC in both low and high doses exerted a significant protective action against the reproductive toxicity of ATZ, while higher dose of QT failed induce immune-stimulant effect against ATZ in adult male Albino rats. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  2. High-dose 8% capsaicin patch in treatment of chemotherapy-induced peripheral neuropathy: single-center experience.

    Science.gov (United States)

    Filipczak-Bryniarska, Iwona; Krzyzewski, Roger M; Kucharz, Jakub; Michalowska-Kaczmarczyk, Anna; Kleja, Justyna; Woron, Jarosław; Strzepek, Katarzyna; Kazior, Lucyna; Wordliczek, Jerzy; Grodzicki, Tomasz; Krzemieniecki, Krzysztof

    2017-08-17

    High-dose capsaicin patch is effective in treatment of neuropathic pain in HIV-associated neuropathy and diabetic neuropathy. There are no studies assessing effectiveness of high-dose capsaicin patch in treatment of chemotherapy-induced peripheral neuropathy. We sought to determine the effectiveness of treatment of pain associated with chemotherapy-induced peripheral neuropathy with high-dose capsaicin patch. Our study group consisted of 18 patients with clinically confirmed oxaliplatin-induced neuropathy. Baseline characteristic including underling disease, received cumulative dose of neurotoxic agent, neuropathic symptoms, prior treatment and initial pain level were recorded. Pain was evaluated with Numeric Rating Scale prior to treatment with high-dose capsaicin and after 1.8 day and after 8 and 12 weeks after introducing treatment. Patients were divided into two groups accordingly to the amount of neurotoxic agent that caused neuropathy (high sensitivity and low sensitivity group). Most frequent symptoms of chemotherapy-induced neuropathy were: pain (88.89%), paresthesis (100%), sock and gloves sensation (100%) and hypoesthesis (100%). Initial pain level was 7.45 ± 1.14. Mean cumulative dose of oxaliplatin after which patients developed symptoms was 648.07 mg/m 2 . Mean pain level after 12 weeks of treatment was 0.20 ± 0.41. When examined according to high and low sensitivity to neurotoxic agent patients with low sensitivity had higher pain reduction, especially after 8 days after introducing treatment (69.55 ± 12.09 vs. 49.40 ± 20.34%; p = 0.02) and after 12 weeks (96.96 ± 5.56 vs. 83.93 ± 18.59%; p = 0.04). High-dose capsaicin patch is an effective treatment for pain associated with chemotherapy-induced neuropathy in patients treated with oxaliplatin. Patients with lower sensitivity to neurotoxic agents have better response to treatment and pain reduction.

  3. Possible radioprotective effect of folic acid supplementation on low dose ionizing radiation-induced genomic instability in vitro.

    Science.gov (United States)

    Padula, Gisel; Ponzinibbio, María Virginia; Seoane, Analia I

    2016-08-01

    Ionizing radiation (IR) induces DNA damage through production of single and double-strand breaks and reactive oxygen species (ROS). Folic acid (FA) prevents radiation-induced DNA damage by modification of DNA synthesis and/or repair and as a radical scavenger. We hypothesized that in vitro supplementation with FA will decrease the sensitivity of cells to genetic damage induced by low dose of ionizing radiation. Annexin V, comet and micronucleus assays were performed in cultured CHO cells. After 7 days of pre-treatment with 0, 100, 200 or 300 nM FA, cultures were exposed to radiation (100 mSv). Two un-irradiated controls were executed (0 and 100 nM FA). Data were statistically analyzed with X2-test and linear regression analysis (P 0.05). We observed a significantly decreased frequency of apoptotic cells with the increasing FA concentration (P <0.05). The same trend was observed when analyzing DNA damage and chromosomal instability (P <0.05 for 300 nM). Only micronuclei frequencies showed significant differences for linear regression analysis (R2=94.04; P <0.01). Our results have demonstrated the radioprotective effect of folic acid supplementation on low dose ionizing radiation-induced genomic instability in vitro; folate status should be taken into account when studying the effect of low dose radiation in environmental or occupational exposure.

  4. cDNA cloning and transcriptional controlling of a novel low dose radiation-induced gene and its function analysis

    International Nuclear Information System (INIS)

    Zhou Pingkun; Sui Jianli

    2002-01-01

    Objective: To clone a novel low dose radiation-induced gene (LRIGx) and study its function as well as its transcriptional changes after irradiation. Methods: Its cDNA was obtained by DDRT-PCR and RACE techniques. Northern blot hybridization was used to investigate the gene transcription. Bioinformatics was employed to analysis structure and function of this gene. Results: LRIGx cDNA was cloned. The sequence of LRIGx was identical to a DNA clone located in human chromosome 20 q 11.2-12 Bioinformatics analysis predicted an encoded protein with a conserved helicase domain. Northern analysis revealed a ∼8.5 kb transcript which was induced after 0.2 Gy as well as 0.02 Gy irradiation, and the transcript level was increased 5 times at 4 h after 0.2 Gy irradiation. The induced level of LRIGx transcript by 2.0 Gy high dose was lower than by 0.2 Gy. Conclusion: A novel low dose radiation-induced gene has been cloned. It encodes a protein with a conserved helicase domain that could involve in DNA metabolism in the cellular process of radiation response

  5. What kind of prior low dose radiation does the adaptive response induce?

    International Nuclear Information System (INIS)

    Suzuki, Masao

    2009-01-01

    Described are the adaptive response (AR) and genetic instability (GI) induced by different kind of low dose radiation (LDR) and their relation with the bystander effect. For this, human normal cells were placed at 2.65 m distance from the target of National Institute of Radiological Sciences (NIRS) Heavy Ion Medical Accelerator in Chiba (HIMAC) to see the biological effect of LDR of mixed radiations (1-1.5 mGy/day; mixture of 94% gamma ray, 1.9% neutron (N) and particle ions mainly containing proton (P) in the rest). Cells were then irradiated with 1.5 Gy X-ray. No effect on the lethality was observed as compared with control cells without LDR. The mutation on hprt gene was found significantly elevated 2-30 days after LDR, suggesting that GI had been induced. To see the effect of each radiation on GI, gamma ray ( 137 Cs), N ( 241 Am-Be) and heavy ion (HIMAC He, C and Fe) as LDR were separately irradiated to cells with total 1 mGy/7-8 hr and then acutely with the X-ray. He and C ions were found to promote mutation 1.9 and 4.0 times higher on frequencies, respectively, and N, to reduce the mutation rate to 15% (AR). Results indicated that cell responses were quite different dependently on linear energy transfer. The probability of hit number of ions in the cell population was calculated to be 61, 15 and 2% for He, C and Fe, respectively, suggesting an existence of considerable number of cells not irradiated. Presence of a gap-junction specific inhibitor (GSI) at LDR resulted in normalization of mutation rate in all groups of cells, suggesting that the bystander effect through cell-cell signal transduction affected the cell response to X-irradiation. For AR induction by N, when 1.5% of cells in culture were irradiated by P in NIRS SPICE as LDR, AR in mutation was observed and was inhibited by GSI, suggesting that N completely destroyed the hit cell but concomitantly yielded recoil P substantially acted as LDR. Above findings indicated that the exact radiation risk can

  6. Chromosome aberrations induced by low doses of X-rays in human lymphocytes in vitro

    International Nuclear Information System (INIS)

    Ziemba-Zoltowska, B.; Bocian, E.; Rosiek, O.; Sablinski, J.

    1980-01-01

    Curves derived from the dose-response data for the yield of aberrations in human lymphocytes can be represented by a quadratic equation at all but low dose ranges. A calibration curve has therefore been determined at a low dose range of X-radiation (11.5 to 57.5 rad). The frequencies of dicentrics plus centric rings, and of acentrics were better fitted by linear dose-response models than quadratic. The linearity of the relationship indicated that asymmetrical chromosome exchanges at low doses of radiation are produced predominantly by a single track mechanism. A dose-response curve for dicentrics plus centric rings (5 to 60 rad) has also been derived by pooling published data with the results of this study. This calibration curve is relevant to cytogenetic dosimetry in radiological protection. (UK)

  7. Dose-rate effects on gamma-induced genetic injury in rat spermatogonia

    International Nuclear Information System (INIS)

    Vyglenov, A.

    1990-01-01

    Data for correlation between the reciprocal translocations (RT) yield in rat germ cells and the doses of 0.5 - 3.0 Gy are presented. A 60 Co source has been used with dose rates of 0.25, 8 x 10 -2 and 7 x 10 -3 Gy/min. The results from the cytogenetic analysis made 6 months after irradiation have shown an increase of the yield with the increase of the dose, which can be described as a linear unthreshold dependence. The dose rate effect is expressed in decrease of mutation frequency. The comparison with earlier author's data from similar experiments for acute irradiation allows to determine the RBE of gamma irradiation at the three dose rates investigated as 0.6, 0.2 and 0.1 respectively. The reported results are connected with the problem of variety specificity of the dose rate effect. 2 figs., 2 tabs., 15 refs

  8. Radiation induced bystander effects: mechanisms and implication for low dose radiation risk assessment

    International Nuclear Information System (INIS)

    Hei, T.L.; Randers-Pehrson, G.; Zhou, H.

    2003-01-01

    Using a precision microbeam to target an exact fraction of cells in a population and irradiated their nuclei with exactly one alpha particle each, we found that the frequencies of induced mutations and chromosomal changes in populations where some known fractions of nuclei were hit are consistent with non-hit cells contributing significantly to the response. In fact, irradiation of 10% of a mammalian cell population with a single alpha particle per cell results in a mutant yield similar to that observed when all of the cells in the population are irradiated. Although the bystander observations have been well established, the underlying mechanism(s) remain largely unknown. There are indications that multiple pathways are involved in the bystander phenomenon and different cell types respond differently to the bystander signaling. In confluent monolayers, there is evident that gap junctional communication is crucial in mediating the bystander effect whereas reactive oxygen and reactive nitrogen species have been implicated as the mediating molecules in sub-confluent cultures. Although p53 is not necessary for the expression of bystander effect, there is evident that repair deficient cells may express a higher bystander response. Using cDNA microarrays, a number of cellular signaling genes have been shown to be differentially expressed among bystander cells. The functional roles of these genes in the bystander effect will be discussed. The bystander observations imply that the relevant target for various radiobiological endpoints is larger than an individual cell and suggest a need to reconsider the validity of the linear extrapolation in making risk estimate for low dose radiation exposure. (Work supported by NIH grants CA 49062 and CA-RR11623)

  9. [Comparative study on the tolerance and efficacy of high doses of metoclopramide and clebopride in vomiting induced by cisplatin].

    Science.gov (United States)

    Martín, M; Díaz-Rubio, E

    1989-06-10

    Forty-one patients treated with cisplatin (100-120 mg/m2), alone or associated with vindesine (3 mg/m2), were included in a randomized crossover pilot study which compared 3 different doses of intravenous clebopride with intravenous metoclopramide. The patients were randomly assigned to receive clebopride in the first chemotherapy course in one of the three dose levels used (0.5 mg/kg, 21 patients; 0.75 mg/kg, 11 patients; 1 mg/kg, 10 patients) or metoclopramide (10 mg/kg). In the second course of the same chemotherapy the patients received the alternative antiemetic, and thus each patient was his own control. The total dose of both antiemetic drugs was infused in 5 intravenous fractions given every 2 hours. The antiemetic activity of clebopride was moderately lower to that of metoclopramide with the first two tested doses (overall doses of 0.5 and 0.75 mg/kg) and similar with the last dose (1 mg/kg). Clebopride was reasonably well tolerated at the used dosages, inducing sedation in 20% of cases (versus 24% with metoclopramide) and diarrhea in 37% (versus 20% with metoclopramide). Extrapyramidal reactions developed in 17% of the courses which included metoclopramide and in none including clebopride. This difference was statistically significant.

  10. Morphological changes induced by different doses of gamma irradiation in garlic sprouts

    Energy Technology Data Exchange (ETDEWEB)

    Pellegrini, C.N. E-mail: pellegri@criba.edu.ar; Croci, C.A.; Orioli, G.A

    2000-03-01

    The objective of this work was to evaluate the effects of different doses of gamma rays applied in dormancy and post-dormancy on garlic bulbs in relation with some morphophysiological parameters. High (commercial) doses cause the complete inhibition of sprouting and mitosis (due to nuclear aberrations). Relatively low doses show no effects on bulbs but doses of 10 Gy applied in post-dormancy reduce sprouting and stop mitosis. This inhibition becomes noticeable from 150 days post-harvest onwards. Exogenous growth regulators can reverse these effects. Results may reinforce the good practice of radioinhibition processes in garlic. (author)0.

  11. Mode of action analysis for the synthetic pyrethroid metofluthrin-induced rat liver tumors: evidence for hepatic CYP2B induction and hepatocyte proliferation.

    Science.gov (United States)

    Deguchi, Yoshihito; Yamada, Tomoya; Hirose, Yukihiro; Nagahori, Hirohisa; Kushida, Masahiko; Sumida, Kayo; Sukata, Tokuo; Tomigahara, Yoshitaka; Nishioka, Kazuhiko; Uwagawa, Satoshi; Kawamura, Satoshi; Okuno, Yasuyoshi

    2009-03-01

    Two-year treatment with high doses of Metofluthrin produced hepatocellular tumors in both sexes of Wistar rats. To understand the mode of action (MOA) by which the tumors are produced, a series of studies examined the effects of Metofluthrin on hepatic microsomal cytochrome P450 (CYP) content, hepatocellular proliferation, hepatic gap junctional intercellular communication (GJIC), oxidative stress and apoptosis was conducted after one or two weeks of treatment. The global gene expression profile indicated that most genes with upregulated expression with Metofluthrin were metabolic enzymes that were also upregulated with phenobarbital. Metofluthrin induced CYP2B and increased liver weights associated with centrilobular hepatocyte hypertrophy (increased smooth endoplasmic reticulum [SER]), and induction of increased hepatocellular DNA replication. CYP2B1 mRNA induction by Metofluthrin was not observed in CAR knockdown rat hepatocytes using the RNA interference technique, demonstrating that Metofluthrin induces CYP2B1 through CAR activation. Metofluthrin also suppressed hepatic GJIC and induced oxidative stress and increased antioxidant enzymes, but showed no alteration in apoptosis. The above parameters related to the key events in Metofluthrin-induced liver tumors were observed at or below tumorigenic dose levels. All of these effects were reversible upon cessation of treatment. Metofluthrin did not cause cytotoxicity or peroxisome proliferation. Thus, it is highly likely that the MOA for Metofluthrin-induced liver tumors in rats is through CYP induction and increased hepatocyte proliferation, similar to that seen for phenobarbital. Based on analysis with the International Life Sciences Institute/Risk Science Institute MOA framework, it is reasonable to conclude that Metofluthrin will not have any hepatocarcinogenic activity in humans, at least at expected levels of exposure.

  12. Bisphenol A (BPA) aggravates multiple low-dose streptozotocin-induced Type 1 diabetes in C57BL/6 mice.

    Science.gov (United States)

    Cetkovic-Cvrlje, Marina; Thinamany, Sinduja; Bruner, Kylie A

    2017-12-01

    Type 1 diabetes (T1D) is a T-cell-mediated autoimmune disorder characterized by destruction of insulin-producing pancreatic β-cells. Whereas epidemiological data implicate environmental factors in the increasing incidence of T1D, their identity remains unknown. Though exposure to bisphenol A (BPA) has been associated with several disorders, no epidemiologic evidence has linked BPA exposure and T1D. The goal of this study was to elucidate diabetogenic potentials of BPA and underlying mechanisms in the context of T-cell immunity, in a multiple low-dose streptozotocin (MLDSTZ)-induced autoimmune mouse T1D model. C57BL/6 mice were orally exposed to 1 or 10 mg BPA/L starting at 4 wk of age; diabetes was induced at 9 wk of age with STZ. T-cell composition, function, and insulitis levels were studied at Days 11 and 50 during diabetes development (i.e. post-first STZ injection). Results showed both BPA doses increased diabetes incidence and affected T-cell immunity. However, mechanisms of diabetogenic action appeared divergent based on dose. Low-dose BPA fits a profile of an agent that exhibits pro-diabetogenic effects via T-cell immunomodulation in the early stages of disease development, i.e. decreases in splenic T-cell subpopulations [especially CD4 + T-cells] along with a trend in elevation of splenic T-cell formation of pro-inflammatory cytokines (IFN-γ, TNF-α, and IL-6). In contrast, high-dose BPA did not affect T-cell populations and led to decreased levels of IFN-γ and TNF-α. Both treatments did not affect insulitis levels at the disease early stage, but aggravated it later on. By the study end, besides decreasing T-cell proliferative capacity, low-dose BPA did not affect other T-cell-related parameters, including cytokine secretion, comparable to the effects of high-dose BPA. In conclusion, this study confirmed BPA as a potential diabetogenic compound with immunomodulatory mechanisms of action - in the context of T-cell immunity - that seemed to be dose

  13. Radiation-Induced Noncancer Risks in Interventional Cardiology: Optimisation of Procedures and Staff and Patient Dose Reduction

    Science.gov (United States)

    Khairuddin Md Yusof, Ahmad

    2013-01-01

    Concerns about ionizing radiation during interventional cardiology have been increased in recent years as a result of rapid growth in interventional procedure volumes and the high radiation doses associated with some procedures. Noncancer radiation risks to cardiologists and medical staff in terms of radiation-induced cataracts and skin injuries for patients appear clear potential consequences of interventional cardiology procedures, while radiation-induced potential risk of developing cardiovascular effects remains less clear. This paper provides an overview of the evidence-based reviews of concerns about noncancer risks of radiation exposure in interventional cardiology. Strategies commonly undertaken to reduce radiation doses to both medical staff and patients during interventional cardiology procedures are discussed; optimisation of interventional cardiology procedures is highlighted. PMID:24027768

  14. Dose and time relations in Hg(++)-induced tubular necrosis and regeneration

    DEFF Research Database (Denmark)

    Nielsen, J B; Andersen, H R; Andersen, O

    1994-01-01

    relationship is caused by a dose-related induction of kidney damage leading to increasing leakage of mercury through the kidneys. Histopathologic investigation revealed extensive necrosis of the proximal tubules in kidneys from mice exposed to 100 mumole HgCl2/kg or higher doses. Moreover, maximum renal damage...

  15. Protection against soman-induced seizures in rats: relationship among doses of prophylactics, soman, and adjuncts

    International Nuclear Information System (INIS)

    Myhrer, Trond; Nguyen, Nga H.T.; Andersen, Jannike M.; Aas, Paal

    2004-01-01

    The combined effects of physostigmine and procyclidine (antagonizing muscarinic, nicotinic, and NMDA receptors) were tested against various doses of soman. Physostigmine (0.1 mg/kg) in combination with procyclidine doses of 1, 3, or 6 mg/kg effectively prevented the development of convulsions and hippocampally monitored seizures when the doses of soman were 1.3, 1.6, or 2 x LD50, respectively. Results from [ 3 H]MK-801-binding experiments showed that procyclidine inhibits the phencyclidine site at the NMDA receptor in a concentration-dependent manner. Physostigmine (0.1 mg/kg) and procyclidine in a dose of 1 mg/kg did not prevent convulsions or seizures when the soman dose was 1.6 x LD50. Subsequent treatment with scopolamine in doses of 0.5 or 1 mg/kg immediately after (3 min) seizure onset showed that only the highest dose produced a reliable termination. When scopolamine (1 mg/kg) was given later (10 min) after onset of seizures, no effect was obtained. The sustained seizures were subsequently treated with diazepam (10 mg/kg) and pentobarbital (30 mg/kg) and finally terminated 25 min after onset. In rats given inadequate prophylaxis, both modified convulsions and seizures were seen. It is suggested that moderate doses of prophylactics should be preferred to avoid adverse effects on cognitive functions because insufficient prophylaxis can be compensated for by adjunct treatment

  16. Time-effect relationship of immunological adaptive response induced by low dose X-irradiation in mice

    International Nuclear Information System (INIS)

    Zhao Yong; Gong Shouliang; Liu Shuzheng

    1995-01-01

    Kunming mice irradiated with whole-body X-rays were used to observe time-effect relationship of immunological adaptive response induced by ionizing radiation. The results showed that pre-irradiation dose of 75 mGy X-rays with the intervals of 6-48 h between pre-irradiation and challenge irradiation could induce immunological adaptive response in the spontaneous proliferation of thymocytes and the responses of splenocytes to Con A and LPS in mice at 18-24 h after challenge irradiation with 1.5-2.0 Gy X-rays

  17. Low doses of dextromethorphan attenuate morphine-induced rewarding via the sigma-1 receptor at ventral tegmental area in rats.

    Science.gov (United States)

    Chen, Shiou-Lan; Hsu, Kuei-Ying; Huang, Eagle Yi-Kung; Lu, Ru-Band; Tao, Pao-Luh

    2011-09-01

    Chronic use of morphine causes rewarding and behavioral sensitization, which may lead to the development of psychological craving. In our previous study, we found that a widely used antitussive dextromethorphan (known as a low affinity NMDA receptor antagonist), at doses of 10-20 mg/kg (i.p.), effectively decreased morphine rewarding in rats. In this study, we further investigated the effects and mechanisms of low doses of DM (μg/kg range) on morphine rewarding and behavioral sensitization. A conditioned place preference test was used to determine the rewarding and a locomotor activity test was used to determine the behavioral sensitization induced by the drug(s) in rats. When a low dose of DM (3 or 10 μg/kg, i.p.) was co-administered with morphine (5 mg/kg, s.c.), the rewarding effect, but not behavioral sensitization, induced by morphine was inhibited. The inhibiting effect of DM could be blocked by systemically administering a sigma-1 receptor antagonist, BD1047 (3 mg/kg, i.p.). When BD1047 (5 nmole/site) was locally given at the VTA, it also blocked the effects of a low dose of DM in inhibiting morphine rewarding. Our findings suggest that the activation of the sigma-1 receptor at the VTA may be involved in the mechanism of low doses of DM in inhibiting the morphine rewarding effect and the possibility of using extremely low doses of DM in treatment of opioid addiction in clinics. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  18. A Single Sub-anesthetic Dose of Ketamine Relieves Depression-like Behaviors Induced by Neuropathic Pain in Rats

    Science.gov (United States)

    Wang, Jing; Goffer, Yossef; Xu, Duo; Tukey, David S.; Shamir, D. B.; Eberle, Sarah E.; Zou, Anthony H.; Blanck, Thomas J.J.; Ziff, Edward B.

    2011-01-01

    Background Chronic pain is associated with depression. In rodents, pain is often assessed by sensory hypersensitivity, which does not sufficiently measure affective responses. Low-dose ketamine has been used to treat both pain and depression, but it is not clear whether ketamine can relieve depression associated with chronic pain and whether this antidepressant effect depends on its anti-nociceptive properties. Methods We examined whether the spared nerve injury (SNI) model of neuropathic pain induces depressive behavior in rats, using sucrose preference test and forced swim test, and tested whether a subanesthetic dose of ketamine treats SNI-induced depression. Results SNI-treated rats, compared with control, showed decreased sucrose preference (0.719 ± 0.068 (mean ± SEM) vs. 0.946 ± 0.010) and enhanced immobility in the forced swim test (107.3 ± 14.6s vs. 56.2 ± 12.5s). Further, sham-operated rats demonstrated depressive behaviors in the acute postoperative period (0.790 ± 0.062 on postoperative day 2). A single subanesthetic dose of ketamine (10mg/kg) did not alter SNI-induced hypersensitivity; however, it treated SNI-associated depression-like behaviors (0.896 ± 0.020 for ketamine vs. 0.663 ± 0.080 for control 1 day after administration; 0.858 ± 0.017 for ketamine vs. 0.683 ± 0.077 for control 5 days after administration). Conclusions Chronic neuropathic pain leads to depression-like behaviors. The postoperative period also confers vulnerability to depression, possibly due to acute pain. Sucrose preference test and forced swim test may be used to compliment sensory tests for assessment of pain in animal studies. Low-dose ketamine can treat depression-like behaviors induced by chronic neuropathic pain. PMID:21934410

  19. Effect of Bcl-2/Bax gene expression on apoptosis of spermatogenic cells of mouse testes induced by low dose radiation

    International Nuclear Information System (INIS)

    Liu Guangwei; Wang Chunyan; Lu Zhe; Liu Shunchun; Gong Shouliang

    2003-01-01

    The different kinds of spermatogenic cells were separated using density gradient centrifugation and their apoptosis and Bcl-2 and Bax protein expression were measured with flow cytometry and immunohistochemical method, respectively. The results showed the apoptosis in all kinds of spermatogenic cells induced by low dose radiation (LDR) had a obvious regularity. When the doses were 0.025 and 0.05 Gy, spermatogonia apoptosis was dominant. With the increase of irradiation dose (0.075-0.2 Gy), spermatocytes also showed an apoptotic change, but the apoptotic percentage of spermatogonia was significantly higher than that of spermatocytes. Moreover, the apoptosis of spermatids and spermatozoa scarcely occurred after LDR. Bax protein was primarily expressed in spermatogonia and spermatocytes, and the former was significantly higher than that of the latter after LDR. With the increase of irradiation dose, Bax protein expression showed a upgrading tendency, but that of spermatids and spermatozoa scarcely occurred. Bcl-2 protein was primarily expressed in spermatids and spermatozoa, but the Bcl-2 protein expressions of spermatogonia and spermatocytes scarcely occurred after LDR. These results imply that the interacting regulation of Bcl-2 and Bax gene expression might be involved in selective apoptosis of spermatogenic cells induced by LDR, which provided an experimental evidence for further exploring the apoptotic mechanism of adaptive response of spermatogenic cells by LDR

  20. Low dose β-emitter source induces sexual reproduction instead of fragmentation in an earthworm, Enchytraeus japonensis

    International Nuclear Information System (INIS)

    Miyachi, Yukihisa; Kanao, Tomoko; Okamoto, Takehito

    2005-01-01

    We examined whether background radiation, or radiation at a slightly higher level, plays a role in the reproduction of a terrestrial earthworm. Enchytraeus japonensis a recently described terrestrial oligochaete, reproduces asexually by fragmentation and subsequent regeneration. Following radiation exposure in which the worms were subjected to a 32 P β-emitter source at 15 times the background dose rate (4.5 μGy/h), a statistically significant decrease in the number of fragmentations was observed as compared with the sham controls. At that time, in a stained preparation with haematoxylin and eosin (HE), sexual reproduction occurred instead of asexual fragmentation, and mature oocytes were observed in the body of grown worms. However, increasing the radiation dose rate by 30 μGy/h resulted in the complete disappearance of the radiation-induced effects, i.e., fragmentation again occurred after 14 h. The results of this study indicate that a lower dose of radiation may be essential to achieve sexual reproduction, inducing an inhibition of fragmentation (asexual reproduction), but at higher, more cytotoxic doses of radiation these effects are negated

  1. Comparison of early treatment with low doses of nilotinib, imatinib and a clinically relevant dose of silymarin in thioacetamide-induced liver fibrosis.

    Science.gov (United States)

    Shaker, Mohamed E; Shiha, Gamal E; Ibrahim, Tarek M

    2011-11-30

    Our previous study has already confirmed a promising anti-fibrotic activity especially for nilotinib; when given at a daily dose of 10 mg/kg during the last 4 weeks of thioacetamide (TAA)-induced liver fibrosis for 12 weeks in rats. Therefore, this study was carried out to compare the prophylactic potential of low dose of nilotinib to that of its predecessor, imatinib, and a clinically relevant dose of the standard hepatoprotective treatment, silymarin, in TAA-intoxication. Male Wistar rats received intraperitoneal injections of TAA (150 mg/kg, twice weekly) for 8 weeks, as well as oral treatments with imatinib (5 mg/kg/day), nilotinib (5 mg/kg/day) and silymarin (50 mg/kg/day) from the first day of TAA-intoxication. At the end of the study, chronic hepatic injury was evaluated by analysis of liver function tests in serum. Hepatic oxidative stress was assessed by measuring malondialdehyde, 4-hydroxynonenal, total nitrate/nitrite and reduced glutathione contents, as well as myeloperoxidase and superoxide dismutase activities. Hepatic fibrosis was evaluated by histopathology and collagen content. Our results suggest that the prophylactic potential of nilotinib (5 mg/kg/day), imatinib (5mg/kg/day) and silymarin (50 mg/kg/day) in TAA-intoxication for 8 weeks is lower than the late treatments of nilotinib (10 mg/kg/day), imatinib (10mg/kg/day) and silymarin (100 mg/kg/day) during the last 4 weeks of TAA-intoxication for 12 weeks in rats. Taken together, this study suggests that nilotinib may have higher anti-fibrotic activity when administered at a significant stage of fibrosis as a result of impairment of its metabolism in the fibrotic livers. Copyright © 2011 Elsevier B.V. All rights reserved.

  2. High and Low Doses of Ionizing Radiation Induce Different Secretome Profiles in a Human Skin Model

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Qibin; Matzke, Melissa M.; Schepmoes, Athena A.; Moore, Ronald J.; Webb-Robertson, Bobbie-Jo M.; Hu, Zeping; Monroe, Matthew E.; Qian, Weijun; Smith, Richard D.; Morgan, William F.

    2014-03-18

    It is postulated that secreted soluble factors are important contributors of bystander effect and adaptive responses observed in low dose ionizing radiation. Using multidimensional liquid chromatography-mass spectrometry based proteomics, we quantified the changes of skin tissue secretome – the proteins secreted from a full thickness, reconstituted 3-dimensional skin tissue model 48 hr after exposure to 3, 10 and 200 cGy of X-rays. Overall, 135 proteins showed statistical significant difference between the sham (0 cGy) and any of the irradiated groups (3, 10 or 200 cGy) on the basis of Dunnett adjusted t-test; among these, 97 proteins showed a trend of downregulation and 9 proteins showed a trend of upregulation with increasing radiation dose. In addition, there were 21 and 8 proteins observed to have irregular trends with the 10 cGy irradiated group either having the highest or the lowest level among all three radiated doses. Moreover, two proteins, carboxypeptidase E and ubiquitin carboxyl-terminal hydrolase isozyme L1 were sensitive to ionizing radiation, but relatively independent of radiation dose. Conversely, proteasome activator complex subunit 2 protein appeared to be sensitive to the dose of radiation, as rapid upregulation of this protein was observed when radiation doses were increased from 3, to 10 or 200 cGy. These results suggest that different mechanisms of action exist at the secretome level for low and high doses of ionizing radiation.

  3. Colza cell autophagy induced of high dose of industrial sewage sludge

    Science.gov (United States)

    Lasoued, Najla; Guenole Bilal, Issam; Rejeb, Saloua; Bilal, Essaid; Rejeb, Nejib

    2013-04-01

    This preliminary study is to evaluate the effects on colza of land application of industrial sludge containing heavy metals especially lead and chromium. We are interested in high doses spreading 100t/ha to better observe the phenomena of induced transformations on colza by the absorption of heavy metals. We used the technique for ultrastructural observation in a transmission electron microscope. The colza cells show a compaction and marginalization of nuclear chromatin, nuclear membrane and cytoplasmic convolution and condensation of cytoplasm. The kernel then fragments, each fragment are surrounded by a jacket. Some cytoplasmic and nuclear elements are released and are phagocytized by neighboring cells. We observed vacuolation of the cytoplasm and the formation of autophagic vesicles. The two main ways to cell death are apoptosis and autophagy. Apoptosis was not seen in plant yet. At the nucleus level cell death main characteristics are the nuclear blebbing and fragmentation. At the molecular level, caspases activity (VPE for plants, or metacaspases I and II), chromatin condensation, degradation of DNA detected by TUNEL assay and DNA laddering detected by comet test are the main events. Autophagy is the major degradation and recycling process in cells. Its aim is to address part of the cytoplasm or organelles to the proteasome. In macro-Autophagy a specific feature is the double membrane structure that we can see in electron microscopy. This membrane is known to fusion with the lysosome/vacuole where this is in process. As a rule, the vacuole grows more and more until no organelles remains. Small lytic vacuoles appear in increasing quantity also. Autophagosomes tend to be pushed against the membrane and wall of the cell. Sometime in the literature it was describe a permeabilization or a tonoplast disruption; this is the last stage called mega-autophagy. The stress generated by heavy metals in industrial sludge spreading, produces in colza cells programmed death

  4. Cytogenetic Effects of Low Dose Radiation in Mammalian Cells Analysis of the Phenomenon Hypersensitivity and Induced Radioresistence

    CERN Document Server

    Shmakova, N L; Nasonova, E A; Krasavin, E A; Rsjanina, A V

    2001-01-01

    The induction of cytogenetic damage after irradiation of chinese hamster cells and human melanoma cells within dose range 1-200 cGy was studied. The anaphase and metaphase analysis of chromosome damage and micronuclei test were applied. The hypersensitivity (HRS) at doses below 20 cGy and the increased radioresistence at higher doses (IR) were shown with all cytogenetic criteria for both cell lines. The phenomenon of HRS/IR was reproduced in synchronic as well as in asynchronic population of chinese hamster cells. This fact shows that HRS was caused by high radiosensitivity of all cells and can not be explained by any differential sensitivity of cells in different phases of the cell cycle. So it was supposed that the increasing radioresistence is determined by the inclusion of the inducible repair processes in all cells. This conclusion agress with the fact that there was no evidence of HRS on dose-effect curves and that some part of pre-existent damage was repaired after preliminary irradiation with low dose...

  5. Suitable gamma ray dose determination in order to induce genetic variation in kaboli chickpea (Cicer Arietinum L)

    International Nuclear Information System (INIS)

    Naserian Khiabani, B.; Ahari Mostafavi, H.; Fathollahi, H.; Vedadi, S.; Mosavi Shalmani, M. A.

    2008-01-01

    In spite of chickpea's use in Iran and its ability of being replaced to adjust the shortage of protein in dietary habits, yield production is very low. One of the main reasons for chickpea's low yield production is its sensitiveness to some diseases, pest and environmental stresses. Genetic variation in chickpea is very low, because of its self pollination. In breeding programs, genetic variation plays an essential role so that the induction of genetic variation in plant population is very important for the plant breeders. The induced mutation through different kinds of mutagens is one of the important ways of genetic variation. In this research, first the sensitiveness of four cultivars (ILC.486, Philip86, Bivinich, Jam) were assessed to different gamma ray doses (100, 200, 300, 400 Gy). The results showed that with an increase in gamma ray dose, the growth rate of chickpea's genotypes decreases. In this respect, the decrease of growth rate has a linear relationship with the gamma ray dose and it is independent from the genotypes. The root length is more sensitive to gamma ray doses than its shoot, and it was observed that at the low doses the root growth decreases, comparing to the shoot growth. On the other hand, in high doses of gamma ray growth abrasion (Ageotropism, Albinism and etc.) were observed. Some traits variation (such as leaf shape, leaf size, leaf color, Albinism, etc.) were seen in M 2 generation, and finally to continue the project, three doses of gamma ray (150,200,250) were selected for the next year

  6. Integral Dose and Radiation-Induced Secondary Malignancies: Comparison between Stereotactic Body Radiation Therapy and Three-Dimensional Conformal Radiotherapy

    Directory of Open Access Journals (Sweden)

    Stefano G. Masciullo

    2012-11-01

    Full Text Available The aim of the present paper is to compare the integral dose received by non-tumor tissue (NTID in stereotactic body radiation therapy (SBRT with modified LINAC with that received by three-dimensional conformal radiotherapy (3D-CRT, estimating possible correlations between NTID and radiation-induced secondary malignancy risk. Eight patients with intrathoracic lesions were treated with SBRT, 23 Gy × 1 fraction. All patients were then replanned for 3D-CRT, maintaining the same target coverage and applying a dose scheme of 2 Gy × 32 fractions. The dose equivalence between the different treatment modalities was achieved assuming α/β = 10Gy for tumor tissue and imposing the same biological effective dose (BED on the target (BED = 76Gy10. Total NTIDs for both techniques was calculated considering α/β = 3Gy for healthy tissue. Excess absolute cancer risk (EAR was calculated for various organs using a mechanistic model that includes fractionation effects. A paired two-tailed Student t-test was performed to determine statistically significant differences between the data (p ≤ 0.05. Our study indicates that despite the fact that for all patients integral dose is higher for SBRT treatments than 3D-CRT (p = 0.002, secondary cancer risk associated to SBRT patients is significantly smaller than that calculated for 3D-CRT (p = 0.001. This suggests that integral dose is not a good estimator for quantifying cancer induction. Indeed, for the model and parameters used, hypofractionated radiotherapy has the potential for secondary cancer reduction. The development of reliable secondary cancer risk models seems to be a key issue in fractionated radiotherapy. Further assessments of integral doses received with 3D-CRT and other special techniques are also strongly encouraged.

  7. Characterizing dose response relationships: Chronic gamma radiation in Lemna minor induces oxidative stress and altered polyploidy level.

    Science.gov (United States)

    Van Hoeck, Arne; Horemans, Nele; Van Hees, May; Nauts, Robin; Knapen, Dries; Vandenhove, Hildegarde; Blust, Ronny

    2015-12-01

    The biological effects and interactions of different radiation types in plants are still far from understood. Among different radiation types, external gamma radiation treatments have been mostly studied to assess the biological impact of radiation toxicity in organisms. Upon exposure of plants to gamma radiation, ionisation events can cause, either directly or indirectly, severe biological damage to DNA and other biomolecules. However, the biological responses and oxidative stress related mechanisms under chronic radiation conditions are poorly understood in plant systems. In the following study, it was questioned if the Lemna minor growth inhibition test is a suitable approach to also assess the radiotoxicity of this freshwater plant. Therefore, L. minor plants were continuously exposed for seven days to 12 different dose rate levels covering almost six orders of magnitude starting from 80 μGy h(-1) up to 1.5 Gy h(-1). Subsequently, growth, antioxidative defence system and genomic responses of L. minor plants were evaluated. Although L. minor plants could survive the exposure treatment at environmental relevant exposure conditions, higher dose rate levels induced dose dependent growth inhibitions starting from approximately 27 mGy h(-1). A ten-percentage growth inhibition of frond area Effective Dose Rate (EDR10) was estimated at 95 ± 7 mGy h(-1), followed by 153 ± 13 mGy h(-1) and 169 ± 12 mGy h(-1) on fresh weight and frond number, respectively. Up to a dose rate of approximately 5 mGy h(-1), antioxidative enzymes and metabolites remained unaffected in plants. A significant change in catalase enzyme activity was found at 27 mGy h(-1) which was accompanied with significant increases of other antioxidative enzyme activities and shifts in ascorbate and glutathione content at higher dose rate levels, indicating an increase in oxidative stress in plants. Recent plant research hypothesized that environmental genotoxic stress conditions

  8. Genetic effects induced by neutrons in Drosophila melanogaster I. Determination of absorbed dose

    International Nuclear Information System (INIS)

    Delfin, A.; Paredes, L.C.; Zambrano, F.; Guzman-Rincon, J.; Urena-Nunez, F.

    2001-01-01

    A method to obtain the absorbed dose in Drosophila melanogaster irradiated in the thermal column facility of the Triga Mark III Reactor has been developed. The method is based on the measurements of neutron activation of gold foils produced by neutron capture to obtain the neutron fluxes. These fluxes, combined with the calculations of kinetic energy released per unit mass, enables one to obtain the absorbed doses in Drosophila melanogaster

  9. Radiation-Induced Color Centers in LiF for Dosimetry at High Absorbed Dose Rates

    DEFF Research Database (Denmark)

    McLaughlin, W. L.; Miller, Arne; Ellis, S. C.

    1980-01-01

    Color centers formed by irradiation of optically clear crystals of pure LiF may be analyzed spectrophotometrically for dosimetry in the absorbed dose range from 102 to 107 Gy. Routine monitoring of intense electron beams is an important application. Both 6LiF and 7LiF forms are commercially...... available, and when used with filters as albedo dosimeters in pairs, they provide discrimination of neutron and gamma-ray doses....

  10. Caffeine at a Moderate Dose Did Not Affect the Skeletal System of Rats with Streptozotocin-Induced Diabetes.

    Science.gov (United States)

    Folwarczna, Joanna; Janas, Aleksandra; Cegieła, Urszula; Pytlik, Maria; Śliwiński, Leszek; Matejczyk, Magdalena; Nowacka, Anna; Rudy, Karolina; Krivošíková, Zora; Štefíková, Kornélia; Gajdoš, Martin

    2017-10-30

    Diabetes may lead to the development of osteoporosis. Coffee drinking, apart from its health benefits, is taken into consideration as an osteoporosis risk factor. Data from human and animal studies on coffee and caffeine bone effects are inconsistent. The aim of the study was to investigate effects of caffeine at a moderate dose on the skeletal system of rats in two models of experimental diabetes induced by streptozotocin. Effects of caffeine administered orally (20 mg/kg aily for four weeks) were investigated in three-month-old female Wistar rats, which, two weeks before the start of caffeine administration, received streptozotocin (60 mg/kg, intraperitoneally) alone or streptozotocin after nicotinamide (230 mg/kg, intraperitoneally). Bone turnover markers, mass, mineral density, histomorphometric parameters, and mechanical properties were examined. Streptozotocin induced diabetes, with profound changes in the skeletal system due to increased bone resorption and decreased bone formation. Although streptozotocin administered after nicotinamide induced slight increases in glucose levels at the beginning of the experiment only, slight, but significant unfavorable changes in the skeletal system were demonstrated. Administration of caffeine did not affect the investigated skeletal parameters of rats with streptozotocin-induced disorders. In conclusion, caffeine at a moderate dose did not exert a damaging effect on the skeletal system of diabetic rats.

  11. Caffeine at a Moderate Dose Did Not Affect the Skeletal System of Rats with Streptozotocin-Induced Diabetes

    Directory of Open Access Journals (Sweden)

    Joanna Folwarczna

    2017-10-01

    Full Text Available Diabetes may lead to the development of osteoporosis. Coffee drinking, apart from its health benefits, is taken into consideration as an osteoporosis risk factor. Data from human and animal studies on coffee and caffeine bone effects are inconsistent. The aim of the study was to investigate effects of caffeine at a moderate dose on the skeletal system of rats in two models of experimental diabetes induced by streptozotocin. Effects of caffeine administered orally (20 mg/kg aily for four weeks were investigated in three-month-old female Wistar rats, which, two weeks before the start of caffeine administration, received streptozotocin (60 mg/kg, intraperitoneally alone or streptozotocin after nicotinamide (230 mg/kg, intraperitoneally. Bone turnover markers, mass, mineral density, histomorphometric parameters, and mechanical properties were examined. Streptozotocin induced diabetes, with profound changes in the skeletal system due to increased bone resorption and decreased bone formation. Although streptozotocin administered after nicotinamide induced slight increases in glucose levels at the beginning of the experiment only, slight, but significant unfavorable changes in the skeletal system were demonstrated. Administration of caffeine did not affect the investigated skeletal parameters of rats with streptozotocin-induced disorders. In conclusion, caffeine at a moderate dose did not exert a damaging effect on the skeletal system of diabetic rats.

  12. Radiation-induced coloration of nitro blue tetrazolium gel dosimeter for low dose applications

    International Nuclear Information System (INIS)

    Abdel-Fattah, A.A.; Beshir, W.B.; Hassan, H.M.; Soliman, Y.S.

    2017-01-01

    A radiochromic sensor of nitro blue tetrazolium (NBT) in gelatin was evaluated as a new gel dosimeter for radiation applications. The NBT gel has the advantage of visual color change from faint yellow to violet at low absorbed doses (10–1000 Gy). This color change appears as a result of the reduction of NBT to colored formazan then to diformazan species with further increase of absorbed doses. Responses of the gel at different NBT concentrations were analyzed at the absorption maximum centered at 527 nm. An increase of NBT concentrations in the gel enhances the radiation dose sensitivity. Energy dependent study implies the tissue equivalency of the gel in the energy range of 0.15–20 MeV. Dependence of the gel response on irradiation temperature, and color stability before and after irradiation were also studied. The combined uncertainty associated with the dose monitoring (10–1000 Gy) is 6.26% (2σ). Thus, the NBT gel shows its suitability for food irradiation, insect population control, and some food irradiation applications. - Highlights: • Preparation of nitro blue tetrazolium (NBT) gel for the dose range of 10–1000 Gy. • The sensitivity of it increases with increasing NBT concentrations. • The response of irradiated dosimeter is stable after 5 h from irradiation. • The prepared gel dosimeter is a tissue equivalent. • Its combined uncertainty is equal to 6.26% for 10–1000 Gy dose level.

  13. γ irradiation with different dose rates induces different DNA damage responses in Petunia x hybrida cells.

    Science.gov (United States)

    Donà, Mattia; Ventura, Lorenzo; Macovei, Anca; Confalonieri, Massimo; Savio, Monica; Giovannini, Annalisa; Carbonera, Daniela; Balestrazzi, Alma

    2013-05-15

    In plants, there is evidence that different dose rate exposures to gamma (γ) rays can cause different biological effects. The dynamics of DNA damage accumulation and molecular mechanisms that regulate recovery from radiation injury as a function of dose rate are poorly explored. To highlight dose-rate dependent differences in DNA damage, single cell gel electrophoresis was carried out on regenerating Petunia x hybrida leaf discs exposed to LDR (total dose 50 Gy, delivered at 0.33 Gy min(-1)) and HDR (total doses 50 and 100 Gy, delivered at 5.15 Gy min(-1)) γ-ray in the 0-24h time period after treatments. Significant fluctuations of double strand breaks and different repair capacities were observed between treatments in the 0-4h time period following irradiation. Dose-rate-dependent changes in the expression of the PhMT2 and PhAPX genes encoding a type 2 metallothionein and the cytosolic isoform of ascorbate peroxidase, respectively, were detected by Quantitative RealTime-Polymerase Chain Reaction. The PhMT2 and PhAPX genes were significantly up-regulated (3.0- and 0.7-fold) in response to HDR. The results are discussed in light of the potential practical applications of LDR-based treatments in mutation breeding. Copyright © 2013 Elsevier GmbH. All rights reserved.

  14. Sulforaphane, a cancer chemopreventive agent, induces pathways associated with membrane biosynthesis in response to tissue damage by aflatoxin B{sub 1}

    Energy Technology Data Exchange (ETDEWEB)

    Techapiesancharoenkij, Nirachara [Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok 10210 (Thailand); Fiala, Jeannette L.A. [Department of Biological Engineering and Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139 (United States); Navasumrit, Panida [Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok 10210 (Thailand); Croy, Robert G.; Wogan, Gerald N. [Department of Biological Engineering and Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139 (United States); Groopman, John D. [Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205 (United States); Ruchirawat, Mathuros [Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok 10210 (Thailand); Essigmann, John M., E-mail: jessig@mit.edu [Department of Biological Engineering and Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139 (United States)

    2015-01-01

    Aflatoxin B{sub 1} (AFB{sub 1}) is one of the major risk factors for liver cancer globally. A recent study showed that sulforaphane (SF), a potent inducer of phase II enzymes that occurs naturally in widely consumed vegetables, effectively induces hepatic glutathione S-transferases (GSTs) and reduces levels of hepatic AFB{sub 1}-DNA adducts in AFB{sub 1}-exposed Sprague Dawley rats. The present study characterized the effects of SF pre-treatment on global gene expression in the livers of similarly treated male rats. Combined treatment with AFB{sub 1} and SF caused reprogramming of a network of genes involved in signal transduction and transcription. Changes in gene regulation were observable 4 h after AFB{sub 1} administration in SF-pretreated animals and may reflect regeneration of cells in the wake of AFB{sub 1}-induced hepatotoxicity. At 24 h after AFB{sub 1} administration, significant induction of genes that play roles in cellular lipid metabolism and acetyl-CoA biosynthesis was detected in SF-pretreated AFB{sub 1}-dosed rats. Induction of this group of genes may indicate a metabolic shift toward glycolysis and fatty acid synthesis to generate and maintain pools of intermediate molecules required for tissue repair, cell growth and compensatory hepatic cell proliferation. Collectively, gene expression data from this study provide insights into molecular mechanisms underlying the protective effects of SF against AFB{sub 1} hepatotoxicity and hepatocarcinogenicity, in addition to the chemopreventive activity of this compound as a GST inducer. - Highlights: • This study revealed sulforaphane (SF)-deregulated gene sets in aflatoxin B{sub 1} (AFB{sub 1})-treated rat livers. • SF redirects biochemical networks toward lipid biosynthesis in AFB{sub 1}-dosed rats. • SF enhanced gene sets that would be expected to favor cell repair and regeneration.

  15. A comparison of radiation dose to the neurovascular bundles in men with and without prostate brachytherapy-induced erectile dysfunction

    International Nuclear Information System (INIS)

    Merrick, Gregory S.; Butler, Wayne M.; Dorsey, Anthony T.; Lief, Jonathan H.; Donzella, Joseph G.

    2000-01-01

    thresholds and side of the gland. The dose distribution over the length of the prostate rose smoothly from the base and apex to peak at midgland in 125 I implants while 103 Pd implants had a relatively constant dose over the length of the prostate. Considering the calculation grid as forming a 6-mm wide ribbon along each side of the prostate, the average patient had 70 mm 2 area receiving at least 300% of mPD. Conclusion: In this study, no relationship between radiation dose to the NVB and the development of post brachytherapy erectile dysfunction was discernible. Such a difference may become evident with additional follow-up. If long-term brachytherapy-induced erectile dysfunction is related to the radiation dose to the NVB, the ultimate preservation of potency following prostate brachytherapy may be markedly inferior to what has been reported. Nevertheless, the majority of this patient population responded favorably to sildenafil

  16. Dose Constraints to Prevent Radiation-Induced Brachial Plexopathy in Patients Treated for Lung Cancer

    International Nuclear Information System (INIS)

    Amini, Arya; Yang Jinzhong; Williamson, Ryan; McBurney, Michelle L.; Erasmus, Jeremy; Allen, Pamela K.; Karhade, Mandar; Komaki, Ritsuko; Liao, Zhongxing; Gomez, Daniel; Cox, James; Dong, Lei; Welsh, James

    2012-01-01

    Purpose: As the recommended radiation dose for non-small-cell lung cancer (NSCLC) increases, meeting dose constraints for critical structures like the brachial plexus becomes increasingly challenging, particularly for tumors in the superior sulcus. In this retrospective analysis, we compared dose-volume histogram information with the incidence of plexopathy to establish the maximum dose tolerated by the brachial plexus. Methods and Materials: We identified 90 patients with NSCLC treated with definitive chemoradiation from March 2007 through September 2010, who had received >55 Gy to the brachial plexus. We used a multiatlas segmentation method combined with deformable image registration to delineate the brachial plexus on the original planning CT scans and scored plexopathy according to Common Terminology Criteria for Adverse Events version 4.03. Results: Median radiation dose to the brachial plexus was 70 Gy (range, 56–87.5 Gy; 1.5–2.5 Gy/fraction). At a median follow-up time of 14.0 months, 14 patients (16%) had brachial plexopathy (8 patients [9%] had Grade 1, and 6 patients [7%] had Grade ≥2); median time to symptom onset was 6.5 months (range, 1.4–37.4 months). On multivariate analysis, receipt of a median brachial plexus dose of >69 Gy (odds ratio [OR] 10.091; 95% confidence interval [CI], 1.512–67.331; p = 0.005), a maximum dose of >75 Gy to 2 cm 3 of the brachial plexus (OR, 4.909; 95% CI, 0.966–24.952; p = 0.038), and the presence of plexopathy before irradiation (OR, 4.722; 95% CI, 1.267–17.606; p = 0.021) were independent predictors of brachial plexopathy. Conclusions: For lung cancers near the apical region, brachial plexopathy is a major concern for high-dose radiation therapy. We developed a computer-assisted image segmentation method that allows us to rapidly and consistently contour the brachial plexus and establish the dose limits to minimize the risk of brachial plexopathy. Our results could be used as a guideline in future

  17. Dose-Related Effects of Acetylsalicylic acid (ASA) on Gamma Radiation-Induced Teratogenicity in Pregnant Albino Rats

    International Nuclear Information System (INIS)

    Ibrahim, M.F.

    2013-01-01

    Reviews of acetylsalicylic acid (ASA), a widely used nonsteroidal anti- inflammatory drug, has consistently suggested a possible association between prenatal ASA ingestion and adverse effects in the pregnant mothers and their developing fetuses. The objective of the current study was to comprehensively define the effect of relatively low and high doses of ASA (25 mg/kg body wt. and 200 mg/kg body wt. respectively) on gestating rats and their possible impact on the irradiated ones. Therefore 36 pregnant rats were randomly divided into 6 equal groups. Three rat groups were daily orally gavaged from the 7th to the 18th gestational days with: distilled water (Group 1), 25 mg/kg body wt. ASA (Group 2) and 200 mg/kg body wt. ASA (Group 3). The other three groups similarly received the same previous treatments besides 2 Gy whole body gamma irradiation of each, to serve as: Group 4 (distilled water + irradiation), Group 5 (25 mg/kg body wt. ASA + irradiation) and Group 6 (200 mg/kg body wt. ASA + irradiation). All rat groups were sacrificed on the 20th day of pregnancy and the uterine contents were examined. The lower ASA dose (25 mg/kg body wt.) treated group (Group 2) displayed healthy mothers and fetuses whereas that of the higher dose (200 mg/kg body wt.) (Group 3) despite not showing significant maternal or fetal mortalities, yet the intrauterine contents presented fetal developmental disorders including stunted growth and resorption together with some head and limb anomalies including plagiocephaly, marked acampsia and acrocontracture. Meanwhile, results have unexpectedly shown a radioprotective role of the lower ASA dose (25 mg/kg. body wt.) (Group 5) to pregnant rats and their fetuses as inspected by its efficacy in retrieving the radiation induced maternal weight loss together with its noticeable ameliorating effects on the intrauterine lethality of the affected fetuses and their externally detected abnormalities in addition toits effectiveness in retaining some

  18. Single Low-Dose Radiation Induced Regulation of Keratinocyte Differentiation in Calcium-Induced HaCaT Cells

    OpenAIRE

    Hahn, Hyung Jin; Youn, Hae Jeong; Cha, Hwa Jun; Kim, Karam; An, Sungkwan; Ahn, Kyu Joong

    2016-01-01

    Background We are continually exposed to low-dose radiation (LDR) in the range 0.1 Gy from natural sources, medical devices, nuclear energy plants, and other industrial sources of ionizing radiation. There are three models for the biological mechanism of LDR: the linear no-threshold model, the hormetic model, and the threshold model. Objective We used keratinocytes as a model system to investigate the molecular genetic effects of LDR on epidermal cell differentiation. Methods To identify kera...

  19. A Systems Genetic Approach to Identify Low Dose Radiation-Induced Lymphoma Susceptibility/DOE2013FinalReport

    Energy Technology Data Exchange (ETDEWEB)

    Balmain, Allan [University of California, San Francisco; Song, Ihn Young [University of California, San Francisco

    2013-05-15

    The ultimate goal of this project is to identify the combinations of genetic variants that confer an individual's susceptibility to the effects of low dose (0.1 Gy) gamma-radiation, in particular with regard to tumor development. In contrast to the known effects of high dose radiation in cancer induction, the responses to low dose radiation (defined as 0.1 Gy or less) are much less well understood, and have been proposed to involve a protective anti-tumor effect in some in vivo scientific models. These conflicting results confound attempts to develop predictive models of the risk of exposure to low dose radiation, particularly when combined with the strong effects of inherited genetic variants on both radiation effects and cancer susceptibility. We have used a Systems Genetics approach in mice that combines genetic background analysis with responses to low and high dose radiation, in order to develop insights that will allow us to reconcile these disparate observations. Using this comprehensive approach we have analyzed normal tissue gene expression (in this case the skin and thymus), together with the changes that take place in this gene expression architecture a) in response to low or high- dose radiation and b) during tumor development. Additionally, we have demonstrated that using our expression analysis approach in our genetically heterogeneous/defined radiation-induced tumor mouse models can uniquely identify genes and pathways relevant to human T-ALL, and uncover interactions between common genetic variants of genes which may lead to tumor susceptibility.

  20. Chromosome aberration yields in human lymphocytes induced by fractionated doses of x-radiation

    International Nuclear Information System (INIS)

    Purrott, R.J.; Reeder, E.

    1976-01-01

    Unstimulated (G 0 ) human peripheral blood lymphocytes were exposed at 37degC to doses of 200 or 500 rad of X-rays delivered in two equal fractions. The dose fractions were separated by intervals of up to 7 h in the 200 rad study and up to 48 h for 500 rad. In both studies the mean levels of dicentrics and total unstable aberrations began to decline when fractions were delivered with intervals of greater than 2 h. With 200 rad the yield had decreased to an additive baseline (i.e. equal to only twice the yield of a single 100-rad fraction) by an interval of 4 h. Following 500 rad the yield declined until 8 h and then remained 20% above the expected additive baseline even when 48 h separated the fractions. Possible explanations for this discrepancy are discussed. In a second experiment PHA stimulated lymphocyte cultures were exposed to 2 doses of 125 rad of X-rays up to 7 h apart in an attempt to demonstrate the late peak in aberration yield originally reported by Lane. Control cultures received unsplit doses of 250 rad at the time of the corresponding second 125-rad fraction. No evidence of a late peak in dicentric yield was observed. The yield remained approximately the same irrespective of the time interval between fractions but these split dose yields were significantly different from the accompanying unsplit controls

  1. Dose intensification of TRAIL-inducing ONC201 inhibits metastasis and promotes intratumoral NK cell recruitment.

    Science.gov (United States)

    Wagner, Jessica; Kline, C Leah; Zhou, Lanlan; Campbell, Kerry S; MacFarlane, Alexander W; Olszanski, Anthony J; Cai, Kathy Q; Hensley, Harvey H; Ross, Eric A; Ralff, Marie D; Zloza, Andrew; Chesson, Charles B; Newman, Jenna H; Kaufman, Howard; Bertino, Joseph; Stein, Mark; El-Deiry, Wafik S

    2018-06-01

    ONC201 is a first-in-class, orally active antitumor agent that upregulates cytotoxic TRAIL pathway signaling in cancer cells. ONC201 has demonstrated safety and preliminary efficacy in a first-in-human trial in which patients were dosed every 3 weeks. We hypothesized that dose intensification of ONC201 may impact antitumor efficacy. We discovered that ONC201 exerts dose- and schedule-dependent effects on tumor progression and cell death signaling in vivo. With dose intensification, we note a potent anti-metastasis effect and inhibition of cancer cell migration and invasion. Our preclinical results prompted a change in ONC201 dosing in all open clinical trials. We observed accumulation of activated NK+ and CD3+ cells within ONC201-treated tumors and that NK cell depletion inhibits ONC201 efficacy in vivo, including against TRAIL/ONC201-resistant Bax-/- tumors. Immunocompetent NCR1-GFP mice, in which NK cells express GFP, demonstrated GFP+ NK cell infiltration of syngeneic MC38 colorectal tumors. Activation of primary human NK cells and increased degranulation occurred in response to ONC201. Coculture experiments identified a role for TRAIL in human NK-mediated antitumor cytotoxicity. Preclinical results indicate the potential utility for ONC201 plus anti-PD-1 therapy. We observed an increase in activated TRAIL-secreting NK cells in the peripheral blood of patients after ONC201 treatment. The results offer what we believe to be a unique pathway of immune stimulation for cancer therapy.

  2. Myocardial protection induced by fentanyl in pigs exposed to high-dose adrenaline.

    Science.gov (United States)

    da Luz, Vinicius Fernando; Otsuki, Denise Aya; Gonzalez, Maria Margarita Castro; Negri, Elnara Marcia; Caldini, Elia Garcia; Damaceno-Rodrigues, Nilsa Regina; Malbouisson, Luiz Marcelo Sá; Viana, Bruno Gonçalves; Vane, Matheus Fachini; Carmona, Maria Jose Carvalho

    2015-10-01

    The use of high doses of adrenaline is common in critical patients, especially during cardiac arrest. During these situations, myocardial dysfunction can be a result of multiple factors, including adrenaline use. In addition, opioids have been shown to have anti-arrhythmic and anti-ischemic mechanisms that may confer cardiac protection. This study aimed to evaluate the effects of fentanyl on myocardial function in pigs exposed to high-dose adrenaline. After institutional ethics committee approval, 26 pigs were randomly allocated to receive either 20 μg/kg fentanyl (n = 10; fentanyl group) administered 5 min before five doses of adrenaline (20 μg/kg), equivalent-volume saline (n = 10; saline group) using the same adrenaline dosing protocol, or neither fentanyl nor adrenaline (n = 6; sham group). The fentanyl group showed lower levels of troponin at the end of the sixth hour compared with the saline group (1.91 ± 1.47 vs 5.44 ± 5.35 ng/mL, P = 0.019). Transmission electron microscopy and immunohistochemistry also showed less myocardial injury in the fentanyl group. The conclusion was reached that fentanyl attenuates myocardial injury caused by high-dose adrenaline without blunting the hemodynamic effect of adrenaline. © 2015 Wiley Publishing Asia Pty Ltd.

  3. Induced mitotic gynogenesis in common carp (Cyprinus carpio L.), optimizing irradiation dose of X- and gamma-ray

    International Nuclear Information System (INIS)

    Yousefian, M.; Amirinia, C.; Bercsenyi, M.; Horvath, L.

    1997-01-01

    Mitotic gynogenesis was induced in common carp, Cyprinus carpio L., in hatchery and laboratory conditions, using 60Co gamma-ray and X-ray for inactivation of sperm DNA and a subsequent heat shock for inducing endomitosis. The parameter examined was the dose of irradiation in the range of 70-140 Krad. Carp spermatozoa irradiated by 70-100 Krad doses showed higher motility and fertilization ability than the ones irradiated by 110-140 Krad. Sperm treated with doses of 70-90 Krad showed the same fertility rate, but lower survival rate at embryo stage compared with 100 Krad. The shock temperature and duration applied in these experiments for restoration of diploidy level were 40 degrees C plus/minus 0.1 and 2 min., respectively. The highest frequency of mitotic gynogenetic larvae was achieved by 100 Krad 60Co gamma ray at 34 min. after fertilization, - up to 12.2 percent (at 23 degrees C incubating temperature)

  4. Apoptosis is signalled early by low doses of ionising radiation in a radiation-induced bystander effect

    International Nuclear Information System (INIS)

    Furlong, Hayley; Mothersill, Carmel; Lyng, Fiona M.; Howe, Orla

    2013-01-01

    Highlights: ► Molecular mechanisms involved in the production of a radiation induced bystander effect are not well known. ► We investigate gene expression changes in apoptotic genes in both direct and bystander responses. ► We demonstrate initiation of the apoptotic cascade in a bystander response. ► Lower doses reveal a specific but differential response related to apoptosis compared to higher doses. - Abstract: It is known that ionising radiation (IR) induces a complex signalling apoptotic cascade post-exposure to low doses ultimately to remove damaged cells from a population, specifically via the intrinsic pathway. Therefore, it was hypothesised that bystander reporter cells may initiate a similar apoptotic response if exposed to low doses of IR (0.05 Gy and 0.5 Gy) and compared to directly irradiated cells. Key apoptotic genes were selected according to their role in the apoptotic cascade; tumour suppressor gene TP53, pro-apoptotic Bax and anti-apoptotic Bcl2, pro-apoptotic JNK and anti-apoptotic ERK, initiator caspase 2 and 9 and effector caspase 3, 6 and 7. The data generated consolidated the role of apoptosis following direct IR exposure for all doses and time points as pro-apoptotic genes such as Bax and JNK as well as initiator caspase 7 and effector caspase 3 and 9 were up-regulated. However, the gene expression profile for the bystander response was quite different and more complex in comparison to the direct response. The 0.05 Gy dose point had a more significant apoptosis gene expression profile compared to the 0.5 Gy dose point and genes were not always expressed within 1 h but were sometimes expressed 24 h later. The bystander data clearly demonstrates initiation of the apoptotic cascade by the up-regulation of TP53, Bax, Bcl-2, initiator caspase 2 and effector caspase 6. The effector caspases 3 and 7 of the bystander samples demonstrated down-regulation in their gene expression levels at 0.05 Gy and 0.5 Gy at both time points therefore not

  5. Apoptosis is signalled early by low doses of ionising radiation in a radiation-induced bystander effect

    Energy Technology Data Exchange (ETDEWEB)

    Furlong, Hayley, E-mail: hayley.furlong@dit.ie [DIT Centre for Radiation and Environmental Science, Focas Research Institute, Dublin Institute of Technology, Kevin St, Dublin 8 (Ireland); School of Biological Sciences, College of Sciences and Health, Dublin Institute of Technology, Kevin St, Dublin 8 (Ireland); Mothersill, Carmel [Medical Physics and Applied Radiation Sciences, Nuclear Research Building, 1280 Hamilton, Ontario L8S 4K1 (Canada); Lyng, Fiona M. [DIT Centre for Radiation and Environmental Science, Focas Research Institute, Dublin Institute of Technology, Kevin St, Dublin 8 (Ireland); Howe, Orla [DIT Centre for Radiation and Environmental Science, Focas Research Institute, Dublin Institute of Technology, Kevin St, Dublin 8 (Ireland); School of Biological Sciences, College of Sciences and Health, Dublin Institute of Technology, Kevin St, Dublin 8 (Ireland)

    2013-01-15

    Highlights: ► Molecular mechanisms involved in the production of a radiation induced bystander effect are not well known. ► We investigate gene expression changes in apoptotic genes in both direct and bystander responses. ► We demonstrate initiation of the apoptotic cascade in a bystander response. ► Lower doses reveal a specific but differential response related to apoptosis compared to higher doses. - Abstract: It is known that ionising radiation (IR) induces a complex signalling apoptotic cascade post-exposure to low doses ultimately to remove damaged cells from a population, specifically via the intrinsic pathway. Therefore, it was hypothesised that bystander reporter cells may initiate a similar apoptotic response if exposed to low doses of IR (0.05 Gy and 0.5 Gy) and compared to directly irradiated cells. Key apoptotic genes were selected according to their role in the apoptotic cascade; tumour suppressor gene TP53, pro-apoptotic Bax and anti-apoptotic Bcl2, pro-apoptotic JNK and anti-apoptotic ERK, initiator caspase 2 and 9 and effector caspase 3, 6 and 7. The data generated consolidated the role of apoptosis following direct IR exposure for all doses and time points as pro-apoptotic genes such as Bax and JNK as well as initiator caspase 7 and effector caspase 3 and 9 were up-regulated. However, the gene expression profile for the bystander response was quite different and more complex in comparison to the direct response. The 0.05 Gy dose point had a more significant apoptosis gene expression profile compared to the 0.5 Gy dose point and genes were not always expressed within 1 h but were sometimes expressed 24 h later. The bystander data clearly demonstrates initiation of the apoptotic cascade by the up-regulation of TP53, Bax, Bcl-2, initiator caspase 2 and effector caspase 6. The effector caspases 3 and 7 of the bystander samples demonstrated down-regulation in their gene expression levels at 0.05 Gy and 0.5 Gy at both time points therefore not

  6. Drug–drug interaction of microdose and regular-dose omeprazole with a CYP2C19 inhibitor and inducer

    Directory of Open Access Journals (Sweden)

    Park G

    2017-03-01

    Full Text Available Gab-jin Park,1 Soo Hyeon Bae,1 Wan-Su Park,1 Seunghoon Han,1 Min-Ho Park,2 Seok-Ho Shin,2 Young G Shin,2 Dong-Seok Yim1,2 1Department of Clinical Pharmacology and Therapeutics, Seoul St Mary’s Hospital, PIPET (Pharmacometrics Institute for Practical Education and Training, College of Medicine, Catholic University of Korea, Seoul, South Korea; 2College of Pharmacy, Chungnam National University, Daejeon, South Korea Purpose: A microdose drug–drug interaction (DDI study may be a valuable tool for anticipating drug interaction at therapeutic doses. This study aimed to compare the magnitude of DDIs at microdoses and regular doses to explore the applicability of a microdose DDI study. Patients and methods: Six healthy male volunteer subjects were enrolled into each DDI study of omeprazole (victim and known perpetrators: fluconazole (inhibitor and rifampin (inducer. For both studies, the microdose (100 µg, cold compound and the regular dose (20 mg of omeprazole were given at days 0 and 1, respectively. On days 2–9, the inhibitor or inducer was given daily, and the microdose and regular dose of omeprazole were repeated at days 8 and 9, respectively. Full omeprazole pharmacokinetic samplings were performed at days 0, 1, 8, and 9 of both studies for noncompartmental analysis. Results: The magnitude of the DDI, the geometric mean ratios (with perpetrator/omeprazole only of maximum concentration (Cmax and area under the curve to the last measurement (AUCt of the microdose and the regular dose were compared. The geometric mean ratios in the inhibition study were: 2.17 (micro and 2.68 (regular for Cmax, and 4.07 (micro, 4.33 (regular for AUCt. For the induction study, they were 0.26 (micro and 0.21 (regular for Cmax, and 0.16 (micro and 0.15 (regular for AUCt. There were no significant statistical differences in the magnitudes of DDIs between microdose and regular-dose conditions, regardless of induction or inhibition. Conclusion: Our results may be

  7. Human lymphocytes exposed to low doses of ionizing radiations become refractory to high doses of radiation as well as to chemical mutagens that induce double-strand breaks in DNA

    International Nuclear Information System (INIS)

    Wolff, Sheldon; Afzal, Veena; Wiencke, J.K.; Olivieri, G.; Michaeli, A.

    1988-01-01

    The results indicate that prior exposure to 0.01 Gy of X-rays reduces the number of chromosome breaks induced by double-strand breaks, and perhaps even by cross-links, in DNA, but has the opposite effect on breaks induced by the alkylating agent MMS. The results also show that the induced repair mechanism is different from that observed in the adaptive reponse that follows exposure to low doses of alkylating agents. (author)

  8. Benchmark studies of induced radioactivity produced in LHC materials, Part II: Remanent dose rates.

    Science.gov (United States)

    Brugger, M; Khater, H; Mayer, S; Prinz, A; Roesler, S; Ulrici, L; Vincke, H

    2005-01-01

    A new method to estimate remanent dose rates, to be used with the Monte Carlo code FLUKA, was benchmarked against measurements from an experiment that was performed at the CERN-EU high-energy reference field facility. An extensive collection of samples of different materials were placed downstream of, and laterally to, a copper target, intercepting a positively charged mixed hadron beam with a momentum of 120 GeV c(-1). Emphasis was put on the reduction of uncertainties by taking measures such as careful monitoring of the irradiation parameters, using different instruments to measure dose rates, adopting detailed elemental analyses of the irradiated materials and making detailed simulations of the irradiation experiment. The measured and calculated dose rates are in good agreement.

  9. The MARS15-based FermiCORD code system for calculation of the accelerator-induced residual dose

    Science.gov (United States)

    Grebe, A.; Leveling, A.; Lu, T.; Mokhov, N.; Pronskikh, V.

    2018-01-01

    The FermiCORD code system, a set of codes based on MARS15 that calculates the accelerator-induced residual doses at experimental facilities of arbitrary configurations, has been developed. FermiCORD is written in C++ as an add-on to Fortran-based MARS15. The FermiCORD algorithm consists of two stages: 1) simulation of residual doses on contact with the surfaces surrounding the studied location and of radionuclide inventories in the structures surrounding those locations using MARS15, and 2) simulation of the emission of the nuclear decay γ-quanta by the residuals in the activated structures and scoring the prompt doses of these γ-quanta at arbitrary distances from those structures. The FermiCORD code system has been benchmarked against similar algorithms based on other code systems and against experimental data from the CERF facility at CERN, and FermiCORD showed reasonable agreement with these. The code system has been applied for calculation of the residual dose of the target station for the Mu2e experiment and the results have been compared to approximate dosimetric approaches.

  10. Stage specificity and dose-response relationships for chromosome aberrations induced in mouse primary spermatocytes following X-irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Matsuda, Y.; Tobari, I.; Utsugi, T.

    1986-05-01

    In this study, dose-response relationships were examined for chromosome aberrations observed at diakinesis-metaphase I of spermatocytes with X-irradiation at various stages of meiosis (diplotene, mid-pachytene, zygotene and leptotene). The frequencies of cells with X-ray-induced chromosome aberrations increased with dose at all stages in the applied range of 0.5-3.0 Gy and tended to increase as the irradiated stages descended after leptotene stage. In three stages, the frequencies increased exponentially with dose, but the rates of induction of chromosome breaks were markedly different depending on the stages at which spermatocytes were irradiated with X-rays. The rate of induction was the highest at diplotene and the lowest at leptotene, suggesting that diplotene spermatocytes had the highest radiosensitivity to the induction of chromosome breaks, followed by pachytene, zygotene and leptotene spermatocytes in that order. The dose-response relationships fitted well to linear equations for deletion-type aberrations at each stage, and to linear-quadratic equations for exchange-type aberrations at all stages except for leptotene. At leptotene, the chromatid exchanges were hardly observed, the aberrations being mainly consisted of iso-chromatid fragments. On the contrary, chromatid exchanges and iso-chromatide deletions were mainly observed at later stages (zygotene-diplotene).

  11. Chromosomal aberrations induced by low-dose γ-irradiation: Study of R-banded chromosomes of human lymphocytes

    International Nuclear Information System (INIS)

    Al-Achkar, W.; Lefrancois, D.; Aurias, A.

    1991-01-01

    The effect of low-dose (0-0.5 Gy) γ-radiations was studied on R-banded chromosomes from lymphocytes of healthy donors of various ages. In cells from newborns, an increase of chromosome damage roughly proportional to the dose was found. In lymphocytes from young adults chromosomal aberrations were not detected at doses of 0.05 and 0.1 Gy, and in lymphocytes from old adults not even at 0.2 Gy. The difficulty in detecting aberrations in lymphocytes from adults is largely due to a considerable background of chromosomal anomalies which should be borne in mind in dosimetry studies. The rate of induction largely depends on the types of rearrangements. One-break terminal deletions are efficiently induced at 0.1 and 0.2 Gy and are the best indicators of exposure at these doses. At 0.5 Gy, the frequencies of 2-break lesions, i.e., dicentrics and reciprocal translocations, increase, whereas the of deletions decreases. (author). 6 refs., 3 figs., 2 tabs

  12. The MARS15-based FermiCORD code system for calculation of the accelerator-induced residual dose

    Energy Technology Data Exchange (ETDEWEB)

    Grebe, A.; Leveling, A.; Lu, T.; Mokhov, N.; Pronskikh, V.

    2018-01-01

    The FermiCORD code system, a set of codes based on MARS15 that calculates the accelerator-induced residual doses at experimental facilities of arbitrary configurations, has been developed. FermiCORD is written in C++ as an add-on to Fortran-based MARS15. The FermiCORD algorithm consists of two stages: 1) simulation of residual doses on contact with the surfaces surrounding the studied location and of radionuclide inventories in the structures surrounding those locations using MARS15, and 2) simulation of the emission of the nuclear decay gamma-quanta by the residuals in the activated structures and scoring the prompt doses of these gamma-quanta at arbitrary distances from those structures. The FermiCORD code system has been benchmarked against similar algorithms based on other code systems and showed a good agreement. The code system has been applied for calculation of the residual dose of the target station for the Mu2e experiment and the results have been compared to approximate dosimetric approaches.

  13. Adaptive response of apoptosis in EL-4 lymphoma cells induced by low dose radiation and its mechanism

    International Nuclear Information System (INIS)

    Liu Shuchun; Gong Pingsheng; Wang Zhicheng; Sun Liguang; Gong Shouliang

    2008-01-01

    EL-4 lymphoma cells were irradiated with the inductive doses (D1: 25-200 mGy, dose rate: 12.5mGy/min) and the challenging dose (D2:0.5-3.0 Gy, dose rate: 287 mGy/min), and the time interval between D1 and D2 was 6 h. The percentage of cell apoptosis and the expressive levels of cell apoptosis-associated gene pro- reins were measured with flow cytometry. The percentages of cell apoptosis in the D1 + D2 group with 25-100 mGy (D1) and 1.5 Gy (D2) or 75 mGy (D1) and 25-200 mGy (D2) were significantly lower than those in the D2 group. As compared with the D2 group, the positive percentage of cell Bcl-2 protein expression increased somewhat, and Bax decreased significantly, meanwhile the ratio of Bcl-2/Bax increased significantly and p53 decreased somewhat in D1 + D2 group with 25-100 mGy (D1) and 1.5 Gy (D2). The adaptive response of EL-4 lymphoma cell apoptosis could be induced by pre-irradiation with 25-100 mGy. Meantime, the expressive levels of cell apoptosis-associated gene Bcl-2, Bax and p53 proteins could change accordingly with cell apoptosis. These gene protein changes may play an important role in the mechanism of the adaptive response. (authors)

  14. Oral cryotherapy for the prevention of high-dose melphalan-induced stomatitis in allogeneic hematopoietic stem cell transplant recipients.

    Science.gov (United States)

    Aisa, Yoshinobu; Mori, Takehiko; Kudo, Masumi; Yashima, Tomoko; Kondo, Sakiko; Yokoyama, Akihiro; Ikeda, Yasuo; Okamoto, Shinichiro

    2005-04-01

    The purpose of this study was to evaluate the efficacy of oral cryotherapy to prevent high-dose melphalan-induced stomatitis. Eighteen consecutive recipients of allogeneic hematopoietic stem cell transplant conditioned with high-dose melphalan (140 mg/m2) in combination with fludarabine alone or with fludarabine and additional chemotherapy or radiation were enrolled. The severity of stomatitis was graded according to the National Cancer Institute Common Toxicity Criteria. Patients were kept on oral cryotherapy using ice chips and ice-cold water shortly before, during, and for additional 90 min after completion of melphalan administration. Only two of 18 patients (11.1%) developed grade 2 or 3 stomatitis while six of seven patients in the historical control developed it (85.7%; P=0.001). These results suggested that oral cryotherapy could effectively prevent stomatitis caused by high-dose melphalan, and we recommend that it should be incorporated into the conditioning regimen with high-dose melphalan.

  15. Comparsion of light dose on topical ALA-mediated photodynamic therapy for DMBA-induced hamster buccal pouch premalignant lesions

    Science.gov (United States)

    Yang, Deng-Fu; Tseng, Meng-Ke; Liu, Chung-Ji; Hsu, Yih-Chih

    2012-03-01

    Oral cancer has becomes the most prominent male cancer disease due to the local betel nut chewing habit combing with smoking and alcohol-drinking lifestyle. In order to minimize the systemic phototoxic effect of 5-aminolevulinic acid (ALA), this study was designed to use a topical ALA-mediated PDT for treatment of DMBA-induced hamster buccal pouch cancerous lesions. DMBA was applied to one of the buccal pouches of hamsters thrice a week for 8 to 10 weeks. Precancerous lesions were induced and proven by histological examination. These DMBA-induced cancerous lesions were used for testing the efficacy of topical ALA -mediated PDT. We found that ALA reached its peak level in cancerous lesions about 2.5 hrs after topical application of ALA gel. The precancerous lesions in hamsters were then treated with topical ALA -mediated PDT with light exposure dose of 75 and 100 J/cm2 using LED 635 nm Wonderlight device. It is suggesting that optimization of the given light dose is critical to the success of PDT results.

  16. 1090 nm infrared radiation at close to threshold dose induces cataract with a time delay.

    Science.gov (United States)

    Yu, Zhaohua; Schulmeister, Karl; Talebizadeh, Nooshin; Kronschläger, Martin; Söderberg, Per G

    2015-03-01

    To investigate whether infrared radiation (IRR)-induced cataract is instant or is associated with a time delay between the exposure and the onset of lens light scattering after an exposure to just above threshold dose. Six-weeks-old albino Sprague-Dawley female rats were unilaterally exposed to 197 W/cm2 IRR at 1090 nm within the dilated pupil. In the first experiment, the animals were exposed with four exposure times of 5, 8, 13 and 20 second, respectively. At 24 hr after exposure, the light scattering in both exposed and contralateral not exposed lenses was measured. Based on the first experiment, four postexposure time groups were exposed unilaterally to 1090 nm IRR of 197 W/cm2 for 8 second. At 6, 18, 55 and 168 hr after exposure, the light scattering in both lenses was measured. A 197 W/cm2 IRR-induced light scattering in the lens with exposures of at least 8 second. Further, after exposure to IRR of 197 W/cm2 for 8 second, the light-scattering increase in the lens was delayed approximately 16 hr after the exposure. There is a time delay between the exposure and the onset of cataract after exposure to close to threshold dose implicating that either near IRR cataract is photochemical or there is a time delay in the biological expression of thermally induced damage. © 2014 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

  17. Toxicogenomic analysis of the particle dose- and size-response relationship of silica particles-induced toxicity in mice

    International Nuclear Information System (INIS)

    Lu Xiaoyan; Jin Tingting; Jin Yachao; Wu Leihong; Hu Bin; Tian Yu; Fan Xiaohui

    2013-01-01

    This study investigated the relationship between particle size and toxicity of silica particles (SP) with diameters of 30, 70, and 300 nm, which is essential to the safe design and application of SP. Data obtained from histopathological examinations suggested that SP of these sizes can all induce acute inflammation in the liver. In vivo imaging showed that intravenously administrated SP are mainly present in the liver, spleen and intestinal tract. Interestingly, in gene expression analysis, the cellular response pathways activated in the liver are predominantly conserved independently of particle dose when the same size SP are administered or are conserved independently of particle size, surface area and particle number when nano- or submicro-sized SP are administered at their toxic doses. Meanwhile, integrated analysis of transcriptomics, previous metabonomics and conventional toxicological results support the view that SP can result in inflammatory and oxidative stress, generate mitochondrial dysfunction, and eventually cause hepatocyte necrosis by neutrophil-mediated liver injury. (paper)

  18. Atrazine Does Not Induce Pica Behavior at Doses that Increase Hypothalamic-Pituitary-Adrenal Axis Activation and Cause Conditioned Taste Avoidance.

    Science.gov (United States)

    Previous work has shown that a single oral administration of atrazine (ATR), a chlorotriazine herbicide, induces dose-dependent increases in plasma adrenocorticotropic hormone (ACTH), serum corticosterone (CORT) and progesterone. The mechanism for these effects is unknown. To tes...

  19. Superantigen-Induced Cytokine Release from Whole-Blood Cell Culture as a Functional Measure of Drug Efficacy after Oral Dosing in Nonhuman Primates

    National Research Council Canada - National Science Library

    Krakauer, Teresa; Stephens, Julie; Buckley, Marilyn; Tate, Mallory

    2007-01-01

    ...) closely resemble humans. We examined the ex vivo cytokine response of superantigen-stimulated whole-blood cells as a first step to therapeutic efficacy testing for bacterial superantigen-induced shock in NHP after oral dosing of pentoxifylline...

  20. Characterizing dose response relationships: Chronic gamma radiation in Lemna minor induces oxidative stress and altered polyploidy level

    International Nuclear Information System (INIS)

    Van Hoeck, Arne; Horemans, Nele; Van Hees, May; Nauts, Robin; Knapen, Dries; Vandenhove, Hildegarde; Blust, Ronny

    2015-01-01

    The biological effects and interactions of different radiation types in plants are still far from understood. Among different radiation types, external gamma radiation treatments have been mostly studied to assess the biological impact of radiation toxicity in organisms. Upon exposure of plants to gamma radiation, ionisation events can cause, either directly or indirectly, severe biological damage to DNA and other biomolecules. However, the biological responses and oxidative stress related mechanisms under chronic radiation conditions are poorly understood in plant systems. In the following study, it was questioned if the Lemna minor growth inhibition test is a suitable approach to also assess the radiotoxicity of this freshwater plant. Therefore, L. minor plants were continuously exposed for seven days to 12 different dose rate levels covering almost six orders of magnitude starting from 80 μGy h"−"1 up to 1.5 Gy h"−"1. Subsequently, growth, antioxidative defence system and genomic responses of L. minor plants were evaluated. Although L. minor plants could survive the exposure treatment at environmental relevant exposure conditions, higher dose rate levels induced dose dependent growth inhibitions starting from approximately 27 mGy h"−"1. A ten-percentage growth inhibition of frond area Effective Dose Rate (EDR_1_0) was estimated at 95 ± 7 mGy h"−"1, followed by 153 ± 13 mGy h"−"1 and 169 ± 12 mGy h"−"1 on fresh weight and frond number, respectively. Up to a dose rate of approximately 5 mGy h"−"1, antioxidative enzymes and metabolites remained unaffected in plants. A significant change in catalase enzyme activity was found at 27 mGy h"−"1 which was accompanied with significant increases of other antioxidative enzyme activities and shifts in ascorbate and glutathione content at higher dose rate levels, indicating an increase in oxidative stress in plants. Recent plant research hypothesized that environmental genotoxic

  1. A combination of low-dose bevacizumab and imatinib enhances vascular normalisation without inducing extracellular matrix deposition.

    Science.gov (United States)

    Schiffmann, L M; Brunold, M; Liwschitz, M; Goede, V; Loges, S; Wroblewski, M; Quaas, A; Alakus, H; Stippel, D; Bruns, C J; Hallek, M; Kashkar, H; Hacker, U T; Coutelle, O

    2017-02-28

    Vascular endothelial growth factor (VEGF)-targeting drugs normalise the tumour vasculature and improve access for chemotherapy. However, excessive VEGF inhibition fails to improve clinical outcome, and successive treatment cycles lead to incremental extracellular matrix (ECM) deposition, which limits perfusion and drug delivery. We show here, that low-dose VEGF inhibition augmented with PDGF-R inhibition leads to superior vascular normalisation without incremental ECM deposition thus maintaining access for therapy. Collagen IV expression was analysed in response to VEGF inhibition in liver metastasis of colorectal cancer (CRC) patients, in syngeneic (Panc02) and xenograft tumours of human colorectal cancer cells (LS174T). The xenograft tumours were treated with low (0.5 mg kg -1 body weight) or high (5 mg kg -1 body weight) doses of the anti-VEGF antibody bevacizumab with or without the tyrosine kinase inhibitor imatinib. Changes in tumour growth, and vascular parameters, including microvessel density, pericyte coverage, leakiness, hypoxia, perfusion, fraction of vessels with an open lumen, and type IV collagen deposition were compared. ECM deposition was increased after standard VEGF inhibition in patients and tumour models. In contrast, treatment with low-dose bevacizumab and imatinib produced similar growth inhibition without inducing detrimental collagen IV deposition, leading to superior vascular normalisation, reduced leakiness, improved oxygenation, more open vessels that permit perfusion and access for therapy. Low-dose bevacizumab augmented by imatinib selects a mature, highly normalised and well perfused tumour vasculature without inducing incremental ECM deposition that normally limits the effectiveness of VEGF targeting drugs.

  2. Cyanotoxins at low doses induce apoptosis and inflammatory effects in murine brain cells: Potential implications for neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Larissa Takser

    Full Text Available Cyanotoxins have been shown to be highly toxic for mammalian cells, including brain cells. However, little is known about their effect on inflammatory pathways. This study investigated whether mammalian brain and immune cells can be a target of certain cyanotoxins, at doses approximating those in the guideline levels for drinking water, either alone or in mixtures. We examined the effects on cellular viability, apoptosis and inflammation signalling of several toxins on murine macrophage-like RAW264.7, microglial BV-2 and neuroblastoma N2a cell lines. We tested cylindrospermopsin (CYN, microcystin-LR (MC-LR, and anatoxin-a (ATX-a, individually as well as their mixture. In addition, we studied the neurotoxins β-N-methylamino-l-alanine (BMAA and its isomer 2,4-diaminobutyric acid (DAB, as well as the mixture of both. Cellular viability was determined by the MTT assay. Apoptosis induction was assessed by measuring the activation of caspases 3/7. Cell death and inflammation are the hallmarks of neurodegenerative diseases. Thus, our final step was to quantify the expression of a major proinflammatory cytokine TNF-α by ELISA. Our results show that CYN, MC-LR and ATX-a, but not BMAA and DAB, at low doses, especially when present in a mixture at threefold less concentrations than individual compounds are 3–15 times more potent at inducing apoptosis and inflammation. Our results suggest that common cyanotoxins at low doses have a potential to induce inflammation and apoptosis in immune and brain cells. Further research of the neuroinflammatory effects of these compounds in vivo is needed to improve safety limit levels for cyanotoxins in drinking water and food. Keywords: Cyanotoxins, Low doses, Apoptosis, Inflammation, Brain cells, Neurodegenerative diseases

  3. Influence of contrast agent dose and ultrasound exposure on cardiomyocyte injury induced by myocardial contrast echocardiography in rats.

    Science.gov (United States)

    Miller, Douglas L; Li, Peng; Dou, Chunyan; Gordon, David; Edwards, Chris A; Armstrong, William F

    2005-10-01

    To detect specific cardiomyocyte injury induced by myocardial contrast material-enhanced echocardiography (ie, myocardial contrast echocardiography) in rats and to ascertain the influences of contrast material dose and ultrasound exposure on this injury. All animal procedures were approved by the university committee for the use and care of animals. Myocardial contrast echocardiography with 1:4 electrocardiographic (ECG) triggering was performed at 1.5 MHz in 61 anesthetized rats. Evans blue (EB) dye was injected as the vital stain for cardiomyocyte injury. At the start of myocardial contrast echocardiography, which lasted 10 minutes, perflutren lipid microsphere-based contrast material was infused through the tail vein for 5 minutes. Premature heartbeats were counted from the ECG record. The numbers of EB-stained cells counted on sections of heart specimens obtained 24 hours after myocardial contrast echocardiography and then either fresh frozen or embedded in paraffin were determined by using fluorescence microscopy. Results were compared statistically by using t tests and Mann-Whitney rank sum tests. EB-stained cells were concentrated in the anterior region of the myocardium. In the paraffin-embedded specimens, EB-stained cells were often accompanied by but largely separate from areas of inflammatory cell infiltration. At end-systolic triggering with a 50 microL/kg dose of microsphere contrast material, the EB-stained cell count increased with increasing peak rarefactional pressure amplitude, with significantly increased cell counts at 1.6 MPa (P .1). EB-stained cell counts increased with increasing contrast material dose, from 10 to 50 microL/kg, at 2.0 MPa. Cardiomyocyte injury was induced by the interaction of ultrasound pulses with contrast agent microbubbles during myocardial contrast echocardiography in rats, and the numbers of injured cells increased with increasing contrast agent dose and ultrasound exposure. RSNA, 2005

  4. Problems induced by the use of acetone as a solvent to dose chlorpyrifos in a microecosystem

    NARCIS (Netherlands)

    Kersting, K.

    1995-01-01

    Recycling aquatic microecosystems consisting of three subsystems with a total volume of 7.5 L were used to study the effects of the insecticide chlorpyrifos. The poorly soluble chlorpyrifos was dosed dissolved in 0.5 ml of acetone. Acetone was found to be responsible for some of the observed

  5. Dose effect relationships for radiation induced cancer: relevance of animal evidence

    International Nuclear Information System (INIS)

    Coggle, J.E.

    1982-01-01

    This article is based upon a paper which was presented at the SRP meeting on the Biological Bases of Radiation Protection Standards, October 1981. It is suggested that experimental radiation carcinogenesis data derived from animal studies will probably never provide numerical evidence of risk that is applicable to man. The uncertainties involved in any extrapolation of risk estimates from mice to men surely outweigh the uncertainties in the human epidemiological data. It is also suggested that at least in the foreseeable future animal data will not solve the perennial problem of the shape at low doses of the dose response curve for radiogenic cancer. At most the data may clarify the debate over linearity-non linearity and over the existence or otherwise of a threshold. However, the paper does suggest a very positive role for animal data in providing semi-quantitative generalisations for radiological protection concerning such variables as dose rate, radiation quality, partial body/organ exposure and in situations where the dose is received in a highly inhomogeneous fashion, e.g. the special problems of internal emitters. (author)

  6. LOW-DOSE BROMOCRIPTINE-INDUCED PLEURAL EFFUSION AND PLEUROPULMONARY FIBROSIS

    NARCIS (Netherlands)

    BRUNT, ERP; BOEREE, MJ

    We describe a parkinsonian patient who developed a slight asymptomatic pleural effusion during prolonged therapy with low dose bromocriptine (BCR) in addition to levodopa, following prior treatment with CQA 206-291. A moderate increase of BCR dosage prompted a severe pleuropulmonary inflammatory

  7. Gender and dose dependent ovalbumin induced hypersensitivity responses in murine model of food allergy

    Science.gov (United States)

    While federal regulations mandate the labeling of major food allergens, allowable food allergen thresholds have yet to be determined. Therefore the aim of this project was to identify the lowest egg allergen ovalbumin (OVA) dose causing hypersensitization using a validated murine model. Mice were or...

  8. Changes in Plasma Corticosterone and Catecholamine Contents Induced by Low Doses of Deltamethrin in Rats

    NARCIS (Netherlands)

    Boer, Sietse F. de; Gugten, Jan van der; Slangen, Jef. L.; Hijzen, Theo H.

    1988-01-01

    The effects of low doses of (S)-α-cyano-3-phenoxybenzyl (1R)-cis-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylate (Roussel UCLAF, Paris, France), (deltamethrin) upon sympathetic-adrenomedullary and pituitary-adrenocortical activity were investigated in rats by measuring plasma noradrenaline

  9. Pharmacological dose of alpha-tocopherol induces cardiotoxicity in Wistar rats determined by echocardiography and histology

    Science.gov (United States)

    The effect of pharmacological dose of alpha-tocopherol on heart health was determined in Wistar rats. Animals were randomly assigned to either C (control, n = 11) or E (alpha-tocopherol, n = 11) group. Animals received corn oil (C) or alpha-tocopherol dissolved in corn oil (250 mg alpha-tocopherol/[...

  10. Reversal of rocuronium-induced neuromuscular block by the selective relaxant binding agent sugammadex: a dose-finding and safety study

    DEFF Research Database (Denmark)

    Sorgenfrei, Iben F; Norrild, Kathrine; Larsen, Per Bo

    2006-01-01

    Sugammadex (Org 25969) forms a complex with steroidal neuromuscular blocking agents, thereby reversing neuromuscular block. This study investigated the dose-response relation, safety, and pharmacokinetics of sugammadex to reverse rocuronium-induced block.......Sugammadex (Org 25969) forms a complex with steroidal neuromuscular blocking agents, thereby reversing neuromuscular block. This study investigated the dose-response relation, safety, and pharmacokinetics of sugammadex to reverse rocuronium-induced block....

  11. Evaluation of changes in serum chemistry in association with feed withdrawal or high dose oral gavage with Dextran Sodium Sulfate (DSS) induced gut leakage in broiler chickens

    Science.gov (United States)

    Dextran sodium sulfate (DSS) has been shown to be effective at inducing enteric inflammation in broiler chickens, resulting in increased leakage of orally administered fluorescein isothiocyanate dextran to circulation. In a previous study, two doses of DSS (0.45g/dose) administered as oral gavage re...

  12. Simulation and measurement of total ionizing dose radiation induced image lag increase in pinned photodiode CMOS image sensors

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Jing [School of Materials Science and Engineering, Xiangtan University, Hunan (China); State Key Laboratory of Intense Pulsed Irradiation Simulation and Effect, Northwest Institute of Nuclear Technology, P.O.Box 69-10, Xi’an (China); Chen, Wei, E-mail: chenwei@nint.ac.cn [State Key Laboratory of Intense Pulsed Irradiation Simulation and Effect, Northwest Institute of Nuclear Technology, P.O.Box 69-10, Xi’an (China); Wang, Zujun, E-mail: wangzujun@nint.ac.cn [State Key Laboratory of Intense Pulsed Irradiation Simulation and Effect, Northwest Institute of Nuclear Technology, P.O.Box 69-10, Xi’an (China); Xue, Yuanyuan; Yao, Zhibin; He, Baoping; Ma, Wuying; Jin, Junshan; Sheng, Jiangkun; Dong, Guantao [State Key Laboratory of Intense Pulsed Irradiation Simulation and Effect, Northwest Institute of Nuclear Technology, P.O.Box 69-10, Xi’an (China)

    2017-06-01

    This paper presents an investigation of total ionizing dose (TID) induced image lag sources in pinned photodiodes (PPD) CMOS image sensors based on radiation experiments and TCAD simulation. The radiation experiments have been carried out at the Cobalt −60 gamma-ray source. The experimental results show the image lag degradation is more and more serious with increasing TID. Combining with the TCAD simulation results, we can confirm that the junction of PPD and transfer gate (TG) is an important region forming image lag during irradiation. These simulations demonstrate that TID can generate a potential pocket leading to incomplete transfer.

  13. Thermal annealing of high dose radiation induced damage at room temperature in alkaline. Stored energy, thermoluminescence and coloration

    International Nuclear Information System (INIS)

    Delgado, L.

    1980-01-01

    The possible relation between stored energy, thermoluminescence and colour centre annealing in gamma and electron irradiated alkali halides is studied. Thermoluminescence occurs at temperature higher than the temperature at which the main stored energy peak appears. No stored energy release is detected in additively coloured KC1 samples. Plastic deformation and doping with Ca and Sr induce a stored energy spectrum different from the spectrum observed in pure and as cleaved samples, but the amount of stored energy does not change for a given irradiation dose.Capacity of alkali halides to store energy by irradiation increases as the cation size decreases. (Author) 51 refs

  14. Anticonvulsants for Nerve Agent-Induced Seizures: The Influence of the Therapeutic Dose of Atropine

    National Research Council Canada - National Science Library

    Shih, Tsung-Ming; Rowland, Tami C; McDonough, John H

    2007-01-01

    Two guinea pig models were used to study the anticonvulsant potency of diazepam, midazolam, and scopolamine against seizures induced by the nerve agents tabun, sarin, soman, cyclosarin, O-ethyl S-(2-(diisopropylamino)ethyl...

  15. Analysis of functional failure mode of commercial deep sub-micron SRAM induced by total dose irradiation

    International Nuclear Information System (INIS)

    Zheng Qi-Wen; Cui Jiang-Wei; Zhou Hang; Yu De-Zhao; Yu Xue-Feng; Lu Wu; Guo Qi; Ren Di-Yuan

    2015-01-01

    Functional failure mode of commercial deep sub-micron static random access memory (SRAM) induced by total dose irradiation is experimentally analyzed and verified by circuit simulation. We extensively characterize the functional failure mode of the device by testing its electrical parameters and function with test patterns covering different functional failure modes. Experimental results reveal that the functional failure mode of the device is a temporary function interruption caused by peripheral circuits being sensitive to the standby current rising. By including radiation-induced threshold shift and off-state leakage current in memory cell transistors, we simulate the influence of radiation on the functionality of the memory cell. Simulation results reveal that the memory cell is tolerant to irradiation due to its high stability, which agrees with our experimental result. (paper)

  16. Intervention effect and dose-dependent response of tanreqing injection on airway inflammation in lipopolysaccharide-induced rats.

    Science.gov (United States)

    Dong, Shoujin; Zhong, Yunqing; Yang, Kun; Xiong, Xiaoling; Mao, Bing

    2013-08-01

    To assess the effect of Tanreqing injection on airway inflammation in rats. A rat model of airway inflammation was generated with lipopolysaccharide (LPS). Tanreqing injection was given by intratracheal instillation, and bronchoalveolar lavage fluid (BALF) from the right lung was collected. BALF total cell and neutrophil counts were then determined. In addition, BALF levels of inflammatory cytokines interleukin-13, cytokine-induced neutrophil chemoat-tractant-1, and tumor necrosis factor-alpha were measured using enzyme linked immunosorbent assay. The middle lobe of the right lung was stained with hematoxylin-eosin and histological changes examined. LPS increased airway inflammation, decreased BALF inflammatory cell count, inflammatory cytokine levels, and suppressed leukocyte influx of the lung. The LPS-induced airway inflammation peaked at 24 h, decreased beginning at 48 h, and had decreased markedly by 96 h. Tanreqing injection contains anti-inflammatory properties, and inhibits airway inflammation in a dose-dependent manner.

  17. Thermal annealing of high dose radiation induced damage at room temperature in alkali halides. Stored energy, thermoluminiscence and colouration

    International Nuclear Information System (INIS)

    Delgado, L.

    1980-01-01

    The possible relation between stored energy, thermoluminiscence and colour centre annealing in gamma and electron irradiated alkali halides is studied. Thermoluminiscence occurs at temperature higher than the temperature at which the main stored energy peak appears. No stored energy release is detected in additively coloured KCl samples. Plastic deformation and doping with Ca and Sr induce a stored energy spectrum different from the spectrum observed in pure and as cleaved samples, but the amount of stored energy does not change for a given irradiation dose. Capacity of alkali halides to sotore energy by irradiation increases as the cation size decreases. It appears that most of the observed release is not related to annealing processes of the radiation induced anion Frenkel pairs. The existence of damage in the cation sublattice with which this energy release might be related is considered. (auth.)

  18. Pattern imprinting in deep sub-micron static random access memories induced by total dose irradiation

    International Nuclear Information System (INIS)

    Zheng Qi-Wen; Yu Xue-Feng; Cui Jiang-Wei; Guo Qi; Ren Di-Yuan; Cong Zhong-Chao; Zhou Hang

    2014-01-01

    Pattern imprinting in deep sub-micron static random access memories (SRAMs) during total dose irradiation is investigated in detail. As the dose accumulates, the data pattern of memory cells loading during irradiation is gradually imprinted on their background data pattern. We build a relationship between the memory cell's static noise margin (SNM) and the background data, and study the influence of irradiation on the probability density function of ΔSNM, which is the difference between two data sides' SNMs, to discuss the reason for pattern imprinting. Finally, we demonstrate that, for micron and deep sub-micron devices, the mechanism of pattern imprinting is the bias-dependent threshold shift of the transistor, but for a deep sub-micron device the shift results from charge trapping in the shallow trench isolation (STI) oxide rather than from the gate oxide of the micron-device. (condensed matter: structural, mechanical, and thermal properties)

  19. Study of dose modification in skin cancers induced by the kind of bolus used - Bibliography

    International Nuclear Information System (INIS)

    Camilleri, Jeremy

    2011-01-01

    As tumour irradiation modalities differ from one pathology to another, and are even proper to each pathology (they depend on tumour nature, histology, size, location, and so on), but as therapeutic objectives remain unchanged (to deliver the prescribed dose to the target-volume with the highest possible precision while preserving as much as possible sane tissues as well as neighbouring organs at risk), this bibliographical study aims, on the one hand, at quantifying the dose variation generated by heterogeneous structures crossed by the electron beam, and on the other hand, at optimising the use of boluses during surface irradiations, notably in the case of skin cancers. The author addresses therapeutic indications of irradiation of skin cancers and of thoracic wall for which the application of a bolus is required, and then the associated irradiation techniques as well as bolus characteristics

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

    International Nuclear Information System (INIS)

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

    1981-09-01

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

  1. Two cases of acute radio-esophagitis induced by a relatively low dose of radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Mikuni, Morio; Ohtani, Tsuyoshi; Ono, Kouichi [Nihon Univ., Tokyo (Japan). School of Medicine] [and others

    1998-06-01

    Case 1 was a female, 48 years of age. After a diagnosis of lung cancer, radiotherapy (2 Gy/day) was started. On the sixth day, when radiotherapy reached a total dose of 12 Gy, swallowing became difficult and painful. Upper gastrointestinal endoscopy was performed, and redness, erosion, and easy bleeding of the mucosa in the chest, mid-esophagus, were demonstrated. Sodium alginate was administered to treat the symptoms and there was an improvement in both the symptoms and endoscopic findings. Case 2 was a male, 75 years of age. After a diagnosis of lung cancer, radiotherapy (2 Gy/day) was started. On the 12th day, when radiotherapy reached a total dose of 20 Gy, painful swallowing occurred. Upper gastrointestinal endoscopy revealed, redness and mild hemorrhage in the mucosal epithelium of the chest, mid-esophagus. Radiotherapy was suspended, and sodium alginate was administered. Symptoms improved, based on the findings of upper gastrointestinal endoscopy as well as subjective symptoms. (author)

  2. Pattern imprinting in deep sub-micron static random access memories induced by total dose irradiation

    Science.gov (United States)

    Zheng, Qi-Wen; Yu, Xue-Feng; Cui, Jiang-Wei; Guo, Qi; Ren, Di-Yuan; Cong, Zhong-Chao; Zhou, Hang

    2014-10-01

    Pattern imprinting in deep sub-micron static random access memories (SRAMs) during total dose irradiation is investigated in detail. As the dose accumulates, the data pattern of memory cells loading during irradiation is gradually imprinted on their background data pattern. We build a relationship between the memory cell's static noise margin (SNM) and the background data, and study the influence of irradiation on the probability density function of ΔSNM, which is the difference between two data sides' SNMs, to discuss the reason for pattern imprinting. Finally, we demonstrate that, for micron and deep sub-micron devices, the mechanism of pattern imprinting is the bias-dependent threshold shift of the transistor, but for a deep sub-micron device the shift results from charge trapping in the shallow trench isolation (STI) oxide rather than from the gate oxide of the micron-device.

  3. Human, recombinant interleukin-2 induces in vitro histamine release in a dose-dependent manner

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen; Petersen, L J; Skov, P S

    1995-01-01

    significantly in the supernatant from cells stimulated by rIL-2 in a dose-dependent manner both in patients and volunteers. Total cell-bound histamine was 49.3 +/- 4.1 ng/ml in patients compared to 78.5 +/- 7.7 ng/ml in volunteers (p ... was significantly enhanced in cancer patients compared to volunteers (*p manner in both cancer patients and volunteers. This may in part explain the severe toxicity observed during high...

  4. Radiation-Induced Rib Fractures After Hypofractionated Stereotactic Body Radiation Therapy: Risk Factors and Dose-Volume Relationship

    Energy Technology Data Exchange (ETDEWEB)

    Asai, Kaori [Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka (Japan); Shioyama, Yoshiyuki, E-mail: shioyama@radiol.med.kyushu-u.ac.jp [Department of Heavy Particle Therapy and Radiation Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka (Japan); Nakamura, Katsumasa; Sasaki, Tomonari; Ohga, Saiji; Nonoshita, Takeshi [Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka (Japan); Yoshitake, Tadamasa [Department of Heavy Particle Therapy and Radiation Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka (Japan); Ohnishi, Kayoko [Department of Radiology, National Center for Global Health and Medicine, Tokyo (Japan); Terashima, Kotaro; Matsumoto, Keiji [Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka (Japan); Hirata, Hideki [Department of Health Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka (Japan); Honda, Hiroshi [Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka (Japan)

    2012-11-01

    Purpose: The purpose of this study was to clarify the incidence, the clinical risk factors, and the dose-volume relationship of radiation-induced rib fracture (RIRF) after hypofractionated stereotactic body radiation therapy (SBRT). Methods and Materials: One hundred sixteen patients treated with SBRT for primary or metastatic lung cancer at our institution, with at least 6 months of follow-up and no previous overlapping radiation exposure, were included in this study. To determine the clinical risk factors associated with RIRF, correlations between the incidence of RIRF and the variables, including age, sex, diagnosis, gross tumor volume diameter, rib-tumor distance, and use of steroid administration, were analyzed. Dose-volume histogram analysis was also conducted. Regarding the maximum dose, V10, V20, V30, and V40 of the rib, and the incidences of RIRF were compared between the two groups divided by the cutoff value determined by the receiver operating characteristic curves. Results: One hundred sixteen patients and 374 ribs met the inclusion criteria. Among the 116 patients, 28 patients (46 ribs) experienced RIRF. The estimated incidence of rib fracture was 37.7% at 3 years. Limited distance from the rib to the tumor (<2.0 cm) was the only significant risk factor for RIRF (p = 0.0001). Among the dosimetric parameters used for receiver operating characteristic analysis, the maximum dose showed the highest area under the curve. The 3-year estimated risk of RIRF and the determined cutoff value were 45.8% vs. 1.4% (maximum dose, {>=}42.4 Gy or less), 51.6% vs. 2.0% (V40, {>=}0.29 cm{sup 3} or less), 45.8% vs. 2.2% (V30, {>=}1.35 cm{sup 3} or less), 42.0% vs. 8.5% (V20, {>=}3.62 cm{sup 3} or less), or 25.9% vs. 10.5% (V10, {>=}5.03 cm{sup 3} or less). Conclusions: The incidence of RIRF after hypofractionated SBRT is relatively high. The maximum dose and high-dose volume are strongly correlated with RIRF.

  5. Radiation-induced heart disease due to intrathonacic tumor radiotherapy of a single dose to the rabbits' heart

    International Nuclear Information System (INIS)

    Zhou Weibing; Feng Yan; Chen Jiayi; Luo Quanyong

    2007-01-01

    Objective: To observe the changes of radiation-induced heart disease (RIHD) in the rabbits irradiated in clinical related dose, and to evaluate the apoptosis and hypoxia in the irradiated heart by the new scintigraphic agents of 99 Tc m -HL91 and 99 Tc m -Annexin V of heart SPECT. Methods: Tenty-four New Zealand white rabbits 4-month old and 2-3 kg by weight were divided into two groups. Group 1 (clinical related dose group): 16 irradiated by a single close from 0 to 18 Gy. Group 2 (high dose group): 8 irradiated dose from 22 to 80 Gy. The serum cTnI/CKMB, ECG, and heart SPECT(using 99 Tc m -MIBI, 99 Tc m -HL91 and 99 Tc m -Annexin V as agents) were detected before and after irradiation. The animals were followed for 5 months. Then biopsy of rabbit heart was performed and pathologic examination was made by H.E. stain. Results: In the 16 rabbits of clinical related dose group, none died of RIHD. Whereas 2 rabbits died of RIHD in the high dose group. One died of myocardial infarction and the other of congestive heart failure. According to the Stewart introduced heart lesion grading system, of the clinical close ann, there were moderate in 1 rabbit, minimal in 14; and of the high dose ann, it was severe in 2, marked in 1, moderate in 5. The parallel relation was observed between the ECG results and the pathological changes (χ 2 =0.08, P=0.771). Serum value of cTnI, was elevated at the 12th hour after irradiation reaching the peak and maintained for 4 months. However, it came down in the 5th month. The difference of serum cTnI value before and after radiation was statistically significant. Myocardial perfusion scintigraphy tested by heart SPECT ( 99 Tc m -MIBI) showed defects was present in all irradiated rabbits. The relationship between the defects and radiation dose or between the defects and the real RIHD was uncertain. The SPECT images displayed that 99 Tc m -HL91 and 99m Tc-Annexin V did not accumulate in the irradiated heart. Conclusions: No serious damage is

  6. Prospective study in the management of high-dose radioactive iodine therapy induced gastritis

    International Nuclear Information System (INIS)

    Carbonell, C.; Ogbac, R.V.

    2007-01-01

    Full text: Gastritis is simply defined as inflammation of the gastric mucosa. In post-RAI patients, this is one of the most common complications that are encountered. Some patients may even require repetitive administration of high doses of radioactive iodine (I-131). Small doses of radiation (up to 1500 R) cause reversible mucosal damage, whereas higher radiation doses cause irreversible damage with atrophy and ischemic-related ulceration. Reversible changes consist of degenerative changes in epithelial cells and nonspecific chronic inflammatory infiltrate in the lamina propria. Higher amounts of radiation cause permanent mucosal damage, with atrophy of fundic glands, mucosal erosions, and capillary hemorrhage. Associated submucosal endarteritis results in mucosal ischemia and secondary ulcer development. Recurrent gastritis, if left untreated, may be a predisposing factor for gastric malignancy. Methods:A total of thirty post-RAI subjects were evaluated for signs and symptoms of gastritis and were divided into 3 groups which were given drugs for gastritis (H2-receptor antagonist, proton pump inhibitor, and sucralfate). Survey forms were distributed to evaluate the presence of nausea, vomiting, epigastric pain (graded according to severity of pain), and gastrointestinal bleeding. Results were tallied accordingly. Results and Discussion: In a total of 3 subjects who were given sucralfate, all of them did not experience any nausea and vomiting. One subject experienced mild epigastric discomfort and another subject was able to experience a non-specific symptom of abdominal bloatedness. (Note: Subjects are still for completion) In theory, radiation irritates the mucosa causing inflammation and mucosal damage which is further irritated by gastric acid secretion. The administration of H2-receptor blockers and proton pump inhibitors only inhibit gastric acid secretion while existing inflammation of mucosa due to high doses of radiation is left untreated. However

  7. Hand-foot syndrome in a patient with metastatic lung adenocarcinoma induced by high-dose icotinib: A case report and review of the literature.

    Science.gov (United States)

    Zheng, Yulong; Fang, Weijia; Xu, Nong

    2012-12-01

    Icotinib is a new oral epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI). The most frequent side-effects of icotinib include rash and diarrhea. Hand-foot syndrome (HFS) induced by EGFR-TKI is rare. The present study describes, for the first time, HFS induced by high-dose icotinib in a 65-year old female with metastatic lung adenocarcinoma. The patient developed HFS during the first week of icotinib treatment with characteristic clinical presentation. HFS regressed after icotinib dose-reduction was initiated. HFS may occur with icotinib, especially when administered in high doses.

  8. Radiation induced wheat-rye chromosomal translocations in triticale. Optimizing the dose using fluorescence in situ hybridization

    International Nuclear Information System (INIS)

    Ahmad, F.; Comeau, A.; Chen, Q.; Collin, J.; St-Pierre, C.A.

    2000-01-01

    Fluorescent in situ hybridization (FISH) was utilized to monitor the level of ionizing radiation ( 60 Co source) in their ability to cause intra- and intergeneric chromosomal aberrations in triticale seeds. Seeds were irradiated with 0, 20, 50, 100, 200, 300, 400, 500 and 1000 Gy doses. The root growth of irradiated seeds was greatly inhibited at 200 Gy and above. Various types of aberrations including wheat-rye, wheat-wheat, rye-rye, wheat-rye-wheat, rye-wheat-rye translocations and acentric fragments with or without translocations were observed. There was a consistent increase in proportion of aberrations per cell with an increase in radiation dose. It was concluded that for an optimal level of chromosomal translocation and least number of acentric fragments, a 20 Gy dose was quite sufficient for inducing a desirable level of wheat-rye chromosomal translocations. The excellent efficiency and importance of utilizing FISH in such studies of alien-introgression via chromosomal translocations are discussed. (author)

  9. Radiation induced wheat-rye chromosomal translocations in triticale. Optimizing the dose using fluorescence in situ hybridization

    Energy Technology Data Exchange (ETDEWEB)

    Ahmad, F. [Brandon Univ., Manitoba (Canada); Comeau, A.; Chen, Q.; Collin, J.; St-Pierre, C.A.

    2000-03-01

    Fluorescent in situ hybridization (FISH) was utilized to monitor the level of ionizing radiation ({sup 60}Co source) in their ability to cause intra- and intergeneric chromosomal aberrations in triticale seeds. Seeds were irradiated with 0, 20, 50, 100, 200, 300, 400, 500 and 1000 Gy doses. The root growth of irradiated seeds was greatly inhibited at 200 Gy and above. Various types of aberrations including wheat-rye, wheat-wheat, rye-rye, wheat-rye-wheat, rye-wheat-rye translocations and acentric fragments with or without translocations were observed. There was a consistent increase in proportion of aberrations per cell with an increase in radiation dose. It was concluded that for an optimal level of chromosomal translocation and least number of acentric fragments, a 20 Gy dose was quite sufficient for inducing a desirable level of wheat-rye chromosomal translocations. The excellent efficiency and importance of utilizing FISH in such studies of alien-introgression via chromosomal translocations are discussed. (author)

  10. Dose-response effect of Red Maca (Lepidium meyenii) on benign prostatic hyperplasia induced by testosterone enanthate.

    Science.gov (United States)

    Gasco, M; Villegas, L; Yucra, S; Rubio, J; Gonzales, G F

    2007-08-01

    The main goal of this study was to determine the effect of a freeze-dried aqueous extract of the red variety of Lepidium meyenii (Red Maca) on testosterone-induced benign prostatic hyperplasia (BPH) in adult rats of the Holtzman strain. Rats were treated with freeze-dried aqueous extract of Red Maca at doses of 0, 0.01, 0.05, 0.1, and 0.5 g/kg body wt. A positive control group received Finasteride (0.6 mg/kg body wt.). After treatment, the animals were sacrificed, and the ventral prostate was extracted, and weighed. HPLC was used to determine the presence of glucosinolates in Red Maca. The prostate weight diminished in a dose-dependent fashion in rats treated with Red Maca. The effect of Red Maca was better than that observed with Finasteride. Finasteride, but not Red Maca, reduced seminal vesicles weight. Analysis of the HPLC indicated the presence of benzyl glucosinolate (Glucotropaeolin) with a content of 0.639%. Serum testosterone levels were not affected by Red Maca. Moreover, serum testosterone levels were not related to prostate or seminal vesicles weight in rats treated with vehicle and Red Maca. In conclusion, Red Maca administered orally in rats seems to exert an inhibitory effect at a level post DHT conversion, on the BPH-induced experimentally, although a direct measure of reductase action would still be required.

  11. Two doses of bovine viral diarrhea virus DNA vaccine delivered by electroporation induce long-term protective immune responses.

    Science.gov (United States)

    van Drunen Littel-van den Hurk, Sylvia; Lawman, Zoe; Snider, Marlene; Wilson, Don; van den Hurk, Jan V; Ellefsen, Barry; Hannaman, Drew

    2013-02-01

    Bovine viral diarrhea virus (BVDV) is a pathogen of major importance in cattle, so there is a need for new effective vaccines. DNA vaccines induce balanced immune responses and are relatively inexpensive and thus promising for both human and veterinary applications. In this study, newborn calves with maternal antibodies were vaccinated intramuscularly (i.m.) with a BVDV E2 DNA vaccine with the TriGrid Delivery System for i.m. delivery (TDS-IM). Two doses of this vaccine spaced 6 or 12 weeks apart were sufficient to induce significant virus-neutralizing antibody titers, numbers of activated T cells, and reduction in viral shedding and clinical presentations after BVDV-2 challenge. In contrast to the placebo-treated animals, the vaccinated calves did not lose any weight, which is an excellent indicator of the well-being of an animal and has a significant economic impact. Furthermore, the interval between the two vaccinations did not influence the magnitude of the immune responses or degree of clinical protection, and a third immunization was not necessary or beneficial. Since electroporation may enhance not only the magnitude but also the duration of immunity after DNA immunization, the interval between vaccination and challenge was extended in a second trial, which showed that two doses of this E2 DNA vaccine again significantly reduced clinical disease against BVDV for several months. These results are promising and support this technology for use against infectious diseases in cattle and large species, including humans, in general.

  12. Sci-Thur AM: YIS – 02: Imaging dose distributions through the detection of radiation-induced acoustic waves

    Energy Technology Data Exchange (ETDEWEB)

    Hickling, Susannah; Lei, Hao; Hobson, Maritza; Leger, Pierre; Wang, Xueding; El Naqa, Issam [University of Michigan, McGill University, McGill University , University of Michigan, University of Michigan/McGill University (United States)

    2016-08-15

    Purpose: X-ray acoustic computed tomography (XACT) is an emerging technique that images the dose deposited within an object following linac irradiation by detecting acoustic waves induced via the photoacoustic effect. This work shows that XACT images can be formed in soft-tissue equivalent material and that dosimetric information can be extracted from such images. Methods: Acoustic waves induced in a water tank following irradiation by a 10 MV flattening filter free photon beam were detected with an immersion ultrasound transducer at 60 angles surrounding the radiation field. A back-projection algorithm was used to reconstruct an XACT image from the detected transducer signals. Profiles extracted from XACT images were compared to profiles measured with ion chambers as per the current clinical protocol. Results: XACT images were successfully formed of simple 4 cm × 4 cm and 6 cm × 3 cm fields, as well as of more complicated multi-leaf collimator defined fields. For the 6 cm × 3 cm field, 74% and 87% of the XACT profile points in the 6 cm and 3 cm dimensions, respectively, passed a 7% / 4 mm gamma test when compared to ion chamber measurements. In a complicated puzzle piece shaped field, 86% of the pixels in an extracted profile passed a 7% / 4 mm gamma test. Conclusions: XACT is capable of imaging the dose distribution delivered by a variety of field sizes and shapes in water, and is a viable technique for both water tank and in vivo dosimetry.

  13. Watermelon (Citrullus lanatus (Thunb.) Matsum. and Nakai) juice modulates oxidative damage induced by low dose X-ray in mice.

    Science.gov (United States)

    Mohammad, Mohd Khairul Amran; Mohamed, Muhamad Idham; Zakaria, Ainul Mardhiyah; Abdul Razak, Hairil Rashmizal; Saad, Wan Mazlina Md

    2014-01-01

    Watermelon is a natural product that contains high level of antioxidants and may prevent oxidative damage in tissues due to free radical generation following an exposure to ionizing radiation. The present study aimed to investigate the radioprotective effects of watermelon (Citrullus lanatus (Thunb.) Matsum. and Nakai) juice against oxidative damage induced by low dose X-ray exposure in mice. Twelve adult male ICR mice were randomly divided into two groups consisting of radiation (Rx) and supplementation (Tx) groups. Rx received filtered tap water, while Tx was supplemented with 50% (v/v) watermelon juice for 28 days ad libitum prior to total body irradiation by 100 μGy X-ray on day 29. Brain, lung, and liver tissues were assessed for the levels of malondialdehyde (MDA), apurinic/apyrimidinic (AP) sites, glutathione (GSH), and superoxide dismutase (SOD) inhibition activities. Results showed significant reduction of MDA levels and AP sites formation of Tx compared to Rx (P watermelon juice restore the intracellular antioxidant activities by significantly increased SOD inhibition activities and GSH levels compared to Rx. These findings may postulate that supplementation of 50% watermelon (Citrullus lanatus (Thunb.) Matsum. and Nakai) juice could modulate oxidative damage induced by low dose X-ray exposure.

  14. Immune cell-derived c3 is required for autoimmune diabetes induced by multiple low doses of streptozotocin.

    Science.gov (United States)

    Lin, Marvin; Yin, Na; Murphy, Barbara; Medof, M Edward; Segerer, Stephan; Heeger, Peter S; Schröppel, Bernd

    2010-09-01

    The complement system contributes to autoimmune injury, but its involvement in promoting the development of autoimmune diabetes is unknown. In this study, our goal was to ascertain the role of complement C3 in autoimmune diabetes. Susceptibility to diabetes development after multiple low-dose streptozotocin treatment in wild-type (WT) and C3-deficient mice was analyzed. Bone marrow chimeras, luminex, and quantitative reverse transcription PCR assays were performed to evaluate the phenotypic and immunologic impact of C3 in the development of this diabetes model. Coincident with the induced elevations in blood glucose levels, we documented alternative pathway complement component gene expression within the islets of the diabetic WT mice. When we repeated the experiments with C3-deficient mice, we observed complete resistance to disease, as assessed by the absence of histologic insulitis and the absence of T-cell reactivity to islet antigens. Studies of WT chimeras bearing C3-deficient bone marrow cells showed that bone marrow cell-derived C3, and not serum C3, is involved in the induction of diabetes in this model. The data reveal a key role for immune cell-derived C3 in the pathogenesis of murine multiple low-dose streptozotocin-induced diabetes and support the concept that immune cell mediated diabetes is in part complement-dependent.

  15. Low-dose X-irradiation of adjuvant-induced arthritis in rats. Efficacy of different fractionation schedules

    International Nuclear Information System (INIS)

    Liebmann, A.; Hindemith, M.; Jahns, J.; Kamprad, F.; Hildebrandt, G.; Madaj-Sterba, P.; Weisheit, S.

    2004-01-01

    Background and purpose: low-dose radiotherapy is widely accepted as a very effective treatment option for inflammatory symptoms associated with painful degenerative joint disorders. Radiation doses and fractionation schedules in practical use are empirical and mainly based on clinical observations. Experimental data are rare. The efficacy of low-dose X-irradiation on adjuvant induced arthritis in rats using different fractionation schemes was investigated in vivo, in order to explore whether there is a dose and fractionation dependence. Material and methods: adjuvant arthritis in female lewis rats (n = 128) was induced by intradermal injection of heat-inactivated Mycobacterium tuberculosis on day 0. Both arthritic hind paws were sham-irradiated (group 1: days 10-14; group 2: days 15-19; group 3: days 22-26) or X-irradiated with either 5 x 1.0 Gy (group 4: days 10-14; group 6: days 15-19; group 8: days 22-26; group 10: days 10, 12, 14, 16, and 18) or 5 x 0.5 Gy (group 5: days 10-14; group 7: days 15-19; group 9: days 22-26; group 11: days 10, 12, 14, 16, and 18; group 12: days 10-14 and 22-26). The clinical parameters arthritis score (AS), hind paw volume (HPV), and body weight were determined. Results: a significant decrease of the clinical arthritis parameters was observed following 5 x 0.5 Gy or 5 x 1.0 Gy during the acute maximum of the inflammatory response (days 15-19). The most pronounced treatment effect was reached after two daily fractionated series of 5 x 0.5 Gy with an early treatment onset (days 10-14) and repetition in interval (days 22-26). After the application of 5 x 1.0 Gy on days 10-14 or in a protracted scheme (days 10, 12, 14, 16, and 18), only a nonsignificant positive trend could be detected. Daily fractionated X-irradiation in the chronic phase of adjuvant arthritis (days 22-26) did not show any positive clinical effect. Conclusion: low-dose radiotherapy is able to prevent a full-blown arthritic reaction if given during the florid phase of

  16. Repeated dose intramuscular injection of the CIMAvax-EGF vaccine in Sprague Dawley rats induces local and systemic toxicity.

    Science.gov (United States)

    Mancebo, A; Casacó, A; González, B; Ledón, N; Sorlozabal, J; León, A; Gómez, D; González, Y; Bada, A M; González, C; Arteaga, M E; Ramírez, H; Fuentes, D

    2012-05-09

    CIMAvax-EGF consists of a human recombinant epidermal growth factor (EGF), coupled to P64k, a recombinant carrier protein from N. meningitis, and Montanide ISA 51 as adjuvant. The vaccine immunization induces a specific antibody production, inhibiting the EGF/EGF-R interaction through EGF deprivation. The objective of this study was to assess the CIMAvax-EGF toxicity in Sprague Dawley rats after intramuscular administration of repeated doses (6 months) and at the same time to determine if rat is a relevant species for studying CIMAvax-EGF vaccine. Rats were randomly distributed into four groups: control, Montanide ISA 51, treated with 1× and 15× of human total dose of the antigen. Animals were immunized weekly during 9 weeks, plus 9 immunizations every 14 days. Rats were inspected daily for clinical signs. Body weight, food consumption, and rectal temperature were measured during the administration of doses. Blood samples were collected for hematological, serum biochemical determinations and EGF titles at the beginning, three months and at the end of experimentation. Gross necropsy and histological examination of tissues were performed on animals at the end of the assay. Vaccine provoked the apparition of antibodies against EGF in the rats, demonstrating rat species relevance in these studies. Body weight gain, food and water consumption were not affected. CIMAvax-EGF and Montanide ISA 51 produced local damage at the administration site, showing multiple cysts and granulomas. Both vaccine-treated groups showed neutrophil elevation, besides an AST increase probably related to the damage at the administration site. Rectal temperature was found to be significantly higher in 15× treated group after immunizations, probably induced by the inflammatory process at the injection site. In summary, the clinical pathology findings together with the body temperature results, appear to be caused by the inflammatory reaction at the administration site of the vaccine, mainly

  17. Lumbosacral plexus delineation, dose distribution, and its correlation with radiation-induced lumbosacral plexopathy in cervical cancer patients

    Directory of Open Access Journals (Sweden)

    Tunio M

    2014-12-01

    Full Text Available Mutahir Tunio,1 Mushabbab Al Asiri,1 Yasser Bayoumi,2 Ali Abdullah O Balbaid,1 Majed AlHameed,3 Stanciu Laura Gabriela,1 Ahmad Amir O Ali1 1Radiation Oncology, Comprehensive Cancer Center, King Fahad Medical City, Riyadh, Saudi Arabia; 2National Cancer Institute, Cairo University, Cairo, Egypt; 3Neurology, Comprehensive Cancer Center, King Fahad Medical City, Riyadh, Saudi Arabia Background: To evaluate the dose distribution to the lumbosacral plexus (LSP and its correlation with radiation-induced lumbosacral plexopathy (RILSP in patients with cervical cancer treated with intensity-modulated radiotherapy (IMRT and high-dose-rate brachytherapy.Materials and methods: After meeting eligibility criteria, 50 patients with cervical cancer were selected who were treated with IMRT and high-dose-rate brachytherapy, and the LSP was contoured. Mean volume; percentages of LSP volume absorbing 40, 50, 55, and 60 Gy (V30, V40, V50, V55, and V60 and point doses (P1, P2, P3, P4, P5, P6, P7, P8, P9, and P10; and RILSP incidence were calculated.Results: At 60 months of follow-up, four patients (8% were found to have grade 2/3 RILSP. The mean maximal LSP dose in patients with RILSP was 59.6 Gy compared with 53.9 Gy in patients without RILSP (control; P=0.04. The mean values of V40, V50, V55, and V60 in patients with RILSP versus control were 61.8% versus 52.8%, 44.4% versus 27.7%, 8.0% versus 0.3% and 1.8% versus 0%, respectively (P=0.01, 0.001, 0.001, and 0.001, respectively.Conclusion: The delineation of the LSP during IMRT planning may reduce the risk for RILSP. The mean values of V40, V50, V55, and V60 for LSP should be less than 55%, 30%, 5%, and 0.5%, respectively; however, further studies are warranted.Keywords: cervical cancer, intensity-modulated radiation therapy, lumbosacral plexus delineation, radiation-induced lumbosacral plexopathy, dosimetric analysis

  18. Cyanotoxins at low doses induce apoptosis and inflammatory effects in murine brain cells: Potential implications for neurodegenerative diseases.

    Science.gov (United States)

    Takser, Larissa; Benachour, Nora; Husk, Barry; Cabana, Hubert; Gris, Denis

    2016-01-01

    Cyanotoxins have been shown to be highly toxic for mammalian cells, including brain cells. However, little is known about their effect on inflammatory pathways. This study investigated whether mammalian brain and immune cells can be a target of certain cyanotoxins, at doses approximating those in the guideline levels for drinking water, either alone or in mixtures. We examined the effects on cellular viability, apoptosis and inflammation signalling of several toxins on murine macrophage-like RAW264.7, microglial BV-2 and neuroblastoma N2a cell lines. We tested cylindrospermopsin (CYN), microcystin-LR (MC-LR), and anatoxin-a (ATX-a), individually as well as their mixture. In addition, we studied the neurotoxins β- N -methylamino-l-alanine (BMAA) and its isomer 2,4-diaminobutyric acid (DAB), as well as the mixture of both. Cellular viability was determined by the MTT assay. Apoptosis induction was assessed by measuring the activation of caspases 3/7. Cell death and inflammation are the hallmarks of neurodegenerative diseases. Thus, our final step was to quantify the expression of a major proinflammatory cytokine TNF-α by ELISA. Our results show that CYN, MC-LR and ATX-a, but not BMAA and DAB, at low doses, especially when present in a mixture at threefold less concentrations than individual compounds are 3-15 times more potent at inducing apoptosis and inflammation. Our results suggest that common cyanotoxins at low doses have a potential to induce inflammation and apoptosis in immune and brain cells. Further research of the neuroinflammatory effects of these compounds in vivo is needed to improve safety limit levels for cyanotoxins in drinking water and food.

  19. Reversal of rocuronium-induced (1.2 mg kg-1) profound neuromuscular block by accidental high dose of sugammadex (40 mg kg-1).

    NARCIS (Netherlands)

    Molina, A.L.; Boer, H.D. de; Klimek, M.; Heeringa, M.; Klein, J.

    2007-01-01

    Sugammadex is the first selective relaxant binding agent and reverses rocuronium-induced neuromuscular block. A case is reported in which a patient accidentally received a high dose of sugammadex (40 mg kg-1) to reverse a rocuronium-induced (1.2 mg kg-1) profound neuromuscular block. A fast and

  20. Intranasal infection with Chlamydia abortus induces dose-dependent latency and abortion in sheep.

    Science.gov (United States)

    Longbottom, David; Livingstone, Morag; Maley, Stephen; van der Zon, Arjan; Rocchi, Mara; Wilson, Kim; Wheelhouse, Nicholas; Dagleish, Mark; Aitchison, Kevin; Wattegedera, Sean; Nath, Mintu; Entrican, Gary; Buxton, David

    2013-01-01

    Latency is a key feature of the animal pathogen Chlamydia abortus, where infection remains inapparent in the non-pregnant animal and only becomes evident during a subsequent pregnancy. Often the first sign that an animal is infected is abortion occurring late in gestation. Despite this, little is understood of the underlying mechanisms that control latency or the recrudescence of infection that occurs during subsequent pregnancy. The aim of this study was to develop an experimental model of latency by mimicking the natural route of infection through the intranasal inoculation of non-pregnant sheep with C. abortus. Three groups of sheep (groups 1, 2 and 3) were experimentally infected with different doses of C. abortus (5×10(3), 5×10(5) and 5×10(7) inclusion forming units (IFU), respectively) prior to mating and monitored over 2 breeding cycles for clinical, microbiological, pathological, immunological and serological outcomes. Two further groups received either negative control inoculum (group 4a,b) or were inoculated subcutaneously on day 70 of gestation with 2×10(6) IFU C. abortus (group 5). Animals in groups 1, 2 and 5 experienced an abortion rate of 50-67%, while only one animal aborted in group 3 and none in group 4a,b. Pathological, microbiological, immunological and serological analyses support the view that the maternal protective immune response is influenced by initial exposure to the bacterium. The results show that intranasal administration of non-pregnant sheep with a low/medium dose of C. abortus results in a latent infection that leads in a subsequent pregnancy to infection of the placenta and abortion. In contrast a high dose stimulates protective immunity, resulting in a much lower abortion rate. This model will be useful in understanding the mechanisms of infection underlying latency and onset of disease, as well as in the development of novel therapeutics and vaccines for controlling infection.

  1. Intranasal infection with Chlamydia abortus induces dose-dependent latency and abortion in sheep.

    Directory of Open Access Journals (Sweden)

    David Longbottom

    Full Text Available Latency is a key feature of the animal pathogen Chlamydia abortus, where infection remains inapparent in the non-pregnant animal and only becomes evident during a subsequent pregnancy. Often the first sign that an animal is infected is abortion occurring late in gestation. Despite this, little is understood of the underlying mechanisms that control latency or the recrudescence of infection that occurs during subsequent pregnancy. The aim of this study was to develop an experimental model of latency by mimicking the natural route of infection through the intranasal inoculation of non-pregnant sheep with C. abortus.Three groups of sheep (groups 1, 2 and 3 were experimentally infected with different doses of C. abortus (5×10(3, 5×10(5 and 5×10(7 inclusion forming units (IFU, respectively prior to mating and monitored over 2 breeding cycles for clinical, microbiological, pathological, immunological and serological outcomes. Two further groups received either negative control inoculum (group 4a,b or were inoculated subcutaneously on day 70 of gestation with 2×10(6 IFU C. abortus (group 5. Animals in groups 1, 2 and 5 experienced an abortion rate of 50-67%, while only one animal aborted in group 3 and none in group 4a,b. Pathological, microbiological, immunological and serological analyses support the view that the maternal protective immune response is influenced by initial exposure to the bacterium.The results show that intranasal administration of non-pregnant sheep with a low/medium dose of C. abortus results in a latent infection that leads in a subsequent pregnancy to infection of the placenta and abortion. In contrast a high dose stimulates protective immunity, resulting in a much lower abortion rate. This model will be useful in understanding the mechanisms of infection underlying latency and onset of disease, as well as in the development of novel therapeutics and vaccines for controlling infection.

  2. Single dose of inducible nitric oxide synthase inhibitor induces prolonged inflammatory cell accumulation and fibrosis around injured tendon and synovium

    Directory of Open Access Journals (Sweden)

    Homa Darmani

    2004-01-01

    Full Text Available THE aim of the current study was to investigate the effect of inhibition of nitric oxide (NO production after injury on inflammatory cell accumulation and fibrosis around digital flexor tendon and synovium. A standard crush injury was applied to the flexor tendons of the middle digit of the hindpaw and the overlying muscle and synovium of female Wistar rats. Thirty animals received an intraperitoneal injection of either isotonic saline or N(G-nitro-l-arginine methyl ester (L-NAME; 5 mg/kg immediately following the crush injury, and five animals were then sacrificed at various intervals and the paws processed for histology. Another group of five animals was sacrificed after 3 days for nitrite determinations. The results showed that nitrite production and hence NO synthase activity is doubled at the acute phase of tendon wound healing, and we can prevent this by administering a single dose of L-NAME immediately after injury. The incidence and severity of fibrocellular adhesions between tendon and synovium was much more marked in animals treated with L-NAME. Treatment with L-NAME elicited a chronic inflammatory response characterised by a persistent and extraordinarily severe accumulation of large numbers of inflammatory cells in the subcutaneous tissues, in muscle and in tendon. These findings indicate that in the case of injured tendon and synovium, NO could act to protect the healing tissue from an uncontrolled inflammatory response.

  3. Radiation-induced liver disease after stereotactic body radiotherapy for small hepatocellular carcinoma: clinical and dose-volumetric parameters

    International Nuclear Information System (INIS)

    Jung, Jinhong; Choi, Eun Kyung; Kim, Jong Hoon; Yoon, Sang Min; Kim, So Yeon; Cho, Byungchul; Park, Jin-hong; Kim, Su Ssan; Song, Si Yeol; Lee, Sang-wook; Ahn, Seung Do

    2013-01-01

    To investigate the clinical and dose–volumetric parameters that predict the risk of radiation-induced liver disease (RILD) for patients with small, unresectable hepatocellular carcinoma (HCC) treated with stereotactic body radiotherapy (SBRT). Between March 2007 and December 2009, 92 patients with HCC treated with SBRT were reviewed for RILD within 3 months of completing treatment. RILD was evaluated according to the Common Terminology Criteria for Adverse Events, version 3.0. A dose of 10–20 Gy (median, 15 Gy) per fraction was given over 3–4 consecutive days for a total dose of 30–60 Gy (median, 45 Gy). The following clinical and dose–volumetric parameters were examined: age, gender, Child-Pugh class, presence of hepatitis B virus, gross tumor volume, normal liver volume, radiation dose, fraction size, mean dose to the normal liver, and normal liver volumes receiving from < 5 Gy to < 60 Gy (in increments of 5 Gy). Seventeen (18.5%) of the 92 patients developed grade 2 or worse RILD after SBRT (49 patients in grade 1, 11 in grade 2, and 6 in ≥ grade 3). On univariate analysis, Child-Pugh class was identified as a significant clinical parameter, while normal liver volume and normal liver volumes receiving from < 15 Gy to < 60 Gy were the significant dose–volumetric parameters. Upon multivariate analysis, only Child-Pugh class was a significant parameter for predicting grade 2 or worse RILD. The Child-Pugh B cirrhosis was found to have a significantly greater susceptibility to the development of grade 2 or worse RILD after SBRT in patients with small, unresectable HCC. Additional efforts aimed at testing other models to predict the risk of RILD in a large series of HCC patients treated with SBRT are needed

  4. Dose response relationships and analysis of primary processes of radiation-induced chromosomal aberrations in human peripheral lymphocytes

    International Nuclear Information System (INIS)

    Schmid, E.

    1977-02-01

    Human peripheral lymphocytes were irradiated with 220 kV X-rays, 3 MeV electrons and 15 MeV neutrons. The frequency of dicentric, acentric and atypical chromosomes and the exhange aberrations were measured and dose effect curves were constructed. The aim is to prepare the chromosome analysis to a biological dosimetry. The aberration findings could be adapted to the linear-quadrativ model y = c+ αD + βD 2 . With increasing LET the quantity lambda increased which is a measure for the share of the linear and quadratical components of the dose effect obtained. In case of electrons the RBE-values increased with increasing doses. In the case of neutrons they had their maximum in the low dose range. The feed back distances which lead to formation of primary lesions are for X-rays and electrons approximately 1 μm, for neutrons 1.7 μm. In a fractionation experiment with X-rays, the time of formation of exchange aberrations in radiation-induced primary breaks was measured. The number of dicentric chromosomes decreased with increasing time, while the intercellular distribution was not changed. The number of primary breaks decreasing per temporal interval is proportional to the number of the existing primary breaks. The average feed back time during which the primary breaks lead to induction of dicentric chromosomes, is 110 min. In order to determine the correspondence of the results of in-vivo and in-vitro experiments 15 patients and their blood were irradiated with 60 C-γ-rays. No significant differences were measured. (AJ) [de

  5. Low dose radiation induced hormesis and its mechanism of free radicals

    International Nuclear Information System (INIS)

    Zhang Liyuan; Huo Hongmei; Zhang Yusong; Zhao Peifeng; Li Wei; Jiang Jiagui

    2008-01-01

    Objective: To investigate whether the supernatant (the stimulating fluid) centrifuged from myeloid cells suspension after low dose radiation in vitro can produce hormesis on the normal or radiation damage cells. The mechanism of free radical was probed. Methods: Mouse myeloid cell suspension was irradiated respectively by 0, 2 and 5 Gy, and cultured in vitro. MTT method was used to measure the reproductive activity of cells. Meanwhile, Cytochrome C reduction method was used to determine the concentration of O 2 - . Lastly, the concentration of O 2 - was decreased or increased by adding DPI or PMA, and the effect of such changes on 'the stimulating fluid' was observed. Results: Co-cultured with 'the stimulating fluid', the reproductive activity of the myeloid cells after large dose radiation or the normal myeloid cells were enhanced. Decreasing the concentration of O 2 - ; may degrade the proliferation of the cells after radiation damage; while increasing it may lead to the opposite result. Conclusions: The stimulating fluid can enhance the proliferation of the myeloid cells after radiation damage and also the normal ones. The mechanism of above-mentioned phenomena might be related with the changes of O 2 - concentration. (authors)

  6. Mechanisms and biological importance of photon-induced bystander responses. Do they have an impact on low-dose radiation responses

    International Nuclear Information System (INIS)

    Tomita, Masanori; Maeda, Munetoshi

    2015-01-01

    Elucidating the biological effect of low linear energy transfer (LET), low-dose and/or low-dose-rate ionizing radiation is essential in ensuring radiation safety. Over the past two decades, non-targeted effects, which are not only a direct consequence of radiation-induced initial lesions produced in cellular DNA but also of intra- and inter-cellular communications involving both targeted and non-targeted cells, have been reported and are currently defining a new paradigm in radiation biology. These effects include radiation-induced adaptive response, low-dose hypersensitivity, genomic instability, and radiation-induced bystander response (RIBR). RIBR is generally defined as a cellular response that is induced in non-irradiated cells that receive bystander signals from directly irradiated cells. RIBR could thus play an important biological role in low-dose irradiation conditions. However, this suggestion was mainly based on findings obtained using high-LET charged-particle radiations. The human population (especially the Japanese, who are exposed to lower doses of radon than the world average) is more frequently exposed to low-LET photons (X-rays or γ-rays) than to high-LET charged-particle radiation on a daily basis. There are currently a growing number of reports describing a distinguishing feature between photon-induced bystander response and high-LET RIBR. In particular, photon-induced by-stander response is strongly influenced by irradiation dose, the irradiated region of the targeted cells, and p53 status. The present review focuses on the photon-induced bystander response, and discusses its impact on the low-dose radiation effect. (author)

  7. Radiation-induced rib fracture after stereotactic body radiotherapy with a total dose of 54-56 Gy given in 9-7 fractions for patients with peripheral lung tumor: impact of maximum dose and fraction size.

    Science.gov (United States)

    Aoki, Masahiko; Sato, Mariko; Hirose, Katsumi; Akimoto, Hiroyoshi; Kawaguchi, Hideo; Hatayama, Yoshiomi; Ono, Shuichi; Takai, Yoshihiro

    2015-04-22

    Radiation-induced rib fracture after stereotactic body radiotherapy (SBRT) for lung cancer has been recently reported. However, incidence of radiation-induced rib fracture after SBRT using moderate fraction sizes with a long-term follow-up time are not clarified. We examined incidence and risk factors of radiation-induced rib fracture after SBRT using moderate fraction sizes for the patients with peripherally located lung tumor. During 2003-2008, 41 patients with 42 lung tumors were treated with SBRT to 54-56 Gy in 9-7 fractions. The endpoint in the study was radiation-induced rib fracture detected by CT scan after the treatment. All ribs where the irradiated doses were more than 80% of prescribed dose were selected and contoured to build the dose-volume histograms (DVHs). Comparisons of the several factors obtained from the DVHs and the probabilities of rib fracture calculated by Kaplan-Meier method were performed in the study. Median follow-up time was 68 months. Among 75 contoured ribs, 23 rib fractures were observed in 34% of the patients during 16-48 months after SBRT, however, no patients complained of chest wall pain. The 4-year probabilities of rib fracture for maximum dose of ribs (Dmax) more than and less than 54 Gy were 47.7% and 12.9% (p = 0.0184), and for fraction size of 6, 7 and 8 Gy were 19.5%, 31.2% and 55.7% (p = 0.0458), respectively. Other factors, such as D2cc, mean dose of ribs, V10-55, age, sex, and planning target volume were not significantly different. The doses and fractionations used in this study resulted in no clinically significant rib fractures for this population, but that higher Dmax and dose per fraction treatments resulted in an increase in asymptomatic grade 1 rib fractures.

  8. Radiation-induced rib fracture after stereotactic body radiotherapy with a total dose of 54–56 Gy given in 9–7 fractions for patients with peripheral lung tumor: impact of maximum dose and fraction size

    International Nuclear Information System (INIS)

    Aoki, Masahiko; Sato, Mariko; Hirose, Katsumi; Akimoto, Hiroyoshi; Kawaguchi, Hideo; Hatayama, Yoshiomi; Ono, Shuichi; Takai, Yoshihiro

    2015-01-01

    Radiation-induced rib fracture after stereotactic body radiotherapy (SBRT) for lung cancer has been recently reported. However, incidence of radiation-induced rib fracture after SBRT using moderate fraction sizes with a long-term follow-up time are not clarified. We examined incidence and risk factors of radiation-induced rib fracture after SBRT using moderate fraction sizes for the patients with peripherally located lung tumor. During 2003–2008, 41 patients with 42 lung tumors were treated with SBRT to 54–56 Gy in 9–7 fractions. The endpoint in the study was radiation-induced rib fracture detected by CT scan after the treatment. All ribs where the irradiated doses were more than 80% of prescribed dose were selected and contoured to build the dose-volume histograms (DVHs). Comparisons of the several factors obtained from the DVHs and the probabilities of rib fracture calculated by Kaplan-Meier method were performed in the study. Median follow-up time was 68 months. Among 75 contoured ribs, 23 rib fractures were observed in 34% of the patients during 16–48 months after SBRT, however, no patients complained of chest wall pain. The 4-year probabilities of rib fracture for maximum dose of ribs (Dmax) more than and less than 54 Gy were 47.7% and 12.9% (p = 0.0184), and for fraction size of 6, 7 and 8 Gy were 19.5%, 31.2% and 55.7% (p = 0.0458), respectively. Other factors, such as D2cc, mean dose of ribs, V10–55, age, sex, and planning target volume were not significantly different. The doses and fractionations used in this study resulted in no clinically significant rib fractures for this population, but that higher Dmax and dose per fraction treatments resulted in an increase in asymptomatic grade 1 rib fractures

  9. Recent results on the linearity of the dose-response relationship for radiation-induced mutations in human cells by low dose levels

    International Nuclear Information System (INIS)

    Traut, H.

    1987-01-01

    Five studies made by various authors in the last years are discussed, which are significant in that the response of human cells to low-dose irradiation is determined directly and not by extrapolation, and which also provide information on the mutagenic effects of low radiation doses. The results of these studies do not indicate any other than a linear response for induction of mutations by low-dose irradiation, nor are there any reasons observable for assuming the existence of a threshold dose. It is very likely therefore that cancer initiation at the low dose level also is characterized by a linear relationship. Although threshold dose levels cannot generally be excluded, and maybe are only too low to be detected by experiment, there is no plausible biophysical argument for assuming the existence of such microdose threshold. (orig./MG) [de

  10. The dependence of the magnitude of induced adaptive responseon on the dose of pre-irradiation of cultured human lymphocytes under the optimum irradiation time scheme

    International Nuclear Information System (INIS)

    Mortazavi, S.M.J.; Mozdarani, H.

    2000-01-01

    Human lymphocytes exposed to low doses of X-rays, become less susceptible to the induction of chromosome aberrations by subsequent exposure to high doses of X-rays. This has been termed the radioadaptive response. One of the most important questions in the adaptive response studies was that of the possible existence of an optimum adapting dose. Early experiments indicated that this response could be induced by low doses of X-rays from 1 cGy to 20 cGy. Recently, it has been interestingly shown that the time scheme of exposure to adapting and challenge doses plays an important role in determination of the magnitude of the induced adaptive response. In this study, using the optimum irradiation time scheme (24-48), we have monitored the cytogenetic endpoint of chromosome aberrations to assess the magnitude of adaptation to ionizing radiation in the cultured human lymphocytes. Lymphocytes were pre-exposed to an adapting dose of 1-20 cGy at 24 hours, before an acute challenge dose of 1 or 2 Gy at 48 hours. Cells were fixed at 54 hours. Lymphocytes, which were pretreated with 5 as well as 10 cGy adapting doses, had significantly fewer chromosome aberrations. In spite of the fact that lymphocytes of some of our blood donors which were pre-treated with 1 or 20 cGy adapting doses, showed an adaptive response, the pooled data (all donors) indicated that such an induction of adaptive response can not be observed in these lymphocytes. The overall pattern of the induced adaptive response, indicated that in human lymphocyte (at least under the above mentioned irradiation scheme), 5 cGy and 10 cGy adapting doses are the optimum doses. (author)

  11. GLUT2 in pancreatic islets: crucial target molecule in diabetes induced with multiple low doses of streptozotocin in mice.

    Science.gov (United States)

    Wang, Z; Gleichmann, H

    1998-01-01

    In mice, diabetes can be induced by multiple low doses of streptozotocin (MLD-STZ), i.e., 40 mg/kg body wt on each of 5 consecutive days. In this model, diabetes develops only when STZ induces both beta-cell toxicity and T-cell-dependent immune reactions. The target molecule(s) of MLD-STZ-induced beta-cell toxicity are not known, however. In this study, we report that GLUT2 is a target molecule for MLD-STZ toxicity. Ex vivo, a gradual decrement of both GLUT2 protein and mRNA expression was found in pancreatic islets isolated from MLD-STZ-treated C57BL/6 male mice, whereas mRNA expression of beta-actin, glucokinase, and proinsulin remained unaffected. Significant reduction of both GLUT2 protein and mRNA expression was first noted 1 day after the third STZ injection, clearly preceding the onset of hyperglycemia. The extent of reduction increased with the number of STZ injections administered and increased over time, after the last, i.e., fifth, STZ injection. The STZ-induced reduction of GLUT2 protein and mRNA was not due to an essential loss of beta-cells, because ex vivo, not only the total RNA yield and protein content in isolated islets, but also proinsulin mRNA expression, failed to differ significantly in the differently treated groups. Furthermore, islets isolated from MLD-STZ-treated donors responded to the nonglucose secretagogue arginine in a pattern similar to that of solvent-treated donors. Interestingly, the MLD-STZ-induced reduction of both GLUT2 protein and mRNA was prevented by preinjecting mice with 5-thio-D-glucose before each STZ injection. Apparently, GLUT2 is a crucial target molecule of MLD-STZ toxicity, and this toxicity seems to precede the immune reactions against beta-cells.

  12. Low dose decitabine treatment induces CD80 expression in cancer cells and stimulates tumor specific cytotoxic T lymphocyte responses.

    Directory of Open Access Journals (Sweden)

    Li-Xin Wang

    Full Text Available Lack of immunogenicity of cancer cells has been considered a major reason for their failure in induction of a tumor specific T cell response. In this paper, we present evidence that decitabine (DAC, a DNA methylation inhibitor that is currently used for the treatment of myelodysplastic syndrome (MDS, acute myeloid leukemia (AML and other malignant neoplasms, is capable of eliciting an anti-tumor cytotoxic T lymphocyte (CTL response in mouse EL4 tumor model. C57BL/6 mice with established EL4 tumors were treated with DAC (1.0 mg/kg body weight once daily for 5 days. We found that DAC treatment resulted in infiltration of IFN-γ producing T lymphocytes into tumors and caused tumor rejection. Depletion of CD8(+, but not CD4(+ T cells resumed tumor growth. DAC-induced CTL response appeared to be elicited by the induction of CD80 expression on tumor cells. Epigenetic evidence suggests that DAC induces CD80 expression in EL4 cells via demethylation of CpG dinucleotide sites in the promoter of CD80 gene. In addition, we also showed that a transient, low-dose DAC treatment can induce CD80 gene expression in a variety of human cancer cells. This study provides the first evidence that epigenetic modulation can induce the expression of a major T cell co-stimulatory molecule on cancer cells, which can overcome immune tolerance, and induce an efficient anti-tumor CTL response. The results have important implications in designing DAC-based cancer immunotherapy.

  13. Low Dose Decitabine Treatment Induces CD80 Expression in Cancer Cells and Stimulates Tumor Specific Cytotoxic T Lymphocyte Responses

    Science.gov (United States)

    Zhou, Ji-Hao; Yao, Yu-Shi; Li, Yong-Hui; Xu, Yi-Han; Li, Jing-Xin; Gao, Xiao-Ning; Zhou, Min-Hang; Jiang, Meng-Meng; Gao, Li; Ding, Yi; Lu, Xue-Chun; Shi, Jin-Long; Luo, Xu-Feng; Wang, Jia; Wang, Li-Li; Qu, Chunfeng; Bai, Xue-Feng; Yu, Li

    2013-01-01

    Lack of immunogenicity of cancer cells has been considered a major reason for their failure in induction of a tumor specific T cell response. In this paper, we present evidence that decitabine (DAC), a DNA methylation inhibitor that is currently used for the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and other malignant neoplasms, is capable of eliciting an anti-tumor cytotoxic T lymphocyte (CTL) response in mouse EL4 tumor model. C57BL/6 mice with established EL4 tumors were treated with DAC (1.0 mg/kg body weight) once daily for 5 days. We found that DAC treatment resulted in infiltration of IFN-γ producing T lymphocytes into tumors and caused tumor rejection. Depletion of CD8+, but not CD4+ T cells resumed tumor growth. DAC-induced CTL response appeared to be elicited by the induction of CD80 expression on tumor cells. Epigenetic evidence suggests that DAC induces CD80 expression in EL4 cells via demethylation of CpG dinucleotide sites in the promoter of CD80 gene. In addition, we also showed that a transient, low-dose DAC treatment can induce CD80 gene expression in a variety of human cancer cells. This study provides the first evidence that epigenetic modulation can induce the expression of a major T cell co-stimulatory molecule on cancer cells, which can overcome immune tolerance, and induce an efficient anti-tumor CTL response. The results have important implications in designing DAC-based cancer immunotherapy. PMID:23671644

  14. Low dose decitabine treatment induces CD80 expression in cancer cells and stimulates tumor specific cytotoxic T lymphocyte responses.

    Science.gov (United States)

    Wang, Li-Xin; Mei, Zhen-Yang; Zhou, Ji-Hao; Yao, Yu-Shi; Li, Yong-Hui; Xu, Yi-Han; Li, Jing-Xin; Gao, Xiao-Ning; Zhou, Min-Hang; Jiang, Meng-Meng; Gao, Li; Ding, Yi; Lu, Xue-Chun; Shi, Jin-Long; Luo, Xu-Feng; Wang, Jia; Wang, Li-Li; Qu, Chunfeng; Bai, Xue-Feng; Yu, Li

    2013-01-01

    Lack of immunogenicity of cancer cells has been considered a major reason for their failure in induction of a tumor specific T cell response. In this paper, we present evidence that decitabine (DAC), a DNA methylation inhibitor that is currently used for the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and other malignant neoplasms, is capable of eliciting an anti-tumor cytotoxic T lymphocyte (CTL) response in mouse EL4 tumor model. C57BL/6 mice with established EL4 tumors were treated with DAC (1.0 mg/kg body weight) once daily for 5 days. We found that DAC treatment resulted in infiltration of IFN-γ producing T lymphocytes into tumors and caused tumor rejection. Depletion of CD8(+), but not CD4(+) T cells resumed tumor growth. DAC-induced CTL response appeared to be elicited by the induction of CD80 expression on tumor cells. Epigenetic evidence suggests that DAC induces CD80 expression in EL4 cells via demethylation of CpG dinucleotide sites in the promoter of CD80 gene. In addition, we also showed that a transient, low-dose DAC treatment can induce CD80 gene expression in a variety of human cancer cells. This study provides the first evidence that epigenetic modulation can induce the expression of a major T cell co-stimulatory molecule on cancer cells, which can overcome immune tolerance, and induce an efficient anti-tumor CTL response. The results have important implications in designing DAC-based cancer immunotherapy.

  15. INDUCED METABOLIC ACIDOSIS BY AMMONIUM CHLORIDE: ACTION MECHANISMS, DOSE AND EFFECTS ON ATHLETIC PERFORMANCE

    OpenAIRE

    Correia-Oliveira, Carlos Rafaell; Kiss, Maria Augusta Peduti Dal’Molin

    2018-01-01

    ABSTRACT The relationship between metabolic acidosis and athletic performance has been investigated over the years through manipulation of the blood and muscle pH. Among the pH manipulation manners, the ammonium chloride (NH4Cl) is the most widely used chemical component when is intentioned to induce a blood acidosis status prior to exercise. However, there is a lack of studies investigating the action of this substance on athletic performance as only two studies were performed in the last 15...

  16. A New Therapeutic Paradigm for Breast Cancer Exploiting Low Dose Estrogen-Induced Apoptosis

    Science.gov (United States)

    2012-06-01

    transcriptional repressor complex with RUNX3 [50], a known tumor suppressor that has been shown to be involved in apoptosis in gastric and colon cancer [51...A, et al. (2008) Apoptotic pathway induced by transduction of RUNX3 in the human gastric carcinoma cell line MKN-1. Cancer Sci 99: 23–30. 51. Tong DD...lung cancer risk in the cancer prevention study II nutrition cohort. Cancer Epidemiol Biomarkers Prev 2008;17:655-660. 115. Ramnath N, Menezes RJ

  17. Radioiodine therapy induces dose-dependent in-vivo oxidation injury

    International Nuclear Information System (INIS)

    Sinzinger, H.; Resch, U.; Tatzber, F.; Weiss, K.

    2002-01-01

    Until now, radiation hazards as a consequence of radioiodine therapy are not examined in detail. Oxidation of lipoproteins may favour vasculopathy. We studied the influence of a single radioiodine therapy with 5 (n=8; 46-71a), 10 (n=6; 54-75a), 20 (n=11; 45-73a), 80 (n=6; 37-75a) or 200 (n=6; 43-67a) mCi on in-vivo oxidation injury in blood (plasma [P], serum [Se]), urine (U) and saliva (Sa) in patients suffering from hyperthyroidism opr thyroid cancer, respectively. The isoprostane 8-epi-prostaglandin (PG) F 2α as a marker of in-vivo oxidation injury (Sa, Se, P, U), oxidation of lipoproteins (LDL, HDL), thromboxane B2 (Sa, Se, P, U), PGE 2 , PGF 2α and circulating endothelial cells (CEC) were examined before therapy, daily for 7 days and weekly thereafter for 6 weeks. Blood was also analyzed for thiobarbituric acid reactive substances (TBARS), relative electrophoretic mobility (REM), baseline dienes (BD), endogenous peroxides (POX) and formation of conjugated dienes in copper-mediated oxidation (CD) expressed in lag-time and rate of propagation. There is a dose-dependent increase in 8-epi-PGF 2α being most pronounced in saliva (p 2 and HDL 3 subfractions 24 h after application, but 48 h and 72 h after application there was a significant increase in TBARS, REM, BD, POX and rate of propagation and a decrease in lag-time in HDL-subfractions independently from applied dose. Also HDL 2 showed more TBARS, REM, BD, POX and shorter lag-time than HDL 3 48 h after application, but this effect was reversed 72 h after application. HDL is the lipoprotein most prone to oxidation by radioiodine treatment. Apparently, when LDL becomes oxidized, it shifts metabolically its oxidation products to HDL. These findings show a significant temporary and dose-dependent endothelial desquamation, oxidation of lipoproteins and long-lasting in-vivo oxidation injury (saliva > urine > blood) as side effect of radioiodine therapy, altogether being potentially proatherogenic

  18. Permanent metabolic stimulation in leaves induced by small gamma irradiation doses and its bioenergetical bases

    International Nuclear Information System (INIS)

    Pozsar, B.

    1979-01-01

    According to Schober (1896) the physiological functions of plants can be stimulated by small-dose acute gamma irradiation. The activity of the alcohol dehydrogenase was tested by the production of the acetaldehyde mg, related to 200 mg fresh leaf weight of bean (Pinto variety) and peas (BR-13 and DCP-94 varieties) plants. The stimulating effect of different reducing compounds (glutathione, ascorbic acid, cysteine) in additive treatment was also investigated in the respect of the alcohol dehydrogenase activity. The reducing compounds remarkably increase the activity of the alcohol dehydrogenase. The experimental results indicate that the primary water ionization is followed by secondary long-lasting proton transport through the reducing compounds to the dehydrogenase system. (author)

  19. Signalling detection of DNA damage induced by low doses of ionizing radiation in human lymphocytes

    International Nuclear Information System (INIS)

    Valente, M.

    2011-01-01

    Individuals spontaneously present different sensitivities to ionizing radiation, measured by the severity of their post-radiotherapy side-effects. Cells from some patients with extreme clinical radiosensitivity have shown altered cellular radiosensitivity measured by different endpoints as apoptosis or DNA damage. Linking clinical and cellular sensitivity is of fundamental importance to establish a clinical test capable of predicting a person's radiosensitivity from a sample. Easily sampled, peripheral blood lymphocytes (PBL) are an appealing cellular model to study individual radiosensitivity as they have been shown to be the most radiosensitive hematopoietic cells. DNA damages and repair can be visualized by observing the kinetics of appearance and disappearance of gamma-H2AX foci on DNA double-strand breaks through immunofluorescence microscopy. The experimental strategy chosen here was to follow lymphocyte gamma-H2AX foci kinetics in response to different levels of irradiation as delayed gamma-H2AX foci disappearance has been observed in cells of individuals with high clinical radiosensitivity. For our initial study we irradiated in vitro samples of radiotherapy patients with different clinical radiosensitivities. The groups of distinct clinical sensitivities showed no corresponding differences in their cellular gamma-H2AX response. In addition, several samples were lost, mainly due to the long transportation period before being treated in our lab. To render this method usable for clinical applications, several changes were made: after improving sample viability, speed was increased by automation of image acquisition (Metasystem) and gamma-H2AX focus scoring (freeware CellProfiler). This technique was able to detect doses as low as 0.005 Gy and gave similar results to manual focus scoring. The possibility of discriminating different lymphocyte subsets (CD4, CD8 and CD19) during analysis was added to identify among the lymphocyte subsets the one producing more

  20. Plumbagin Nanoparticles Induce Dose and pH Dependent Toxicity on Prostate Cancer Cells.

    Science.gov (United States)

    Nair, Harikrishnan A; Snima, K S; Kamath, Ravindranath C; Nair, Shantikumar V; Lakshmanan, Vinoth-Kumar

    2015-01-01

    Stable nano-formulation of Plumbagin nanoparticles from Plumbago zeylanica root extract was explored as a potential natural drug against prostate cancer. Size and morphology analysis by DLS, SEM and AFM revealed the average size of nanoparticles prepared was 100±50nm. In vitro cytotoxicity showed concentration and time dependent toxicity on prostate cancer cells. However, plumbagin crude extract found to be highly toxic to normal cells when compared to plumbagin nanoformulation, thus confirming nano plumbagin cytocompatibility with normal cells and dose dependent toxicity to prostate cells. In vitro hemolysis assay confirmed the blood biocompatibility of the plumbagin nanoparticles. In wound healing assay, plumbagin nanoparticles provided clues that it might play an important role in the anti-migration of prostate cancer cells. DNA fragmentation revealed that partial apoptosis induction by plumbagin nanoparticles could be expected as a potent anti-cancer effect towards prostate cancer.

  1. Dose-dependency and reversibility of radiation-induced injury in cardiac explant-derived cells of mice

    Science.gov (United States)

    Luo, Lan; Yan, Chen; Urata, Yoshishige; Hasan, Al Shaimaa; Goto, Shinji; Guo, Chang-Ying; Zhang, Shouhua; Li, Tao-Sheng

    2017-01-01

    We evaluated the dose-dependency and reversibility of radiation-induced injury in cardiac explant-derived cells (CDCs), a mixed cell population grown from heart tissues. Adult C57BL/6 mice were exposed to 0, 10, 50 and 250 mGy γ-rays for 7 days and atrial tissues were collected for experiments 24 hours after last exposure. The number of CDCs was significantly decreased by daily exposure to over 250 mGy. Interestingly, daily exposure to over 50 mGy significantly decreased the c-kit expression and telomerase activity, increased 53BP1 foci in the nuclei of CDCs. However, CD90 expression and growth factors production in CDCs were not significantly changed even after daily exposure to 250 mGy. We further evaluated the reversibility of radiation-induced injury in CDCs at 1 week and 3 weeks after a single exposure to 3 Gy γ-rays. The number and growth factors production of CDCs were soon recovered at 1 week. However, the increased expression of CD90 were retained at 1 week, but recovered at 3 weeks. Moreover, the decreased expression of c-kit, impaired telomerase activity, and increased 53BP1 foci were poorly recovered even at 3 weeks. These data may help us to find the most sensitive and reliable bio-parameter(s) for evaluating radiation-induced injury in CDCs. PMID:28098222

  2. Impact of DNA repair on the dose-response of colorectal cancer formation induced by dietary carcinogens.

    Science.gov (United States)

    Fahrer, Jörg; Kaina, Bernd

    2017-08-01

    Colorectal cancer (CRC) is one of the most frequently diagnosed cancers, which is causally linked to dietary habits, notably the intake of processed and red meat. Processed and red meat contain dietary carcinogens, including heterocyclic aromatic amines (HCAs) and N-nitroso compounds (NOC). NOC are agents that induce various N-methylated DNA adducts and O 6 -methylguanine (O 6 -MeG), which are removed by base excision repair (BER) and O 6 -methylguanine-DNA methyltransferase (MGMT), respectively. HCAs such as the highly mutagenic 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) cause bulky DNA adducts, which are removed from DNA by nucleotide excision repair (NER). Both O 6 -MeG and HCA-induced DNA adducts are linked to the occurrence of KRAS and APC mutations in colorectal tumors of rodents and humans, thereby driving CRC initiation and progression. In this review, we focus on DNA repair pathways removing DNA lesions induced by NOC and HCA and assess their role in protecting against mutagenicity and carcinogenicity in the large intestine. We further discuss the impact of DNA repair on the dose-response relationship in colorectal carcinogenesis in view of recent studies, demonstrating the existence of 'no effect' point of departures (PoDs), i.e. thresholds for genotoxicity and carcinogenicity. The available data support the threshold concept for NOC with DNA repair being causally involved. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Comparison of ketorolac and low-dose ketamine in preventing tourniquet-induced increase in arterial pressure

    Directory of Open Access Journals (Sweden)

    Raza Zaidi

    2015-01-01

    Full Text Available Background and Aims: Application of tourniquet during orthopaedic procedures causes pain and increase in blood pressure despite adequate anaesthesia and analgesia. In this study, we compared ketorolac with ketamine in patients undergoing elective lower limb surgery with tourniquet in order to discover if ketorolac was equally effective or better than ketamine in preventing tourniquet-induced hypertension. Methods: Approval was granted by the Institutional Ethics Review Committee and informed consent was obtained from all participants. A randomised double-blinded controlled trial with 38 patients each in the ketamine and ketorolac groups undergoing elective knee surgery for anterior cruciate ligament repair or reconstruction was conducted. Induction and maintenance of anaesthesia were standardised in all patients, and the minimum alveolar concentration of isoflurane was maintained at 1.2 throughout the study period. One group received ketamine in a dose of 0.25 mg/kg and the other group received 30 mg ketorolac 10 min before tourniquet inflation. Blood pressure was recorded before induction of anaesthesia (baseline and at 0, 10, 20, 30, 40, 50, and 60 min after tourniquet inflation. Results: The demographic and anaesthetic characteristics were similar in the two groups. At 0 and 10 min, tourniquet-induced rise in blood pressure was not observed in both groups. From 20 min onward, both systolic and diastolic blood pressures were significantly higher in ketorolac group compared to ketamine group. Conclusion: We conclude that ketamine is superior to ketorolac in preventing tourniquet-induced increases in blood pressure.

  4. Fluoxetine treatment induces dose dependent alterations in depression associated behavior and neural plasticity in female mice

    OpenAIRE

    Hodes, Georgia E.; Hill-Smith, Tiffany E.; Lucki, Irwin

    2010-01-01

    Antidepressant induced increases in neurogenesis and neurotrophin mobilization in rodents and primates are proposed to be necessary for behavioral efficacy. The current study examines the relationship between the effects of fluoxetine treatment on behavior, cell proliferation and the neurotrophin BDNF in females. Female MRL/MpJ mice were treated acutely (5 and 10 mg/kg) or chronically (2.5, 5 and 10 mg/kg b.i.d.) with fluoxetine and tested in the tail suspension test (TST) and or novelty indu...

  5. Dose-dependent effects of dihydrotestosterone in the streptozotocin-induced diabetic rat kidney

    OpenAIRE

    Xu, Qin; Prabhu, Anjali; Xu, Shujing; Manigrasso, Michaele B.; Maric, Christine

    2009-01-01

    We recently reported that castration exacerbates albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis associated with diabetic renal disease. The aim of the present study was to examine whether these effects of castration can be attenuated with dihydrotestosterone (DHT) supplementation. The study was performed in castrated male Sprague-Dawley, streptozotocin-induced diabetic rats treated with 0 mg/day DHT (DHT0), 0.75 mg/day DHT (DHT0.75), or 2.0 mg/day DHT (DHT2.0) for 14 wk. Tre...

  6. c-Jun/AP-1 pathway-mediated cyclin D1 expression participates in low dose arsenite-induced transformation in mouse epidermal JB6 Cl41 cells

    International Nuclear Information System (INIS)

    Zhang Dongyun; Li Jingxia; Gao Jimin; Huang Chuanshu

    2009-01-01

    Arsenic is a well-documented human carcinogen associated with skin carcinogenesis. Our previous work reveals that arsenite exposure is able to induce cell transformation in mouse epidermal cell JB6 Cl41 through the activation of ERK, rather than JNK pathway. Our current studies further evaluate downstream pathway in low dose arsenite-induced cell transformation in JB6 Cl41 cells. Our results showed that treatment of cells with low dose arsenite induced activation of c-Jun/AP-1 pathway, and ectopic expression of dominant negative mutant of c-Jun (TAM67) blocked arsenite-induced transformation. Furthermore, our data indicated that cyclin D1 was an important downstream molecule involved in c-Jun/AP-1-mediated cell transformation upon low dose arsenite exposure, because inhibition of cyclin D1 expression by its specific siRNA in the JB6 Cl41 cells resulted in impairment of anchorage-independent growth of cells induced by low dose arsenite. Collectively, our results demonstrate that c-Jun/AP-1-mediated cyclin D1 expression is at least one of the key events implicated in cell transformation upon low dose arsenite exposure

  7. Retrospective Cohort Study of Bronchial Doses and Radiation-Induced Atelectasis After Stereotactic Body Radiation Therapy of Lung Tumors Located Close to the Bronchial Tree

    International Nuclear Information System (INIS)

    Karlsson, Kristin; Nyman, Jan; Baumann, Pia; Wersäll, Peter; Drugge, Ninni; Gagliardi, Giovanna; Johansson, Karl-Axel; Persson, Jan-Olov; Rutkowska, Eva; Tullgren, Owe; Lax, Ingmar

    2013-01-01

    Purpose: To evaluate the dose–response relationship between radiation-induced atelectasis after stereotactic body radiation therapy (SBRT) and bronchial dose. Methods and Materials: Seventy-four patients treated with SBRT for tumors close to main, lobar, or segmental bronchi were selected. The association between incidence of atelectasis and bronchial dose parameters (maximum point-dose and minimum dose to the high-dose bronchial volume [ranging from 0.1 cm 3 up to 2.0 cm 3 ]) was statistically evaluated with survival analysis models. Results: Prescribed doses varied between 4 and 20 Gy per fraction in 2-5 fractions. Eighteen patients (24.3%) developed atelectasis considered to be radiation-induced. Statistical analysis showed a significant correlation between the incidence of radiation-induced atelectasis and minimum dose to the high-dose bronchial volumes, of which 0.1 cm 3 (D 0.1cm3 ) was used for further analysis. The median value of D 0.1cm3 (α/β = 3 Gy) was EQD 2,LQ = 147 Gy 3 (range, 20-293 Gy 3 ). For patients who developed atelectasis the median value was EQD 2,LQ = 210 Gy 3 , and for patients who did not develop atelectasis, EQD 2,LQ = 105 Gy 3 . Median time from treatment to development of atelectasis was 8.0 months (range, 1.1-30.1 months). Conclusion: In this retrospective study a significant dose–response relationship between the incidence of atelectasis and the dose to the high-dose volume of the bronchi is shown

  8. Electiveness of photorepair, influence of dark-repair on shape of dose-response curves, and high-dose decline, in UV-induced colour mutations of Serratia

    International Nuclear Information System (INIS)

    Kaplan, R.W.

    1978-01-01

    Strain CV of Serratia marcescens mutates by UV with high frequency to 3 groups of mutants (w, h, s) differing in colour from the red wild-type. The mutational dose-response curve has a curvature corresponding to about 3 hits. It reaches a peak and declines at high doses. Inactivation curves have a broad shoulder and mostly, but not always, a break to a lesser slope at UV doses near the peak of mutations. Photo reactivation (PR) gives a dose reduction of about 2 for both inactivation and mutation including the break and peak. The dose curve with PR for w-mutations shows 1 hit-, the other types 2-hit curvature leading to a change of mutation spectrum with dose due to PR. The UV-sensitive mutant uvs21 of CV has a survival curve with a small shoulder and a long upward concavity without a break, and the mutation curve is of the one-hit type without a peak and decline. PR gives a dose reduction of 12 for inactivation and of 7.5 for mutation. The 3-hit mutation curve of CV is interpreted by assuming that 2 further hits are required to protect the 1-hit pre-mutations from being abolished by the repair lacking in uvs21. UV induction of SOS repair cannot be responsible for the 3-hit curvature because UVR of phages and induction of prophage are already saturated at rather low doses. As high-dose decline is not observed in uvs21, possibly the non-mutagenic repair lacking from uvs21 interferes with the mutation finishing processes at high doses in the repair-proficient strain CV. However, UV induction of this interference cannot be a one-hit process but requires a very large number of hits. (Auth.)

  9. Oleoylethanolamide dose-dependently attenuates cocaine-induced behaviours through a PPARα receptor-independent mechanism.

    Science.gov (United States)

    Bilbao, Ainhoa; Blanco, Eduardo; Luque-Rojas, María Jesús; Suárez, Juan; Palomino, Ana; Vida, Margarita; Araos, Pedro; Bermúdez-Silva, Francisco J; Fernández-Espejo, Emilio; Spanagel, Rainer; Rodríguez de Fonseca, Fernando

    2013-01-01

    Oleoylethanolamide (OEA) is an acylethanolamide that acts as an agonist of nuclear peroxisome proliferator-activated receptor alpha (PPARα) to exert their biological functions, which include the regulation of appetite and metabolism. Increasing evidence also suggests that OEA may participate in the control of reward-related behaviours. However, direct experimental evidence for the role of the OEA-PPARα receptor interaction in drug-mediated behaviours, such as cocaine-induced behavioural phenotypes, is lacking. The present study explored the role of OEA and its receptor PPARα on the psychomotor and rewarding responsiveness to cocaine using behavioural tests indicative of core components of addiction. We found that acute administration of OEA (1, 5 or 20 mg/kg, i.p.) reduced spontaneous locomotor activity and attenuated psychomotor activation induced by cocaine (20 mg/kg) in C57Bl/6 mice. However, PPARα receptor knockout mice showed normal sensitization, although OEA was capable of reducing behavioural sensitization with fewer efficacies. Furthermore, conditioned place preference and reinstatement to cocaine were intact in these mice. Our results indicate that PPARα receptor does not play a critical, if any, role in mediating short- and long-term psychomotor and rewarding responsiveness to cocaine. However, further research is needed for the identification of the targets of OEA for its inhibitory action on cocaine-mediated responses. © 2012 The Authors, Addiction Biology © 2012 Society for the Study of Addiction.

  10. Pre- and postnatal exposure to low dose glufosinate ammonium induces autism-like phenotypes in mice.

    Science.gov (United States)

    Laugeray, Anthony; Herzine, Ameziane; Perche, Olivier; Hébert, Betty; Aguillon-Naury, Marine; Richard, Olivier; Menuet, Arnaud; Mazaud-Guittot, Séverine; Lesné, Laurianne; Briault, Sylvain; Jegou, Bernard; Pichon, Jacques; Montécot-Dubourg, Céline; Mortaud, Stéphane

    2014-01-01

    Glufosinate ammonium (GLA) is one of the most widely used herbicides in agriculture. As is the case for most pesticides, potential adverse effects of GLA have not been studied from the perspective of developmental neurotoxicity. Early pesticides exposure may weaken the basic structure of the developing brain and cause permanent changes leading to a wide range of lifelong effects on health and/or behavior. Here, we addressed the developmental impact of GLA by exposing female mice to low dose GLA during both pre- and postnatal periods and analyzed potential developmental and behavioral changes of the offspring during infancy and adulthood. A neurobehavioral test battery revealed significant effects of GLA maternal exposure on early reflex development, pup communication, affiliative behaviors, and preference for social olfactory cues, but emotional reactivity and emotional memory remained unaltered. These behavioral alterations showed a striking resemblance to changes seen in animal models of Autistic Spectrum Disorders. At the brain level, GLA maternal exposure caused some increase in relative brain weight of the offspring. In addition, reduced expression of Pten and Peg3 - two genes implicated in autism-like deficits - was observed in the brain of GLA-exposed pups at postnatal day 15. Our work thus provides new data on the link between pre- and postnatal exposure to the herbicide GLA and the onset of autism-like symptoms later in life. It also raises fundamental concerns about the ability of current safety testing to assess risks of pesticide exposure during critical developmental periods.

  11. Perinatal exposure to low dose glufosinate ammonium induces autism-like phenotypes in mice.

    Directory of Open Access Journals (Sweden)

    Anthony eLaugeray

    2014-11-01

    Full Text Available Glufosinate ammonium (GLA is one of the most widely used herbicides in agriculture. As is the case for most pesticides, potential adverse effects of GLA have not been studied from the perspective of developmental neurotoxicity. Early pesticides exposure may weaken the basic structure of the developing brain and cause permanent changes leading to a wide range of lifelong effects on health and/or behavior. Here we addressed the developmental impact of GLA by exposing female mice to low dose GLA during both pre- and postnatal periods and analyzed potential developmental and behavioral changes of the offspring during infancy and adulthood. A neurobehavioral test battery revealed significant effects of GLA maternal exposure on early reflex development, pup communication, affiliative behaviors, and preference for social olfactory cues, but emotional reactivity and emotional memory remained unaltered. These behavioral alterations showed a striking resemblance to changes seen in animal models of Autistic Spectrum Disorders. At the brain level, GLA maternal exposure caused some increase in normalized brain weight of the offspring. In addition, reduced expression of Pten and Peg3 - two genes implicated in autism-like deficits – was observed in the brain of GLA-exposed pups at postnatal day 15. Our work thus provides new data on the link between perinatal exposure to the herbicide GLA and the onset of autism-like symptoms later in life. It also raises fundamental concerns about the ability of current safety testing to assess risks of pesticide exposure during critical developmental periods.

  12. Methadone ameliorates multiple-low-dose streptozotocin-induced type 1 diabetes in mice

    International Nuclear Information System (INIS)

    Amirshahrokhi, K.; Dehpour, A.R.; Hadjati, J.; Sotoudeh, M.; Ghazi-Khansari, M.

    2008-01-01

    Type 1 diabetes is an autoimmune disease characterized by inflammation of pancreatic islets and destruction of β cells by the immune system. Opioids have been shown to modulate a number of immune functions, including T helper 1 (Th1) and T helper 2 (Th2) cytokines. The immunosuppressive effect of long-term administration of opioids has been demonstrated both in animal models and humans. The aim of this study was to determine the effect of methadone, a μ-opioid receptor agonist, on type 1 diabetes. Administration of multiple low doses of streptozotocin (STZ) (MLDS) (40mg/kg intraperitoneally for 5 consecutive days) to mice resulted in autoimmune diabetes. Mice were treated with methadone (10mg/kg/day subcutaneously) for 24days. Blood glucose, insulin and pancreatic cytokine levels were measured. Chronic methadone treatment significantly reduced hyperglycemia and incidence of diabetes, and restored pancreatic insulin secretion in the MLDS model. The protective effect of methadone can be overcome by pretreatment with naltrexone, an opioid receptor antagonist. Also, methadone treatment decreased the proinflammatory Th1 cytokines [interleukin (IL)-1β, tumor necrosis factor-α and interferon-γ] and increased anti-inflammatory Th2 cytokines (IL-4 and IL-10). Histopathological observations indicated that STZ-mediated destruction of β cells was attenuated by methadone treatment. It seems that methadone as an opioid agonist may have a protective effect against destruction of β cells and insulitis in the MLDS model of type 1 diabetes

  13. Modafinil improves attentional performance in healthy, non-sleep deprived humans at doses not inducing hyperarousal across species.

    Science.gov (United States)

    Cope, Zackary A; Minassian, Arpi; Kreitner, Dustin; MacQueen, David A; Milienne-Petiot, Morgane; Geyer, Mark A; Perry, William; Young, Jared W

    2017-10-01

    The wake-promoting drug modafinil is frequently used off-label to improve cognition in psychiatric and academic populations alike. The domain-specific attentional benefits of modafinil have yet to be quantified objectively in healthy human volunteers using tasks validated for comparison across species. Further, given that modafinil is a low-affinity inhibitor for the dopamine and norepinephrine transporters (DAT/NET respectively) it is unclear if any effects are attributable to a non-specific increase in arousal, a feature of many catecholamine reuptake inhibitors (e.g., cocaine, amphetamine). These experiments were designed to test for domain-specific enhancement of attention and cognitive control by modafinil (200 and 400 mg) in healthy volunteers using the 5-choice continuous performance task (5C-CPT) and Wisconsin Card Sort Task (WCST). An additional cross-species assessment of arousal and hyperactivity was performed in this group and in mice (3.2, 10, or 32 mg/kg) using species-specific versions of the behavioral pattern monitor (BPM). Modafinil significantly enhanced attention (d prime) in humans performing the 5C-CPT at doses that did not affect WCST performance or induce hyperactivity in the BPM. In mice, only the highest dose elicited increased activity in the BPM. These results indicate that modafinil produces domain-specific enhancement of attention in humans not driven by hyperarousal, unlike other drugs in this class, and higher equivalent doses were required for hyperarousal in mice. Further, these data support the utility of using the 5C-CPT across species to more precisely determine the mechanism(s) underlying the pro-cognitive effects of modafinil and potentially other pharmacological treatments. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. The possible role of low doses of Cerastes cerastes crude venom in mitigating doxorubicin induced oxidative damage in male rats

    International Nuclear Information System (INIS)

    Salama, S. F.; AL-Sadoon, M. K.

    2012-01-01

    The purpose of this study was to investigate the possible role of Cerastes cerastes crude venom (CCV) in attenuating (doxorubicin) DOX oxidative damage in male rats. Forty male rats, matched in age and weight were sorted into four groups, control, CCV-group, DOX-group and CCV + DOX-groups. DOX given as a single dose i.p. injection of 10 mg per kg body weight) induced a significant increase in serum advanced oxidation protein products (AOPP), malondialdehyde (MDA), urea, total proteins, AST, ALT, triglycerides and cholesterol. Meanwhile significant decrease in reduced glutathione (GSH), superoxide dimutase (SOD),uric acid as well as RBCs, platelet counts, hemoglobin content (Hb), haematocrit value (Hct), total leukocytes, neutrophils and lymphocytes count was recorded after 14 days. CCV i.p. injected daily at a dose of . LD50 for 14 days showed a significant decrease of the content of serum AOPP and MDA, lymphocytes and a significant increase of GSH, uric acid, RBCs count, Hb, Hct, total proteins, triglycerides, neutrophils count compared to control. In DOX+ CCV-group, CCV was given daily for 7 days before DOX, 10 mg/kg, followed by CCV for 7 more days, a significant inhibition of the serum triglycerides, cholesterol, urea and total protein, AST, ALT, AOPP, MDA, and a significant elevation of GSH, SOD, uric acid, RBCs, platelet counts, Hb, Hct, were shown as compared with DOX- group. It could be concluded that CCV at low doses can be used as a natural antioxidant to alleviate oxidative injuries of DOX.

  15. The possible role of low doses of Cerastes cerastes crude venom in mitigating doxorubicin induced oxidative damage in male rats

    International Nuclear Information System (INIS)

    Salama, S.F.; AL-Sadoon, M.K.

    2012-01-01

    The purpose of this study was to investigate the possible role of Cerastes cerastes crude venom (CCV) in attenuating (doxorubicin) DOX oxidative damage in male rats. Forty male rats, matched in age and weight were sorted into four groups, control, CCV-group, DOX-group and CCV + DOX-groups. DOX given as a single dose i.p. injection of 10 mg per kg body weight) induced a significant increase in serum advanced oxidation protein products (AOPP),malondialdehyde (MDA), urea, total proteins, AST, ALT, triglycerides and cholesterol. Meanwhile significant decrease in reduced glutathione (GSH), superoxide dimutase (SOD),uric acid as well as RBCs, platelet counts, hemoglobin content (Hb), haematocrit value (Hct), total leukocytes, neutrophils and lymphocytes count was recorded after 14 days. CCV i.p. injected daily at a dose of 1/4 LD 50 for 14 days showed a significant decrease of the content of serum AOPP and MDA, lymphocytes and a significant increase of GSH, uric acid, RBCs count, Hb, Hct, total proteins, triglycerides, neutrophils count compared to control. In DOX+ CCV-group, CCV was given daily for 7 days before DOX, 10 mg/kg, followed by CCV for 7 more days, a significant inhibition of the serum triglycerides, cholesterol, urea and total protein, AST, ALT, AOPP, MDA, and a significant elevation of GSH, SOD, uric acid, RBCs, platelet counts, Hb, Hct, were shown as compared with DOX- group. It could be concluded that CCV at low doses can be used as a natural antioxidant to alleviate oxidative injuries of DOX.

  16. Changes of mitochondrial structure, ATPase and Ca2+ concentration in spermatogenic cells of mouse testes induced by low dose radiation

    International Nuclear Information System (INIS)

    Wang Zhicheng; Liu Shuchun; Li Pengwu; Kang Shunai; Liang Shuo; Zhao Gang; Gong Shouliang

    2009-01-01

    Objective: To observe the ultrastructure, ATPase activity and Ca 2+ concentration ([Ca 2+ ]i) of mitochondria in the sperematogenic cells of mouse testes 3-24 h after low dose radiation with 0.025-0.200 Gy X-rays, and illuminate the effects of mitochondrion structure and relative biological function on apoptosis. Methods: The ultrastructure changes of mitochondria in the spermatogenic cells were observed with transmission electron microscope; the ATPase activity was measured with protein enzymic method; [Ca 2+ ]i was measured indirectly by flow cytometry with Fluo-3 probes. Results: The mitochondria swelled and vacuolizated, and their cristae were broken in the spermatogonia and spermatocytes 12 h after irradiation, and their nuclei were karyopyknosis, the acrosomal vesicle structure was ambiguity, the membrane structure was unclear, and the mitochondria in spermatids were vacuolization. The activities of Na + -K + -ATPase in mouse testis tissue 12 h after irradiated with 0.025-0.200 Gy decreased compared with those with 0 Gy, the Na + -K + -ATPase activities of the cells irradiated with 0.05-0.200 Gy decreased significantly compared with those with 0 Gy (P 2+ -ATPase of the cells irradiated with 0.025-0.200 Gy decreased significantly compared with those with 0 Gy (P 2+ ]i in mouse testis spermatogenic cells had similar dose-response relationship, [Ca 2+ ]i after irradiated with 0.075 Gy decreased compared with those with 0 Gy (P + -K + -ATPase in mouse testis tissues decreased obviously compared with those at 0 h (P 2+ -ATPase in mouse testis tissues increased slightly at 3 h, then decreased at 6-24 h compared with those at 0 h (P 2+ ]i in mouse testis spermatogenic cells had similar time course-response relationship, [Ca 2+ ]i at 12 h decreased significantly compared with at 0 h (P 2+ ]i induced by low dose radiation. (authors)

  17. Equitoxic doses of 5-azacytidine and 5-aza-2'deoxycytidine induce diverse immediate and overlapping heritable changes in the transcriptome.

    Directory of Open Access Journals (Sweden)

    Xiangning Qiu

    2010-09-01

    Full Text Available The hypomethylating agent 5-Azacytidine (5-Aza-CR is the first drug to prolong overall survival in patients with myelodysplastic syndrome (MDS. Surprisingly, the deoxyribonucleoside analog 5-Aza-2'deoxycytidine (5-Aza-CdR did not have a similar effect on survival in a large clinical trial. Both drugs are thought to exert their effects after incorporation into DNA by covalent binding of DNA methyltransferase (DNMT. While 5-Aza-CdR is incorporated into only DNA, 5-Aza-CR is also incorporated into RNA. Here, we have analyzed whether this difference in nucleic acid incorporation may influence the capacities of these drugs to regulate the expression of mRNA and microRNAs (miRNA, which may potentially affect the activities of the drugs in patients.A hematopoietic (HL-60; acute myeloid leukemia and a solid (T24; transitional cell carcinoma cancer cell line were treated with equitoxic doses of 5-Aza-CR and 5-Aza-CdR for 24 hrs, and the immediate (day 2 and lasting (day 8 effects on RNA expression examined. There was considerable overlap between the RNAs heritably upregulated by both drugs on day 8 but more RNAs were stably induced by the deoxy analog. Both drugs strongly induced expression of cancer testis antigens. On day 2 more RNAs were downregulated by 5-Aza-CR, particularly at higher doses. A remarkable downregulation of miRNAs and a significant upregulation of tRNA synthetases and other genes involved in amino acid metabolism was observed in T24 cells.Overall, this suggests that significant differences exist in the immediate action of the two drugs, however the dominant pattern of the lasting, and possible heritable changes, is overlapping.

  18. Tourniquet-induced ischaemia-reperfusion injury: the comparison of antioxidative effects of small-dose propofol and ketamine

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    Karaca Omer

    Full Text Available Abstract Objectives: The aim of the present study was to investigate the preventive effects of propofol and ketamine as small dose sedation during spinal anaesthesia on tourniquet-induced ischaemia-reperfusion injury. Methods: 30 patients were randomly assigned into two groups of 15 patients. In the propofol group, sedation was performed with propofol 0.2 mg·kg-1 followed by infusion at a rate of 2 mg·kg-1·h-1. In the ketamine group, a continuous infusion of ketamine 0.5 mg·kg-1·h-1 was used until the end of surgery. Intravenous administration of midazolam was not used in any patients. Ramsay sedation scale was used for assessing the sedation level. Venous blood samples were obtained before propofol and ketamine infusion (T1, at 30 minutes (min of tourniquet ischaemia (T2, and 5 min after tourniquet deflation (T3 for malondialdehyde (MDA measurements. Results: No differences were noted between the groups in haemodynamic (p > 0.05 and demographic data (p > 0.05. There was no statistically significant difference between the two groups in terms of T1, T2 and T3 periods (p > 0.05. There was a statistically increase observed in MDA values respectively both in Group P and Group K between the reperfusion period (1.95 ± 0.59, 2.31 ± 0.48 and pre-ischaemia (1.41 ± 0.38, 1.54 ± 0.45, and ischaemia (1.76 ± 0.70, 1.71 ± 0.38 (µmoL-1 periods (p < 0.05. Conclusions: Small-dose propofol and ketamine has similar potential to reduce the oxidative stress caused by tourniquet-induced ischaemia-reperfusion injury in patients undergoing arthroscopic knee surgery under spinal anaesthesia.

  19. Radiation sources providing increased UVA/UVB ratios induce photoprotection dependent on the UVA dose in hairless mice.

    Science.gov (United States)

    Reeve, Vivienne E; Domanski, Diane; Slater, Michael

    2006-01-01

    In studies involving mice in which doses of UVA (320-400 nm) and UVB (290-320 nm) radiation were administered alone or combined sequentially, we observed a protective effect of UVA against UVB-induced erythema/edema and systemic suppression of contact hypersensitivity. The UVA immunoprotection was mediated by the induction of the stress enzyme heme oxygenase-1 (HO-1) in the skin, protection of the cutaneous Th1 cytokines interferon-gamma (IFN-gamma) and IL-12 and inhibition of the UVB-induced expression of the Th2 cytokine IL-10. In this study, we seek evidence for an immunological waveband interaction when UVA and UVB are administered concurrently to hairless mice as occurs during sunlight exposure in humans. A series of spectra providing varying ratios of UVA/UVB were developed, with the UVA ratio increased to approximately 3.5 times the UVA component in solar simulated UV (SSUV). We report that progressively increasing the UVA component of the radiation while maintaining a constant UVB dose resulted in a reduction of both the erythema/edema reaction and the degree of systemic immunosuppression, as measured as contact hypersensitivity. The UVA-enhanced immunoprotection was abrogated in mice treated with a specific HO enzyme inhibitor. UVA-enhanced radiation also upregulated the expression of cutaneous IFN-gamma and IL-12 and inhibited expression of both IL-6 and IL-10, compared with the activity of SSUV. The results were consistent with the previously characterized mechanisms of photoprotection by the UVA waveband alone and suggest that the UVA component of solar UV may have beneficial properties for humans.

  20. Alzheimer ’s Disease: Possible Mechanisms Behind Neurohormesis Induced by Exposure to Low Doses of Ionizing Radiation

    Science.gov (United States)

    Bevelacqua, J.J.; Mortazavi, S.M.J.

    2018-01-01

    In 2016, scientists reported that human exposure to low doses of ionizing radiation (CT scans of the brain) might relieve symptoms of both Alzheimer’s disease (AD) and Parkinson disease (PD). The findings were unbelievable for those who were not familiar with neurohormesis. X-ray stimulation of the patient’s adaptive protection systems against neurodegenerative diseases was the mechanism proposed by those authors. Now, some more recent studies performed in the field of neurobiological research confirm that low levels of stress can produce protective responses against the pathogenic processes. This paper outlines possible protective consequences of LDR in preventing the pathogenesis of AD through mechanisms such as restoring the myelin sheath and preventing neurodegeneration caused by oxidative stress. Focal demyelination is frequently reported in the proximity of beta-amyloid plaques within neocortex. Extracellular accumulation of amyloid is among well-characterized pathological changes in AD. It should be noted that LDR has been shown to contribute to the regeneration and functional recovery after transverse peripheral nerve injury (through inducing increased production of VEGF and GAP-43), which advances both the axonal regeneration and myelination. Another mechanism which is possibly involved is preventing neurodegeneration caused by oxidative stress. While high doses can induce reactive oxygen species (ROS) formation, oxidative stress and neuro-inflammation, substantial evidence now indicates that LDR can mitigate tissue damage through antioxidant defenses. Although adult neurogenesis has been reported to be beneficial for the regeneration of nervous system, some studies demonstrate that neurogenesis increases in AD brains. In spite of these reports, cellular therapy is introduced as a promising strategy for AD, and hence, LDR can affect the proliferation and differentiation of neural stem cells. Although such mechanisms are not fully known yet, it is hoped

  1. Angiotensin converting enzyme inhibitors mitigate collagen synthesis induced by a single dose of radiation to the whole thorax

    International Nuclear Information System (INIS)

    Kma, L.; Gao, F.; Fish, B.L.; Moulder, J.E.; Jacobs, E.R.; Medhora, M.

    2012-01-01

    Our long-term goal is to use angiotensin converting enzyme (ACE) inhibitors to mitigate the increase in lung collagen synthesis that is induced by irradiation to the lung, which could result from accidental exposure or radiological terrorism. Rats (WAG/RijCmcr) were given a single dose of 13 Gy (dose rate of 1.43 Gy/min) of X-irradiation to the thorax. Three structurally-different ACE inhibitors, captopril, enalapril and fosinopril were provided in drinking water beginning 1 week after irradiation. Rats that survived acute pneumonitis (at 6-12 weeks) were evaluated monthly for synthesis of lung collagen. Other endpoints included breathing rate, wet to dry lung weight ratio, and analysis of lung structure. Treatment with captopril (145-207 mg/m 2 /day) or enalapril (19-28 mg/m 2 /day), but not fosinopril (19-28 mg/m 2 /day), decreased morbidity from acute pneumonitis. Lung collagen in the surviving irradiated rats was increased over that of controls by 7 months after irradiation. This increase in collagen synthesis was not observed in rats treated with any of the three ACE inhibitors. Analysis of the lung morphology at 7 months supports the efficacy of ACE inhibitors against radiation-induced fibrosis. The effectiveness of fosinopril against fibrosis, but not against acute pneumonitis, suggests that pulmonary fibrosis may not be a simple consequence of injury during acute pneumonitis. In summary, three structurally-different ACE inhibitors mitigate the increase in collagen synthesis 7 months following irradiation of the whole thorax and do so, even when therapy is started one week after irradiation. (author)

  2. Low-dose aspartame consumption differentially affects gut microbiota-host metabolic interactions in the diet-induced obese rat.

    Directory of Open Access Journals (Sweden)

    Marie S A Palmnäs

    Full Text Available Aspartame consumption is implicated in the development of obesity and metabolic disease despite the intention of limiting caloric intake. The mechanisms responsible for this association remain unclear, but may involve circulating metabolites and the gut microbiota. Aims were to examine the impact of chronic low-dose aspartame consumption on anthropometric, metabolic and microbial parameters in a diet-induced obese model. Male Sprague-Dawley rats were randomized into a standard chow diet (CH, 12% kcal fat or high fat (HF, 60% kcal fat and further into ad libitum water control (W or low-dose aspartame (A, 5-7 mg/kg/d in drinking water treatments for 8 week (n = 10-12 animals/treatment. Animals on aspartame consumed fewer calories, gained less weight and had a more favorable body composition when challenged with HF compared to animals consuming water. Despite this, aspartame elevated fasting glucose levels and an insulin tolerance test showed aspartame to impair insulin-stimulated glucose disposal in both CH and HF, independently of body composition. Fecal analysis of gut bacterial composition showed aspartame to increase total bacteria, the abundance of Enterobacteriaceae and Clostridium leptum. An interaction between HF and aspartame was also observed for Roseburia ssp wherein HF-A was higher than HF-W (P<0.05. Within HF, aspartame attenuated the typical HF-induced increase in the Firmicutes:Bacteroidetes ratio. Serum metabolomics analysis revealed aspartame to be rapidly metabolized and to be associated with elevations in the short chain fatty acid propionate, a bacterial end product and highly gluconeogenic substrate, potentially explaining its negative affects on insulin tolerance. How aspartame influences gut microbial composition and the implications of these changes on the development of metabolic disease require further investigation.

  3. Low-dose aspartame consumption differentially affects gut microbiota-host metabolic interactions in the diet-induced obese rat.

    Science.gov (United States)

    Palmnäs, Marie S A; Cowan, Theresa E; Bomhof, Marc R; Su, Juliet; Reimer, Raylene A; Vogel, Hans J; Hittel, Dustin S; Shearer, Jane

    2014-01-01

    Aspartame consumption is implicated in the development of obesity and metabolic disease despite the intention of limiting caloric intake. The mechanisms responsible for this association remain unclear, but may involve circulating metabolites and the gut microbiota. Aims were to examine the impact of chronic low-dose aspartame consumption on anthropometric, metabolic and microbial parameters in a diet-induced obese model. Male Sprague-Dawley rats were randomized into a standard chow diet (CH, 12% kcal fat) or high fat (HF, 60% kcal fat) and further into ad libitum water control (W) or low-dose aspartame (A, 5-7 mg/kg/d in drinking water) treatments for 8 week (n = 10-12 animals/treatment). Animals on aspartame consumed fewer calories, gained less weight and had a more favorable body composition when challenged with HF compared to animals consuming water. Despite this, aspartame elevated fasting glucose levels and an insulin tolerance test showed aspartame to impair insulin-stimulated glucose disposal in both CH and HF, independently of body composition. Fecal analysis of gut bacterial composition showed aspartame to increase total bacteria, the abundance of Enterobacteriaceae and Clostridium leptum. An interaction between HF and aspartame was also observed for Roseburia ssp wherein HF-A was higher than HF-W (Paspartame attenuated the typical HF-induced increase in the Firmicutes:Bacteroidetes ratio. Serum metabolomics analysis revealed aspartame to be rapidly metabolized and to be associated with elevations in the short chain fatty acid propionate, a bacterial end product and highly gluconeogenic substrate, potentially explaining its negative affects on insulin tolerance. How aspartame influences gut microbial composition and the implications of these changes on the development of metabolic disease require further investigation.

  4. Schistosoma mansoni: is acquired immunity induced by highly x-irradiated cercariae dependent on the size of the challenging dose

    International Nuclear Information System (INIS)

    Hsue, S.Y.; Hsue, H.F.; Osborne, J.W.; Johnson, S.C.

    1982-01-01

    A high degree of immunity, as shown by a 91% reduction of the number of worms recovered was found in five groups of mice that were immunized five times with highly X-irradiated cercariae and then challenged with 10, 20, 50, 100, or 500 normal Schistosoma mansoni cercariae. The results indicated that there were no significant differences in worm reduction in immunized mice challenged with different numbers of cercariae; consequently the immunity induced by this immunization method did not appear to be challenge-dose-dependent. However, the results also showed that when immunized mice were challenged with 500, 100, 50, 20, and 10 cercariae, 0, 13, 26, 56, and 68%, respectively, of the experimental animals were free of worms. Thus, the percentage of worm-negative cases increased as the number of challenge cercariae decreased. When viewed in this manner, the acquired immunity may be considered challenge-dose-dependent as well. If this method of vaccination is used for schistosomiasis control, we may anticipate that in both hypo- and hyperendemic areas, the intensity of infection and the severity of the disease will be reduced owing to a reduction in worms burdens, and in hypoendemic areas, there will be a number of worm-free cases

  5. Induced Mitogenic Activity in AML-12 Mouse Hepatocytes Exposed to Low-dose Ultra-Wideband Electromagnetic Radiation

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    P. B. Tchounwou

    2005-04-01

    Full Text Available Ultra–wideband (UWB technology has increased with the use of various civilian and military applications. In the present study, we hypothesized that low-dose UWB electromagnetic radiation (UWBR could elicit a mitogenic effect in AML-12 mouse hepatocytes, in vitro. To test this hypothesis, we exposed AML-12 mouse hepatocytes, to UWBR in a specially constructed gigahertz transverse electromagnetic mode (GTEM cell. Cells were exposed to UWBR for 2 h at a temperature of 23°C, a pulse width of 10 ns, a repetition rate of 1 kHz, and field strength of 5-20 kV/m. UWB pulses were triggered by an external pulse generator for UWBR exposure but were not triggered for the sham exposure. We performed an MTT Assay to assess cell viability for UWBR-treated and sham-exposed hepatocytes. Data from viability studies indicated a time-related increase in hepatocytes at time intervals from 8-24 h post exposure. UWBR exerted a statistically significant (p < 0.05 dose-dependent response in cell viability in both serum-treated and serum free medium (SFM -treated hepatocytes. Western blot analysis of hepatocyte lysates demonstrated that cyclin A protein was induced in hepatocytes, suggesting that increased MTT activity after UWBR exposure was due to cell proliferation. This study indicates that UWBR has a mitogenic effect on AML-12 mouse hepatocytes and implicates a possible role for UWBR in hepatocarcinoma.

  6. High-dose thiamine therapy counters dyslipidemia and advanced glycation of plasma protein in streptozotocin-induced diabetic rats.

    Science.gov (United States)

    Karachalias, Nikolaos; Babaei-Jadidi, Roya; Kupich, Christian; Ahmed, Naila; Thornalley, Paul J

    2005-06-01

    The streptozotocin-induced (STZ) diabetic rat experimental model of diabetes on insulin maintenance therapy exhibits dyslipidemia, mild thiamine deficiency, and increased plasma protein advanced glycation end products (AGEs). The reversal of thiamine deficiency by high-dose thiamine and S-benzoylthiamine monophosphate (benfotiamine) prevented the development of incipient nephropathy. Recently, we reported that high-dose thiamine (but not benfotiamine) countered diabetic dyslipidemia. To understand further the differences between the effects of thiamine and benfotiamine therapy, we quantified the levels of the AGEs in plasma protein. We found hydroimidazolone AGE residues derived from glyoxal and methylglyoxal, G-H1 and MG-H1, were increased 115% and 68% in STZ diabetic rats, with respect to normal controls, and were normalized by both thiamine and benfotiamine; whereas N-carboxymethyl-lysine (CML) and N-carboxyethyl-lysine (CEL) residues were increased 74% and 118% in STZ diabetic rats and were normalized by thiamine only. The lack of effect of benfotiamine on plasma CML and CEL residue concentrations suggests there may be important precursors of plasma protein CML and CEL residues other than glyoxal and methylglyoxal. These are probably lipid-derived aldehydes.

  7. Low-dose penicillin in early life induces long-term changes in murine gut microbiota, brain cytokines and behavior

    Science.gov (United States)

    Leclercq, Sophie; Mian, Firoz M.; Stanisz, Andrew M.; Bindels, Laure B.; Cambier, Emmanuel; Ben-Amram, Hila; Koren, Omry; Forsythe, Paul; Bienenstock, John

    2017-01-01

    There is increasing concern about potential long-term effects of antibiotics on children's health. Epidemiological studies have revealed that early-life antibiotic exposure can increase the risk of developing immune and metabolic diseases, and rodent studies have shown that administration of high doses of antibiotics has long-term effects on brain neurochemistry and behaviour. Here we investigate whether low-dose penicillin in late pregnancy and early postnatal life induces long-term effects in the offspring of mice. We find that penicillin has lasting effects in both sexes on gut microbiota, increases cytokine expression in frontal cortex, modifies blood–brain barrier integrity and alters behaviour. The antibiotic-treated mice exhibit impaired anxiety-like and social behaviours, and display aggression. Concurrent supplementation with Lactobacillus rhamnosus JB-1 prevents some of these alterations. These results warrant further studies on the potential role of early-life antibiotic use in the development of neuropsychiatric disorders, and the possible attenuation of these by beneficial bacteria. PMID:28375200

  8. Mechanism-based risk assessment strategy for drug-induced cholestasis using the transcriptional benchmark dose derived by toxicogenomics.

    Science.gov (United States)

    Kawamoto, Taisuke; Ito, Yuichi; Morita, Osamu; Honda, Hiroshi

    2017-01-01

    Cholestasis is one of the major causes of drug-induced liver injury (DILI), which can result in withdrawal of approved drugs from the market. Early identification of cholestatic drugs is difficult due to the complex mechanisms involved. In order to develop a strategy for mechanism-based risk assessment of cholestatic drugs, we analyzed gene expression data obtained from the livers of rats that had been orally administered with 12 known cholestatic compounds repeatedly for 28 days at three dose levels. Qualitative analyses were performed using two statistical approaches (hierarchical clustering and principle component analysis), in addition to pathway analysis. The transcriptional benchmark dose (tBMD) and tBMD 95% lower limit (tBMDL) were used for quantitative analyses, which revealed three compound sub-groups that produced different types of differential gene expression; these groups of genes were mainly involved in inflammation, cholesterol biosynthesis, and oxidative stress. Furthermore, the tBMDL values for each test compound were in good agreement with the relevant no observed adverse effect level. These results indicate that our novel strategy for drug safety evaluation using mechanism-based classification and tBMDL would facilitate the application of toxicogenomics for risk assessment of cholestatic DILI.

  9. Single-dose-dexketoprofen-induced acute kidney injury due to massive rhabdomyolysis.

    Science.gov (United States)

    Sav, Tansu; Unal, Aydin; Erden, Abdulsamet; Gunal, Ali Ihsan

    2012-10-01

    A 70-year-old male patient was admitted complaining of weakness and pain in his arms and lower limbs. His serum creatine kinase and serum creatinine were markedly elevated (36,248 IU/L and 2.8 mg/dL, respectively). He had taken dexketoprofen trometamol because of a common cold, which had developed the previous night. Acute kidney injury caused by dexketoprofen-induced rhabdomyolysis was diagnosed by ruling out other possible causes, such as dermato/polymyositis, myxedema, brucellosis, and hepatitis. Dexketoprofen administration was stopped. As diuresis did not restore spontaneously, the patient was treated with I.V. alkaline solutions and mannitol. Hemodialysis was performed because of anuria and severe metabolic acidosis. The patient's renal function later recovered. In conclusion, dexketoprofen may be a potential risk factor for acute kidney injury and rhabdomyolysis.

  10. High-dose benfotiamine rescues cardiomyocyte contractile dysfunction in streptozotocin-induced diabetes mellitus.

    Science.gov (United States)

    Ceylan-Isik, Asli F; Wu, Shan; Li, Qun; Li, Shi-Yan; Ren, Jun

    2006-01-01

    Diabetic cardiomyopathy is characterized by cardiac dysfunction. This study was designed to examine the effect of benfotiamine, a lipophilic derivative of thiamine, on streptozotocin (STZ)-induced cardiac contractile dysfunction in mouse cardiomyocytes. Adult male FVB mice were made diabetic with a single injection of STZ (200 mg/kg ip). Fourteen days later, control and diabetic (fasting plasma glucose > 13.9 mM) mice were put on benfotiamine therapy (100 mg.kg(-1).day(-1) ip) for another 14 days. Mechanical and intracellular Ca2+ properties were evaluated in left ventricular myocytes using an IonOptix MyoCam system. The following indexes were evaluated: peak shortening (PS), time to PS (TPS), time to 90% relengthening (TR90), maximal velocity of shortening/relengthening, resting and rise of intracellular Ca2+ in response to electrical stimulus, sarcoplasmic reticulum (SR) Ca2+ load, and intracellular Ca2+ decay rate (tau). Two- or four-week STZ treatment led to hyperglycemia, prolonged TPS and TR90, reduced SR Ca2+ load, elevated resting intracellular Ca2+ level and prolonged tau associated with normal PS, maximal velocity of shortening/relengthening, and intracellular Ca2+ rise in response to electrical stimulus. Benfotiamine treatment abolished prolongation in TPS, TR90, and tau, as well as reduction in SR Ca2+ load without affecting hyperglycemia and elevated resting intracellular Ca2+. Diabetes triggered oxidative stress, measured by GSH-to-GSSG ratio and formation of advanced glycation end product (AGE) in the hearts. Benfotiamine treatment alleviated oxidative stress without affecting AGE or protein carbonyl formation. Collectively, our results indicated that benfotiamine may rescue STZ-induced cardiomyocyte dysfunction but not AGE formation in short-term diabetes.

  11. Molecular mechanisms of macrophage activation induced by the synergistic effects of low dose irradiation and adoptive T cell therapy

    International Nuclear Information System (INIS)

    Bender, Noemi

    2016-01-01

    The detection of cancerous cells by the immune system elicits spontaneous antitumour immune responses. Still, during their progression, tumours acquire characteristics that enable them to escape immune surveillance. Cancer immunotherapy aims to reverse tumour immune evasion by activating and directing the immune system against transformed tumour cells. However, the tumours' intrinsic resistance mechanisms limit the success of many immunotherapeutic approaches. The functionally and morphologically abnormal tumour vasculature forms a physical barrier and prevents the entry of tumour-reactive immune effector cells, while the immunosuppressive tumour microenvironment impairs their function. To block tumour immune evasion, therapeutic strategies are being developed that combine cancer immunotherapy with treatment modalities, such as radiotherapy, that reprogram the tumour microenvironment to increase treatment efficacies and improve clinical outcome. In various preclinical models radiotherapy was shown to enhance the efficacy of adoptive T cell therapy. Our group showed that in the RIP1-TAg5 mouse model of spontaneous insulinoma, the transfer of in vitro-activated tumour-specific T cells induces T cell infiltration and promotes long-term survival only in combination with neoadjuvant local low dose irradiation (LDI). These treatment effects were mediated by iNOS+ macrophages. In this thesis, we investigated the mechanisms underlying the improved T cell infiltration and prolonged survival upon combination therapy with adoptive T cell transfer and local LDI. We demonstrate that combination therapy leads to a normalization of the aberrant tumour vasculature and endothelial activation, an increase in intratumoural macrophages, a reduction of intratumoural myeloid derived suppressor cells and, most importantly, to tumour regression. These findings suggest that this treatment inhibits tumour immune suppression but also facilitates immune effector cell infiltration through the

  12. Molecular mechanisms of macrophage activation induced by the synergistic effects of low dose irradiation and adoptive T cell therapy

    Energy Technology Data Exchange (ETDEWEB)

    Bender, Noemi

    2016-12-19

    The detection of cancerous cells by the immune system elicits spontaneous antitumour immune responses. Still, during their progression, tumours acquire characteristics that enable them to escape immune surveillance. Cancer immunotherapy aims to reverse tumour immune evasion by activating and directing the immune system against transformed tumour cells. However, the tumours' intrinsic resistance mechanisms limit the success of many immunotherapeutic approaches. The functionally and morphologically abnormal tumour vasculature forms a physical barrier and prevents the entry of tumour-reactive immune effector cells, while the immunosuppressive tumour microenvironment impairs their function. To block tumour immune evasion, therapeutic strategies are being developed that combine cancer immunotherapy with treatment modalities, such as radiotherapy, that reprogram the tumour microenvironment to increase treatment efficacies and improve clinical outcome. In various preclinical models radiotherapy was shown to enhance the efficacy of adoptive T cell therapy. Our group showed that in the RIP1-TAg5 mouse model of spontaneous insulinoma, the transfer of in vitro-activated tumour-specific T cells induces T cell infiltration and promotes long-term survival only in combination with neoadjuvant local low dose irradiation (LDI). These treatment effects were mediated by iNOS+ macrophages. In this thesis, we investigated the mechanisms underlying the improved T cell infiltration and prolonged survival upon combination therapy with adoptive T cell transfer and local LDI. We demonstrate that combination therapy leads to a normalization of the aberrant tumour vasculature and endothelial activation, an increase in intratumoural macrophages, a reduction of intratumoural myeloid derived suppressor cells and, most importantly, to tumour regression. These findings suggest that this treatment inhibits tumour immune suppression but also facilitates immune effector cell infiltration through

  13. Prevention of propofol-induced pain in children: pretreatment with small doses of ketamine.

    Science.gov (United States)

    Zhao, Guang-yi; Guo, Yao; Bao, Shu-min; Meng, Ling-xin; Zhang, Li-hong

    2012-06-01

    To evaluate the efficacy of ketamine in preventing propofol injection pain in children. Prospective, randomized, double-blinded, placebo-controlled study. University-affiliated hospital. 192 ASA physical status 1 and 2 pediatric patients. Patients were randomly assigned to 4 groups. Group S (control) received normal saline as a placebo; Group K1, Group K3, and Group K5 received 0.1 mg/kg, 0.3 mg/kg, and 0.5 mg/kg of ketamine, respectively. Fifteen seconds after the ketamine injection, patients were injected with propofol at a rate of 12 mL/min until loss-of-eyelash reflex. Pain was evaluated blindly at the time of induction using a 4-point scale: 0 = no pain, 1 = mild pain, 2 = moderate pain, and 3 = severe pain. Adverse effects were recorded. Characteristics of induction of anesthesia, such as dose of propofol and time from propofol injection to loss of consciousness (induction duration), were noted. 39 (84.8%) Group S (control) patients had pain. Pretreatment with ketamine reduced the frequency of pain significantly to 56.5%, 17.0%, and 14.9% in Groups K1, K3, and K5, respectively. Furthermore, the frequency of moderate and severe pain in Group K1 (21.8%), Group K3 (6.4%), and Group K5 (4.3%) was significantly (P ketamine (0.3 mg/kg) reduced the frequency and intensity of propofol injection pain without severe adverse effects. Copyright © 2012 Elsevier Inc. All rights reserved.

  14. Impact of high dose versus low dose atorvastatin on contrast induced nephropathy in diabetic patients with acute coronary syndrome undergoing early percutaneous coronary intervention

    Directory of Open Access Journals (Sweden)

    Haitham Galal

    2015-12-01

    Conclusion: No significant difference between high and low doses of atorvastatin in preventing CIN in diabetic patients with normal or mild renal impairment presenting with acute coronary syndrome who underwent early PCI.

  15. Antidiabetic Effect of Fresh Nopal (Opuntia ficus-indica in Low-Dose Streptozotocin-Induced Diabetic Rats Fed a High-Fat Diet

    Directory of Open Access Journals (Sweden)

    Seung Hwan Hwang

    2017-01-01

    Full Text Available The objective of the present study was to evaluate α-glucosidase inhibitory and antidiabetic effects of Nopal water extract (NPWE and Nopal dry power (NADP in low-dose streptozotocin- (STZ- induced diabetic rats fed a high-fat diet (HFD. The type 2 diabetic rat model was induced by HFD and low-dose STZ. The rats were divided into four groups as follows: (1 nondiabetic rats fed a regular diet (RD-Control; (2 low-dose STZ-induced diabetic rats fed HFD (HF-STZ-Control; (3 low-dose STZ-induced diabetic rats fed HFD and supplemented with NPWE (100 mg/kg body weight, HF-STZ-NPWE; and (4 low-dose STZ-induced diabetic rats fed HFD and supplemented with comparison medication (rosiglitazone, 10 mg/kg, body weight, HF-STZ-Rosiglitazone. In results, NPWE and NADP had IC50 values of 67.33 and 86.68 μg/mL, both of which exhibit inhibitory activities but lower than that of acarbose (38.05 μg/mL while NPWE group significantly decreased blood glucose levels compared to control and NPDP group on glucose tolerance in the high-fat diet fed rats model (P<0.05. Also, the blood glucose levels of HR-STZ-NPWE group were significantly lower (P<0.05 than HR-STZ-Control group on low-dose STZ-induced diabetic rats fed HFD. Based on these findings, we suggested that NPWE could be considered for the prevention and/or treatment of blood glucose and a potential use as a dietary supplement.

  16. Antidiabetic Effect of Fresh Nopal (Opuntia ficus-indica) in Low-Dose Streptozotocin-Induced Diabetic Rats Fed a High-Fat Diet.

    Science.gov (United States)

    Hwang, Seung Hwan; Kang, Il-Jun; Lim, Soon Sung

    2017-01-01

    The objective of the present study was to evaluate α -glucosidase inhibitory and antidiabetic effects of Nopal water extract (NPWE) and Nopal dry power (NADP) in low-dose streptozotocin- (STZ-) induced diabetic rats fed a high-fat diet (HFD). The type 2 diabetic rat model was induced by HFD and low-dose STZ. The rats were divided into four groups as follows: (1) nondiabetic rats fed a regular diet (RD-Control); (2) low-dose STZ-induced diabetic rats fed HFD (HF-STZ-Control); (3) low-dose STZ-induced diabetic rats fed HFD and supplemented with NPWE (100 mg/kg body weight, HF-STZ-NPWE); and (4) low-dose STZ-induced diabetic rats fed HFD and supplemented with comparison medication (rosiglitazone, 10 mg/kg, body weight, HF-STZ-Rosiglitazone). In results, NPWE and NADP had IC 50 values of 67.33 and 86.68  μ g/mL, both of which exhibit inhibitory activities but lower than that of acarbose (38.05  μ g/mL) while NPWE group significantly decreased blood glucose levels compared to control and NPDP group on glucose tolerance in the high-fat diet fed rats model ( P < 0.05). Also, the blood glucose levels of HR-STZ-NPWE group were significantly lower ( P < 0.05) than HR-STZ-Control group on low-dose STZ-induced diabetic rats fed HFD. Based on these findings, we suggested that NPWE could be considered for the prevention and/or treatment of blood glucose and a potential use as a dietary supplement.

  17. MK-801, but not naloxone, attenuates high-dose dextromethorphan-induced convulsive behavior: Possible involvement of the GluN2B receptor.

    Science.gov (United States)

    Tran, Hai-Quyen; Chung, Yoon Hee; Shin, Eun-Joo; Tran, The-Vinh; Jeong, Ji Hoon; Jang, Choon-Gon; Nah, Seung-Yeol; Yamada, Kiyofumi; Nabeshima, Toshitaka; Kim, Hyoung-Chun

    2017-11-01

    Dextromethorphan (DM) is a dextrorotatory isomer of levorphanol, a typical morphine-like opioid. When administered at supra-antitussive doses, DM produces psychotoxic and neurotoxic effects in humans. Although DM abuse has been well-documented, few studies have examined the effects of high-dose DM. The present study aimed to explore the effects of a single high dose of DM on mortality and seizure occurrence. After intraperitoneal administration with a high dose of DM (80mg/kg), Sprague-Dawley rats showed increased seizure occurrence and intensity. Hippocampal expression levels of N-methyl-d-aspartate (NMDA) receptor subunits (GluN1induced ultrastructural degeneration in the hippocampus. A non-competitive NMDA receptor antagonist, MK-801, attenuated these effects of high-dose DM, whereas an opioid antagonist, naloxone, did not affect DM-induced neurotoxicity. Moreover, pretreatment with a highly specific GluN2B subunit inhibitor, traxoprodil, was selectively effective in preventing DM-induced c-Fos expression and apoptotic changes. These results suggest that high-dose DM produces convulsive behaviors by activating GluN2B/NMDA signaling that leads to pro-apoptotic changes. Copyright © 2017. Published by Elsevier Inc.

  18. Low dose/low fluence ionizing radiation-induced biological effects: The role of intercellular communication and oxidative metabolism

    Science.gov (United States)

    Azzam, Edouard

    Mechanistic investigations have been considered critical to understanding the health risks of exposure to ionizing radiation. To gain greater insight in the biological effects of exposure to low dose/low fluence space radiations with different linear energy transfer (LET) properties, we examined short and long-term biological responses to energetic protons and high charge (Z) and high energy (E) ions (HZE particles) in human cells maintained in culture and in targeted and non-targeted tissues of irradiated rodents. Particular focus of the studies has been on mod-ulation of gene expression, proliferative capacity, induction of DNA damage and perturbations in oxidative metabolism. Exposure to mean doses of 1000 MeV/nucleon iron ions, by which a small to moderate proportion of cells in an exposed population is targeted through the nucleus by an HZE particle, induced stressful effects in the irradiated and non-irradiated cells in the population. Direct intercellular communication via gap-junctions was a primary mediator of the propagation of stressful effects from irradiated to non-irradiated cells. Compromised prolif-erative capacity, elevated level of DNA damage and oxidative stress evaluated by measurements of protein carbonylation, lipid peroxidation and activity of metabolic enzymes persisted in the progeny of irradiated and non-irradiated cells. In contrast, progeny of cells exposed to high or low doses from 150-1000 MeV protons retained the ability to form colonies and harbored similar levels of micronuclei, a surrogate form of DNA damage, as control, which correlated with normal reactive oxygen species (ROS) levels. Importantly, a significant increase in the spontaneous neoplastic transformation frequency was observed in progeny of bystander mouse embryo fibroblasts (MEFs) co-cultured with MEFs irradiated with energetic iron ions but not protons. Of particular significance, stressful effects were detected in non-targeted tissues of rats that received partial

  19. Longitudinal follow-up study of smoking-induced emphysema progression in low-dose CT screening of lung cancer

    Science.gov (United States)

    Suzuki, H.; Matsuhiro, M.; Kawata, Y.; Niki, N.; Nakano, Y.; Ohmatsu, H.; Kusumoto, M.; Tsuchida, T.; Eguchi, K.; Kaneko, Masahiro; Moriyama, N.

    2014-03-01

    Chronic obstructive pulmonary disease is a major public health problem that is predicted to be third leading cause of death in 2030. Although spirometry is traditionally used to quantify emphysema progression, it is difficult to detect the loss of pulmonary function by emphysema in early stage, and to assess the susceptibility to smoking. This study presents quantification method of smoking-induced emphysema progression based on annual changes of low attenuation volume (LAV) by each lung lobe acquired from low-dose CT images in lung cancer screening. The method consists of three steps. First, lung lobes are segmented using extracted interlobar fissures by enhancement filter based on fourdimensional curvature. Second, LAV of each lung lobe is segmented. Finally, smoking-induced emphysema progression is assessed by statistical analysis of the annual changes represented by linear regression of LAV percentage in each lung lobe. This method was applied to 140 participants in lung cancer CT screening for six years. The results showed that LAV progressions of nonsmokers, past smokers, and current smokers are different in terms of pack-year and smoking cessation duration. This study demonstrates effectiveness in diagnosis and prognosis of early emphysema in lung cancer CT screening.

  20. Nanoscale-Barrier Formation Induced by Low-Dose Electron-Beam Exposure in Ultrathin MoS2 Transistors.

    Science.gov (United States)

    Matsunaga, Masahiro; Higuchi, Ayaka; He, Guanchen; Yamada, Tetsushi; Krüger, Peter; Ochiai, Yuichi; Gong, Yongji; Vajtai, Robert; Ajayan, Pulickel M; Bird, Jonathan P; Aoki, Nobuyuki

    2016-10-05

    Utilizing an innovative combination of scanning-probe and spectroscopic techniques, supported by first-principles calculations, we demonstrate how electron-beam exposure of field-effect transistors, implemented from ultrathin molybdenum disulfide (MoS 2 ), may cause nanoscale structural modifications that in turn significantly modify the electrical operation of these devices. Quite surprisingly, these modifications are induced by even the relatively low electron doses used in conventional electron-beam lithography, which are found to induce compressive strain in the atomically thin MoS 2 . Likely arising from sulfur-vacancy formation in the exposed regions, the strain gives rise to a local widening of the MoS 2 bandgap, an idea that is supported both by our experiment and by the results of first-principles calculations. A nanoscale potential barrier develops at the boundary between exposed and unexposed regions and may cause extrinsic variations in the resulting electrical characteristics exhibited by the transistor. The widespread use of electron-beam lithography in nanofabrication implies that the presence of such strain must be carefully considered when seeking to harness the potential of atomically thin transistors. At the same time, this work also promises the possibility of exploiting the strain as a means to achieve "bandstructure engineering" in such devices.

  1. Negligible risk of inducing resistance in Mycobacterium tuberculosis with single-dose rifampicin as post-exposure prophylaxis for leprosy.

    Science.gov (United States)

    Mieras, Liesbeth; Anthony, Richard; van Brakel, Wim; Bratschi, Martin W; van den Broek, Jacques; Cambau, Emmanuelle; Cavaliero, Arielle; Kasang, Christa; Perera, Geethal; Reichman, Lee; Richardus, Jan Hendrik; Saunderson, Paul; Steinmann, Peter; Yew, Wing Wai

    2016-06-08

    Post-exposure prophylaxis (PEP) for leprosy is administered as one single dose of rifampicin (SDR) to the contacts of newly diagnosed leprosy patients. SDR reduces the risk of developing leprosy among contacts by around 60 % in the first 2-3 years after receiving SDR. In countries where SDR is currently being implemented under routine programme conditions in defined areas, questions were raised by health authorities and professional bodies about the possible risk of inducing rifampicin resistance among the M. tuberculosis strains circulating in these areas. This issue has not been addressed in scientific literature to date. To produce an authoritative consensus statement about the risk that SDR would induce rifampicin-resistant tuberculosis, a meeting was convened with tuberculosis (TB) and leprosy experts. The experts carefully reviewed and discussed the available evidence regarding the mechanisms and risk factors for the development of (multi) drug-resistance in M. tuberculosis with a view to the special situation of the use of SDR as PEP for leprosy. They concluded that SDR given to contacts of leprosy patients, in the absence of symptoms of active TB, poses a negligible risk of generating resistance in M. tuberculosis in individuals and at the population level. Thus, the benefits of SDR prophylaxis in reducing the risk of developing leprosy in contacts of new leprosy patients far outweigh the risks of generating drug resistance in M. tuberculosis.

  2. The effect of radiosensitizers on the survival response of hypoxic mammalian cells: The low X-ray dose region, hypersensitivity and induced radioresistance

    International Nuclear Information System (INIS)

    Skov, K.A.; MacPhail, H.S.; Marples, B.

    1994-01-01

    It has been shown previously that the extent of chemical modification of the hypoxic radiation response is dependent on dose. Some types of sensitizer are more effective at low doses (to 4 Gy) than at higher doses. Since such drugs are possible adjuvants to radiotherapy, the mechanisms responsible for the variable response at clinical doses are summarized, and the effects of cisplatin and buthionine sulfoximine on the purported induced response to radiation in hypoxic cells are presented. Cisplatin at a low, nontoxic concentration (1 μM) appears to abolish the increased radioresistant portion of the survival response. A role for high-mobility-group protein binding by platinum drugs is hypothesized to explain their interaction with radiation, and conversely, it is suggested that the heretofore unexplained different behavior of certain hypoxic sensitizers at low doses could be, at least in part, an effect on the induction of resistance. 36 refs., 2 figs

  3. Chronic ingestion of a low dose of caffeine induces tolerance to the performance benefits of caffeine.

    Science.gov (United States)

    Beaumont, Ross; Cordery, Philip; Funnell, Mark; Mears, Stephen; James, Lewis; Watson, Phillip

    2017-10-01

    This study examined effects of 4 weeks of caffeine supplementation on endurance performance. Eighteen low-habitual caffeine consumers (caffeine (1.5-3.0 mg · kg -1 day -1 ; titrated) or placebo for 28 days. Groups were matched for age, body mass, V̇O 2peak and W max (P > 0.05). Before supplementation, all participants completed one V̇O 2peak test, one practice trial and 2 experimental trials (acute 3 mg · kg -1 caffeine [precaf] and placebo [testpla]). During the supplementation period a second V̇O 2peak test was completed on day 21 before a final, acute 3 mg · kg -1 caffeine trial (postcaf) on day 29. Trials consisted of 60 min cycle exercise at 60% V̇O 2peak followed by a 30 min performance task. All participants produced more external work during the precaf trial than testpla, with increases in the caffeine (383.3 ± 75 kJ vs. 344.9 ± 80.3 kJ; Cohen's d effect size [ES] = 0.49; P = 0.001) and placebo (354.5 ± 55.2 kJ vs. 333.1 ± 56.4 kJ; ES = 0.38; P = 0.004) supplementation group, respectively. This performance benefit was no longer apparent after 4 weeks of caffeine supplementation (precaf: 383.3 ± 75.0 kJ vs. postcaf: 358.0 ± 89.8 kJ; ES = 0.31; P = 0.025), but was retained in the placebo group (precaf: 354.5 ± 55.2 kJ vs. postcaf: 351.8 ± 49.4 kJ; ES = 0.05; P > 0.05). Circulating caffeine, hormonal concentrations and substrate oxidation did not differ between groups (all P > 0.05). Chronic ingestion of a low dose of caffeine develops tolerance in low-caffeine consumers. Therefore, individuals with low-habitual intakes should refrain from chronic caffeine supplementation to maximise performance benefits from acute caffeine ingestion.

  4. Subchronic exposure to high-dose ACE-inhibitor moexipril induces catalase activity in rat liver.

    Science.gov (United States)

    Adeghate, E; Hasan, M Y; Ponery, A S; Nurulain, S M; Petroianu, G A

    2005-12-01

    The long-term clinical effects of ACE-inhibitors have similarities with those of both fibrates and glitazones, activators of peroxisome proliferator activator receptor (PPAR) alpha and gamma, respectively. The antioxidant enzyme catalase, a heme protein that degrades hydrogen peroxide, is found at high concentrations in peroxisomes. Catalase activity is one of the recognized surrogate markers indicative of PPAR activation in the rat liver. The purpose of the study was to establish the effect of moexipril on catalase activity and to compare it with the effect of both saline controls and that of the known PPAR agonist clofibrate (positive control). Three groups of seven rats were used. All substances were applied i.p. daily for 5 days, followed by a 2-day break. The cycle was repeated eight times. After the final cycle (day 56) the animals were sacrificed and liver tissue collected. The number of catalase positive cells in both moexipril group (95% CI 57-61) and clofibrate group (95% CI 72-80) is higher than in controls (95% CI 3-16) (p catalase positive cells in the clofibrate group is higher than in the moexipril group (p inhibitor moexipril induces catalase activity in the rat liver to an extent comparable to fibrates. We suggest that some of the long-term advantages of ACE inhibitor use - beyond mere BP lowering - might be due to a PPAR mediated effect.

  5. Osteomalacia induced by long-term low-dose adefovir dipivoxil: Clinical characteristics and genetic predictors.

    Science.gov (United States)

    Wei, Zhe; He, Jin-Wei; Fu, Wen-Zhen; Zhang, Zhen-Lin

    2016-12-01

    Adefovir dipivoxil (ADV) was an important cause of adult-onset hypophosphatemic osteomalacia. However, its clinical characteristics and mechanisms have not been well defined. The objective of the study was to summarize the clinical characteristics of ADV-induced osteomalacia and to explore the association between ADV-associated tubulopathy and polymorphisms in genes encoding drug transporters. Seventy-six affected patients were clinically studied. The SLC22A6 and ABCC2 genes were screened and compared with healthy people from the HapMap. Hypophosphatemia, high serum alkaline phosphatase (ALP) levels, hypouricemia, nondiabetic glycosuria, proteinuria, metabolic acidosis and high bone turnover markers were the main metabolic characteristics. Fractures and pseudofractures occurred in 39 patients. Stopping ADV administration, supplementing calcitriol and calcium was effective during the follow-up period. Single SNP analysis revealed a higher percentage of the G/A genotype at c.2934 in exon 22 of the ABCC2 gene (rs3740070) in patients than in healthy people (12% [7 of 58 patients] vs. 0% [0 of 45 patients]; P=0.017), while there was no subject with homozygosity for the A allele at c.2934. ADV can be nephrotoxic at a conventional dosage. The G/A genotype at c.2934 of the ABCC2 gene may be a predictor of patients at greater risk for developing ADV-associated tubulopathy. Larger case-control studies are needed to further verify this finding. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Editorial: dose-dependent ZnO particle-induced acute phase response in humans warrants re-evaluation of occupational exposure limits for metal oxides

    DEFF Research Database (Denmark)

    Vogel, Ulla Birgitte; Cassee, Flemming R.

    2018-01-01

    in autonomic imbalance and particle-induced pulmonary inflammation and acute phase response.The acute phase response is the systemic response to acute and chronic inflammatory states caused by for example bacterial infection, virus infection, trauma and infarction. It is characterized by differential...... studies and SAA has been causally related to the formation of plaques in the aorta in animal studies.In a recent paper in Particle and Fibre Toxicology, Christian Monse et al. provide evidence that inhalation of ZnO nanoparticles induces dose-dependent acute phase response in humans at dose levels well...

  7. Comparative studies of dose-response curves for recessive lethal mutations induced by ethylnitrosourea in spermatogonia and in spermatozoa of Drosophila melanogaster

    Energy Technology Data Exchange (ETDEWEB)

    Yoshikawa, I.; Ayaki, T.; Ohshima, K.

    1984-01-01

    Induction of recessive lethal mutation by N-ethyl-N-nitrosourea (ENU) was studied for the second chromosome of spermatogonia and spermatozoa in Drosophila melanogaster. ENU (0.03, 0.3, and 1.0 mM) was given to flies by dissolving it in feeding sucrose solution. When plotted against absorbed doses of ENU, the observed frequencies to recessive lethals showed a linear relationship for induction in spermatozoa but a sigmoidal relationship for induction in spermatogonia. These results suggest that in spermatogonia ENU-induced mutational damage is more repairable in a lower dose range of ENU. Mosaic lethal mutations were induced by ENU but not in spermatogonia.

  8. Histological alterations in the liver of rats induced by different gold nanoparticle sizes, doses and exposure duration

    Directory of Open Access Journals (Sweden)

    Abdelhalim Mohamed

    2012-01-01

    Full Text Available Abstract Background Nanoparticles (NPs can potentially cause adverse effects on organ, tissue, cellular, subcellular and protein levels due to their unusual physicochemical properties. Advances in nanotechnology have identified promising candidates for many biological and biomedical applications. Since the properties of NPs differ from that of their bulk materials, they are being increasingly exploited for medical uses and other industrial applications. The aim of the present study was to investigate the particle-size effect of gold nanoparticles (GNPs on the hepatic tissue in an attempt to cover and understand the toxicity and the potential threat of their therapeutic and diagnostic use. Methods To investigate particle-size effect of GNPs on the hepatic tissue, a total of 70 healthy male Wistar-Kyoto rats were exposed to GNPs received 50 or 100 ul of GNPs infusion of size (10, 20 and 50 nm for 3 or 7 days. Results In comparison with respective control rats, exposure to GNPs doses has produced alterations in the hepatocytes, portal triads and the sinusoids. The alterations in the hepatocytes were mainly summarized as hydropic degeneration, cloudy swelling, fatty degeneration, portal and lobular infiltrate by chronic inflammatory cells and congestive dilated central veins. Conclusions The induced histological alterations might be an indication of injured hepatocytes due to GNPs toxicity that became unable to deal with the accumulated residues resulting from metabolic and structural disturbances caused by these NPs. These alterations were size-dependent with smaller ones induced the most effects and related with time exposure of GNPs. The appearance of hepatocytes cytoplasmic degeneration and nuclear destruction may suggest that GNPs interact with proteins and enzymes of the hepatic tissue interfering with the antioxidant defense mechanism and leading to reactive oxygen species (ROS generation which in turn may induce stress in the hepatocytes to

  9. Genome-wide screen of DNA methylation changes induced by low dose X-ray radiation in mice.

    Directory of Open Access Journals (Sweden)

    Jingzi Wang

    Full Text Available Epigenetic mechanisms play a key role in non-targeted effects of radiation. The purpose of this study was to investigate global hypomethylation and promoter hypermethylation of particular genes induced by low dose radiation (LDR. Thirty male BALB/c mice were divided into 3 groups: control, acutely exposed (0.5 Gy X-rays, and chronic exposure for 10 days (0.05Gy/d×10d. High-performance liquid chromatography (HPLC and MeDIP-quantitative polymerase chain reaction (qPCR were used to study methylation profiles. DNMT1 and MBD2 expression was determined by qPCR and western blot assays. Methylation and expression of Rad23b and Ddit3 were determined by bisulfate sequencing primers (BSP and qPCR, respectively. The results show that LDR induced genomic hypomethylation in blood 2 h postirraditaion, but was not retained at 1-month. DNMT1 and MBD2 were downregulated in a tissue-specific manner but did not persist. Specific hypermethylation was observed for 811 regions in the group receiving chronic exposure, which covered almost all key biological processes as indicated by GO and KEGG pathway analysis. Eight hypermethylated genes (Rad23b, Tdg, Ccnd1, Ddit3, Llgl1, Rasl11a, Tbx2, Scl6a15 were verified by MeDIP-qPCR. Among them, Rad23b and Ddit3 gene displayed tissue-specific methylation and downregulation, which persisted for 1-month postirradiation. Thus, LDR induced global hypomethylation and tissue-specific promoter hypermethylation of particular genes. Promoter hypermethylation, rather than global hypomethylation, was relatively stable. Dysregulation of methylation might be correlated with down-regulation of DNMT1 and MBD2, but much better understanding the molecular mechanisms involved in this process will require further study.

  10. Characterization of a Mouse Model of Emphysema Induced by Multiple Instillations of Low-Dose Elastase

    Directory of Open Access Journals (Sweden)

    Milena V. Oliveira

    2016-10-01

    Full Text Available Many experimental models have been proposed to study the pathophysiological features of emphysema, as well as to search for new therapeutic approaches for acute or chronically injured lung parenchyma. We aimed to characterize an emphysema model induced by multiple instillations of elastase by tracking the changes in inflammation, remodeling, and cardiac function after each instillation. Forty-eight C57BL/6 mice were randomly assigned across 2 groups. Emphysema (ELA animals received 1, 2, 3, or 4 intratracheal instillations of pancreatic porcine elastase (PPE, 0.2 IU with a 1-week interval between them. Controls (C received saline following the same protocol. Before and after implementation of the protocol, animals underwent echocardiographic analysis. After the first instillation of PPE, the percentage of mononuclear cells in the lung parenchyma was increased compared to C (p = 0.0001. The second instillation resulted in hyperinflated alveoli, increased mean linear intercept, and reduced elastic fiber content in lung parenchyma compared to C (p=0.0197. Following the third instillation, neutrophils and collagen fiber content in alveolar septa and airways were increased, whereas static lung elastance was reduced compared to C (p=0.0094. After the fourth instillation, the percentage of M1 macrophages in lungs; levels of interleukin-1beta, keratinocyte-derived chemokine, hepatocyte growth factor, and vascular endothelial growth factor; and collagen fiber content in the pulmonary vessel wall were increased compared to C (p=0.0096. At this time point, pulmonary arterial hypertension was apparent, with increased diastolic right ventricular wall thickness. In conclusion, the initial phase of emphysema was characterized by lung inflammation with predominance of mononuclear cells, whereas at the late stage, impairment of pulmonary and cardiovascular functions was observed. This model enables analysis of therapies at different time points during controlled

  11. Lipid Emulsion Inhibits Vasodilation Induced by a Toxic Dose of Bupivacaine via Attenuated Dephosphorylation of Myosin Phosphatase Target Subunit 1 in Isolated Rat Aorta

    Science.gov (United States)

    Ok, Seong-Ho; Byon, Hyo-Jin; Kwon, Seong-Chun; Park, Jungchul; Lee, Youngju; Hwang, Yeran; Baik, Jiseok; Choi, Mun-Jeoung; Sohn, Ju-Tae

    2015-01-01

    Lipid emulsions are widely used for the treatment of systemic toxicity that arises from local anesthetics. The goal of this in vitro study was to examine the cellular mechanism associated with the lipid emulsion-mediated attenuation of vasodilation induced by a toxic dose of bupivacaine in isolated endothelium-denuded rat aorta. The effects of lipid emulsion on vasodilation induced by bupivacaine, mepivacaine, and verapamil were assessed in isolated aorta precontracted with phenylephrine, the Rho kinase stimulant NaF, and the protein kinase C activator phorbol 12,13-dibutyrate (PDBu). The effects of Rho kinase inhibitor Y-27632 on contraction induced by phenylephrine or NaF were assessed. The effects of bupivacaine on intracellular calcium concentrations ([Ca2+]i) and tension induced by NaF were simultaneously measured. The effects of bupivacaine alone and lipid emulsion plus bupivacaine on myosin phosphatase target subunit 1 (MYPT1) phosphorylation induced by NaF were examined in rat aortic vascular smooth muscle cells. In precontracted aorta, the lipid emulsion attenuated bupivacaine-induced vasodilation but had no effect on mepivacaine-induced vasodilation. Y-27632 attenuated contraction induced by either phenylephrine or NaF. The lipid emulsion attenuated verapamil-induced vasodilation. Compared with phenylephrine-induced precontracted aorta, bupivacaine-induced vasodilation was slightly attenuated in NaF-induced precontracted aorta. The magnitude of the bupivacaine-induced vasodilation was higher than that of a bupivacaine-induced decrease in [Ca2+]i. Bupivacaine attenuated NaF-induced MYPT1 phosphorylation, whereas lipid emulsion pretreatment attenuated the bupivacaine-induced inhibition of MYPT1 phosphorylation induced by NaF. Taken together, these results suggest that lipid emulsions attenuate bupivacaine-induced vasodilation via the attenuation of inhibition of MYPT1 phosphorylation evoked by NaF. PMID:26664257

  12. Failure of antimony trioxide to induce micronuclei or chromosomal aberrations in rat bone-marrow after sub-chronic oral dosing.

    Science.gov (United States)

    Kirkland, David; Whitwell, James; Deyo, James; Serex, Tessa

    2007-03-05

    Antimony trioxide (Sb2O3, CAS 1309-64-4) is widely used as a flame retardant synergist in a number of household products, as a fining agent in glass manufacture, and as a catalyst in the manufacture of various types of polyester plastics. It does not induce point mutations in bacteria or mammalian cells, but is able to induce chromosomal aberrations (CA) in cultured cells in vitro. Although no CA or micronuclei (MN) have been induced after acute oral dosing of mice, repeated oral dosing for 14 or 21 days resulted in increased CA in one report, but did not result in increased MN in another. In order to further investigate its in vivo genotoxicity, Sb2O3 was dosed orally to groups of rats for 21 days at 250, 500 and 1000 mg/kg day. There were no clinical signs of toxicity in the Sb2O3-exposed animals except for some reductions in body-weight gain in the top dose group. Toxicokinetic measurements in a separate study confirmed bone-marrow exposure, and at higher levels than would have been achieved by single oral dosing. Large numbers of cells were scored for CA (600 metaphases/sex group) and MN (12,000 PCE/sex group) but frequencies of CA or MN in Sb2O3-treated rats were very similar to controls, and not biologically or statistically different, at all doses. These results provide further indication that Sb2O3 is not genotoxic to the bone marrow of rodents after 21 days of oral administration at high doses close to the maximum tolerated dose.

  13. Hand-foot syndrome in a patient with metastatic lung adenocarcinoma induced by high-dose icotinib: A case report and review of the literature

    OpenAIRE

    ZHENG, YULONG; FANG, WEIJIA; XU, NONG

    2012-01-01

    Icotinib is a new oral epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI). The most frequent side-effects of icotinib include rash and diarrhea. Hand-foot syndrome (HFS) induced by EGFR-TKI is rare. The present study describes, for the first time, HFS induced by high-dose icotinib in a 65-year old female with metastatic lung adenocarcinoma. The patient developed HFS during the first week of icotinib treatment with characteristic clinical presentation. HFS regressed after icotinib do...

  14. Hypoxia-Inducible Factor Pathway Inhibition Resolves Tumor Hypoxia and Improves Local Tumor Control After Single-Dose Irradiation

    International Nuclear Information System (INIS)

    Helbig, Linda; Koi, Lydia; Brüchner, Kerstin; Gurtner, Kristin; Hess-Stumpp, Holger; Unterschemmann, Kerstin; Pruschy, Martin

    2014-01-01

    Purpose: To study the effects of BAY-84-7296, a novel orally bioavailable inhibitor of mitochondrial complex I and hypoxia-inducible factor 1 (HIF-1) activity, on hypoxia, microenvironment, and radiation response of tumors. Methods and Materials: UT-SCC-5 and UT-SCC-14 human squamous cell carcinomas were transplanted subcutaneously in nude mice. When tumors reached 4 mm in diameter BAY-84-7296 (Bayer Pharma AG) or carrier was daily administered to the animals. At 7 mm tumors were either excised for Western blot and immunohistologic investigations or were irradiated with single doses. After irradiation animals were randomized to receive BAY-84-7296 maintenance or carrier. Local tumor control was evaluated 150 days after irradiation, and the dose to control 50% of tumors (TCD 50 ) was calculated. Results: BAY-84-7296 decreased nuclear HIF-1α expression. Daily administration of inhibitor for approximately 2 weeks resulted in a marked decrease of pimonidazole hypoxic fraction in UT-SCC-5 (0.5% vs 21%, P 50 , with an enhancement ratio of 1.37 (95% confidence interval [CI] 1.13-1.72) in UT-SCC-5 and of 1.55 (95% CI 1.26-1.94) in UT-SCC-14. BAY-84-7296 maintenance after irradiation did not further decrease TCD 50 . Conclusions: BAY-84-7296 resulted in a marked decrease in tumor hypoxia and substantially reduced radioresistance of tumor cells with the capacity to cause a local recurrence after irradiation. The data suggest that reduction of cellular hypoxia tolerance by BAY-84-7296 may represent the primary biological mechanism underlying the observed enhancement of radiation response. Whether this mechanism contributes to the improved outcome of fractionated chemoradiation therapy warrants further investigation

  15. Protective/detoxicative function of metallothionein in the rat brain and blood induced by controlled cadmium doses

    Directory of Open Access Journals (Sweden)

    H. N. Shiyntum

    2015-09-01

    Full Text Available Cadmiumclassified as a major carcinogen is considered a poisonous and unwanted heavy metal to a lot of tissues in many organisms. Of many publications already available, the general consensus is that the cadmium attenuating element is metallothionein (MT through its interchangeable mechanism with Zn triggered by the presence of Cd, providing binding sites for Cd ions. MT was first discovered in the kidney cortex of the horse; it represents a low molecular weight protein, rich in cysteine residues which effectively bind with metals. Its functions consist in detoxification of heavy metals like mercury, arsenic, cadmium, homeostasis of essential metals including copper and zinc, anti-oxidation against reactive oxygen species, protection against DNA damage, oxidative stress, cell survival, angiogenesis, apoptosis, and increase of proliferation. In this work, we sought to highlight the protective function of MT in the brain and serum of rats by means of detoxification under induced effects of controlled Cd doses. We have done this by exposing Wistar rats to Cd at different doses in drinking water at different time intervals. In two independent experiments, 58 rats were subjected to 0.1 or 1.0 µg Cd2+/kg of body weight for 15 or 36 days under different conditions. The obtained data indicates the different functioning systems for the brain and the blood for MT metabolism under Cd effect. Our results indicate significant loss of metallothionein level in the brain and important increases in the amount of MT in serum proving that even minimal ingestion of toxic Cd is enough to trigger the release of MT protein in blood.

  16. Chronic low-dose γ-irradiation of Drosophila melanogaster larvae induces gene expression changes and enhances locomotive behavior

    International Nuclear Information System (INIS)

    Kim, Cha Soon; Lee, Byung Sub; Lee, In Kyung; Yang, Kwang Hee; Kim, Ji-Young; Nam, Seon Young; Seong, Ki Moon

    2015-01-01

    Although radiation effects have been extensively studied, the biological effects of low-dose radiation (LDR) are controversial. This study investigates LDR-induced alterations in locomotive behavior and gene expression profiles of Drosophila melanogaster. We measured locomotive behavior using larval pupation height and the rapid iterative negative geotaxis (RING) assay after exposure to 0.1 Gy γ-radiation (dose rate of 16.7 mGy/h). We also observed chronic LDR effects on development (pupation and eclosion rates) and longevity (life span). To identify chronic LDR effects on gene expression, we performed whole-genome expression analysis using gene-expression microarrays, and confirmed the results using quantitative real-time PCR. The pupation height of the LDR-treated group at the first larval instar was significantly higher (∼2-fold increase in PHI value, P < 0.05). The locomotive behavior of LDR-treated male flies (∼3 − 5 weeks of age) was significantly increased by 7.7%, 29% and 138%, respectively (P < 0.01), but pupation and eclosion rates and life spans were not significantly altered. Genome-wide expression analysis identified 344 genes that were differentially expressed in irradiated larvae compared with in control larvae. We identified several genes belonging to larval behavior functional groups such as locomotion (1.1%), oxidation reduction (8.0%), and genes involved in conventional functional groups modulated by irradiation such as defense response (4.9%), and sensory and perception (2.5%). Four candidate genes were confirmed as differentially expressed genes in irradiated larvae using qRT-PCR (>2-fold change). These data suggest that LDR stimulates locomotion-related genes, and these genes can be used as potential markers for LDR. (author)

  17. Adaptive Response to ionizing Radiation Induced by Low Doses of Gamma Rays in Human Lymphoblastoid Cell Lines

    International Nuclear Information System (INIS)

    Seong, Jin Sil; Suh, Chang Ok; Kim, Gwi Eon

    1994-01-01

    When cells are exposed to low doses of a mutagenic or clastogenic agents, they often become less sensitive to the effects of a higher does administered subsequently. Such adaptive responses were first described in Escherichia coli and mammalian cells to low doses of an alkylating agent. Since most of the studies have been carried out with human lymphocytes, it is urgently necessary to study this effect in different cellular systems. Its relation with inherent cellular radiosensitivity and underlying mechanism also remain to be answered. In this study, adaptive response by 1 cGy of gamma rays was investigated in three human lymphoblastoid cell lines which were derived from ataxia telangiectasia homozygote, ataxia telangiectasia heterozygote, and normal individual. Experiments were carried out by delivering 1 cGy followed by 50 cGy of gamma radiation and chromatid breaks were scored as an endpoint. The results indicate that prior exposure to 1 cGy of gamma rays reduces the number of chromatid breaks induced by subsequent higher does (50 cGy). The expression of this adaptive response was similar among three cell lines despite of their different radiosensitivity. When 3-aminobenzamide, an inhibitor of poly (ADP-ribose) polymerase, was added after 50 cGy, adaptive responses were abolished in all the tested cell lines. Therefore it is suggested that the adaptive response can be observed in human lymphoblastoid cell lines. Which was first documented through this study. The expression of adaptive response was similar among the cell lines regardless of their radiosensitivity. The elimination of the adaptive response by 3-aminobenzamide is consistent with the proposal that this adaptive response is the result of the induction of a certain chromosomal repair mechanism

  18. Hypophosphatemic osteomalacia induced by low-dose adefovir therapy: focus on manifestations in the skeletal system and literature review.

    Science.gov (United States)

    Kim, Du Hwan; Sung, Duk Hyun; Min, Yong Ki

    2013-03-01

    Osteomalacia is a metabolic bone disease that leads to softening of the bones and can be caused by hypophosphatemia. Large clinical studies of low-dose adefovir dipivoxil (adefovir) have found no evidence of renal tubular dysfunction leading to hypophosphatemia after 48 weeks of treatment. We report two cases of low-dose adefovir-induced hypophosphatemic osteomalacia that initially presented with diffuse musculoskeletal pain. The first patient was a 62-year-old man with a 2-year history of bone pain involving the dorsal mid-thorax, lower anterior chest wall, right sacroiliac joint area, and both knees. The patient had been receiving adefovir for 5 years before confirmation of hypophosphatemia and urinary phosphate wasting. Bone scintigraphy revealed multifocal lesions including multiple ribs, costochondral junctions, costovertebral junctions, sacrum, both posterior iliac bones, both proximal tibia, right calcaneus, and the left second metatarsophalangeal joint area, which were suggestive of metabolic bone disorder. Bone pain was significantly reduced within 3 months after supplementation with phosphate and calcitriol. The second patient was a 54-year-old male who presented with an 18-month history of severe bone pain of the right medial knee and low back. The patient had been taking adefovir for approximately 40 months before the development of bone pain. Laboratory data revealed hypophosphatemia and vitamin D deficiency. Bone scintigraphy showed increased uptake in bilateral ribs, sternum, both scapulae, both costovertebral junctions, both pelvic bones, medial cortex of the right proximal femur, right proximal tibia, and the left lateral tarsal bone. The symptoms improved by changing the antiviral agent from adefovir to entecavir. Because osteomalacia often presents with diffuse bone pain, non-specific radiologic findings and non-characteristic routine serum biochemical changes, the disease can be confused with various musculoskeletal diseases and a high index

  19. Neuroprotection and mechanisms of atractylenolide III in preventing learning and memory impairment induced by chronic high-dose homocysteine administration in rats.

    Science.gov (United States)

    Zhao, H; Ji, Z-H; Liu, C; Yu, X-Y

    2015-04-02

    Studies demonstrated that chronic high-dose homocysteine administration induced learning and memory impairment in animals. Atractylenolide III (Aen-III), a neuroprotective constituent of Atractylodis macrocephalae Koidz, was isolated in our previous study. In this study, we investigated potential benefits of Aen-III in preventing learning and memory impairment following chronic high-dose homocysteine administration in rats. Results showed that administration of Aen-III significantly ameliorated learning and memory impairment induced by chronic high-dose homocysteine administration in rats, decreased homocysteine-induced reactive oxygen species (ROS) formation and restored homocysteine-induced decrease of phosphorylated protein kinase C expression level. Moreover, Aen-III protected primary cultured neurons from apoptotic death induced by homocysteine treatment. This study provides the first evidence for the neuroprotective effect of Aen-III in preventing learning and impairment induced by chronic administration of homocysteine. Aen-III may have therapeutic potential in treating homocysteine-mediated cognitive impairment and neuronal injury. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  20. The Effect of Nicotine Administration on Physical and Psychological Signs of Withdrawal Syndrome Induced by Single or Frequent Doses of Morphine in Rats

    Directory of Open Access Journals (Sweden)

    Mohammad Allahtavakoli

    2012-07-01

    Full Text Available Introduction. Morphine addiction and morphine withdrawal syndrome are the two main problems of today’s human society. The present study has investigated the effects of nicotine on the strength of physical and psychological dependency in single and repeated doses morphine administrated rats. Materials and methods. Male Wistar rats were subjected to morphine consumption with single or frequent dose protocols. In the single dose protocol, rats received only one dose of morphine and 24hrs later they also received one dose of nicotine 30 min prior to injection of naloxone. In the repeated dose protocol, rats received incremental doses of morphine for 7 days and 24hr after the last dose (the 8th day were given naloxone. However, the nicotine regimen of this group was injected 15 min before the morphine injection, for 4 days, from the 4th to the 7th day. Five minutes after naloxone injection, each rat′s behavior was captured for 30 min, and then physical and psychological signs of withdrawal syndrome were recorded. Data were analyzed by ANOVA followed by Tukey tests and p<0.05 was considered as significant difference. Findings. Results showed that the injection of frequent and single doses of morphine lead to morphine dependency. In single dose protocol, nicotine consumption attenuated the signs of withdrawal syndrome, especially weight of excrement and total withdrawal score. In frequent dose protocol, in addition to these effects, nicotine induced weight loss and place aversion. Conclusion. The inhibitory effects of nicotine on signs of withdrawal syndrome may involve a dopaminergic portion of the central nervous system and is mediated by central nicotinic receptors. There is also a cross-dependence between nicotine and morphine.

  1. ‌‌The effect of nicotine administration on physical and psychological signs of withdrawal syndrome induced by single or frequent doses of morphine in rats

    Directory of Open Access Journals (Sweden)

    Ali Shamsizadeh

    2012-07-01

    Full Text Available Introduction: Morphine addiction and morphine withdrawal syndrome are the two main problems of today’s human society. The present study has investigated the effects of nicotine on the strength of physical and psychological dependency in single and repeated doses morphine administrated rats. Methods: Male Wistar rats were subjected to morphine consumption with single or frequent dose protocols. In the single dose protocol, rats received only one dose of morphine and 24hrs later they also received one dose of nicotine 30 min prior to injection of naloxone. In the repeated dose protocol, rats received incremental doses of morphine for 7 days and 24hr after the last dose (the 8th day were given naloxone. However, the nicotine regimen of this group was injected 15 min before the morphine injection, for 4 days, from the 4th to the 7th day. Five minutes after naloxone injection, each rat′s behavior was captured for 30 min, and then physical and psychological signs of withdrawal syndrome were recorded. Data were analyzed by ANOVA followed by Tukey tests and p<0.05 was considered as significant difference. Results: Results showed that the injection of frequent and single doses of morphine lead to morphine dependency. In single dose protocol, nicotine consumption attenuated the signs of withdrawal syndrome, especially weight of excrement and total withdrawal score. In frequent dose protocol, in addition to these effects, nicotine induced weight loss and place aversion. Discussion: The inhibitory effects of nicotine on signs of withdrawal syndrome may involve a dopaminergic portion of the central nervous system and is mediated by central nicotinic receptors. There is also a cross-dependence between nicotine and morphine.

  2. Hypoxia-Inducible Factor Pathway Inhibition Resolves Tumor Hypoxia and Improves Local Tumor Control After Single-Dose Irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Helbig, Linda [OncoRay–National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden (Germany); Department of Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden (Germany); Koi, Lydia [OncoRay–National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden (Germany); Department of Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden (Germany); Deutsches Konsortium für Translationale Krebsforschung, Site Dresden, Dresden (Germany); Brüchner, Kerstin [Department of Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden (Germany); Institute of Radiooncology Helmholtz-Zentrum Dresden-Rossendorf, Dresden (Germany); Gurtner, Kristin [Department of Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden (Germany); Hess-Stumpp, Holger; Unterschemmann, Kerstin [Global Drug Discovery, Bayer Pharma, Berlin (Germany); Pruschy, Martin [Radiation Oncology, University of Zurich, Zurich (Switzerland); and others

    2014-01-01

    Purpose: To study the effects of BAY-84-7296, a novel orally bioavailable inhibitor of mitochondrial complex I and hypoxia-inducible factor 1 (HIF-1) activity, on hypoxia, microenvironment, and radiation response of tumors. Methods and Materials: UT-SCC-5 and UT-SCC-14 human squamous cell carcinomas were transplanted subcutaneously in nude mice. When tumors reached 4 mm in diameter BAY-84-7296 (Bayer Pharma AG) or carrier was daily administered to the animals. At 7 mm tumors were either excised for Western blot and immunohistologic investigations or were irradiated with single doses. After irradiation animals were randomized to receive BAY-84-7296 maintenance or carrier. Local tumor control was evaluated 150 days after irradiation, and the dose to control 50% of tumors (TCD{sub 50}) was calculated. Results: BAY-84-7296 decreased nuclear HIF-1α expression. Daily administration of inhibitor for approximately 2 weeks resulted in a marked decrease of pimonidazole hypoxic fraction in UT-SCC-5 (0.5% vs 21%, P<.0001) and in UT-SCC-14 (0.3% vs 19%, P<.0001). This decrease was accompanied by a significant increase in fraction of perfused vessels in UT-SCC-14 but not in UT-SCC-5. Bromodeoxyuridine and Ki67 labeling indices were significantly reduced only in UT-SCC-5. No significant changes were observed in vascular area or necrosis. BAY-84-7296 before single-dose irradiation significantly decreased TCD{sub 50}, with an enhancement ratio of 1.37 (95% confidence interval [CI] 1.13-1.72) in UT-SCC-5 and of 1.55 (95% CI 1.26-1.94) in UT-SCC-14. BAY-84-7296 maintenance after irradiation did not further decrease TCD{sub 50}. Conclusions: BAY-84-7296 resulted in a marked decrease in tumor hypoxia and substantially reduced radioresistance of tumor cells with the capacity to cause a local recurrence after irradiation. The data suggest that reduction of cellular hypoxia tolerance by BAY-84-7296 may represent the primary biological mechanism underlying the observed enhancement of

  3. A Locomotor Deficit Induced by Sublethal Doses of Pyrethroid and Neonicotinoid Insecticides in the Honeybee Apis mellifera.

    Science.gov (United States)

    Charreton, Mercédès; Decourtye, Axel; Henry, Mickaël; Rodet, Guy; Sandoz, Jean-Christophe; Charnet, Pierre; Collet, Claude

    2015-01-01

    The toxicity of pesticides used in agriculture towards non-targeted organisms and especially pollinators has recently drawn the attention from a broad scientific community. Increased honeybee mortality observed worldwide certainly contributes to this interest. The potential role of several neurotoxic insecticides in triggering or potentiating honeybee mortality was considered, in particular phenylpyrazoles and neonicotinoids, given that they are widely used and highly toxic for insects. Along with their ability to kill insects at lethal doses, they can compromise survival at sublethal doses by producing subtle deleterious effects. In this study, we compared the bee's locomotor ability, which is crucial for many tasks within the hive (e.g. cleaning brood cells, feeding larvae…), before and after an acute sublethal exposure to one insecticide belonging to the two insecticide classes, fipronil and thiamethoxam. Additionally, we examined the locomotor ability after exposure to pyrethroids, an older chemical insecticide class still widely used and known to be highly toxic to bees as well. Our study focused on young bees (day 1 after emergence) since (i) few studies are available on locomotion at this stage and (ii) in recent years, pesticides have been reported to accumulate in different hive matrices, where young bees undergo their early development. At sublethal doses (SLD48h, i.e. causing no mortality at 48 h), three pyrethroids, namely cypermethrin (2.5 ng/bee), tetramethrin (70 ng/bee), tau-fluvalinate (33 ng/bee) and the neonicotinoid thiamethoxam (3.8 ng/bee) caused a locomotor deficit in honeybees. While the SLD48h of fipronil (a phenylpyrazole, 0.5 ng/bee) had no measurable effect on locomotion, we observed high mortality several days after exposure, an effect that was not observed with the other insecticides. Although locomotor deficits observed in the sublethal range of pyrethroids and thiamethoxam would suggest deleterious effects in the field, the case of

  4. A Locomotor Deficit Induced by Sublethal Doses of Pyrethroid and Neonicotinoid Insecticides in the Honeybee Apis mellifera.

    Directory of Open Access Journals (Sweden)

    Mercédès Charreton

    Full Text Available The toxicity of pesticides used in agriculture towards non-targeted organisms and especially pollinators has recently drawn the attention from a broad scientific community. Increased honeybee mortality observed worldwide certainly contributes to this interest. The potential role of several neurotoxic insecticides in triggering or potentiating honeybee mortality was considered, in particular phenylpyrazoles and neonicotinoids, given that they are widely used and highly toxic for insects. Along with their ability to kill insects at lethal doses, they can compromise survival at sublethal doses by producing subtle deleterious effects. In this study, we compared the bee's locomotor ability, which is crucial for many tasks within the hive (e.g. cleaning brood cells, feeding larvae…, before and after an acute sublethal exposure to one insecticide belonging to the two insecticide classes, fipronil and thiamethoxam. Additionally, we examined the locomotor ability after exposure to pyrethroids, an older chemical insecticide class still widely used and known to be highly toxic to bees as well. Our study focused on young bees (day 1 after emergence since (i few studies are available on locomotion at this stage and (ii in recent years, pesticides have been reported to accumulate in different hive matrices, where young bees undergo their early development. At sublethal doses (SLD48h, i.e. causing no mortality at 48 h, three pyrethroids, namely cypermethrin (2.5 ng/bee, tetramethrin (70 ng/bee, tau-fluvalinate (33 ng/bee and the neonicotinoid thiamethoxam (3.8 ng/bee caused a locomotor deficit in honeybees. While the SLD48h of fipronil (a phenylpyrazole, 0.5 ng/bee had no measurable effect on locomotion, we observed high mortality several days after exposure, an effect that was not observed with the other insecticides. Although locomotor deficits observed in the sublethal range of pyrethroids and thiamethoxam would suggest deleterious effects in the field

  5. In an animal model nephrogenic systemic fibrosis cannot be induced by intraperitoneal injection of high-dose gadolinium based contrast agents

    International Nuclear Information System (INIS)

    Langer, R.D.; Lorke, D.E.; Neidl van Gorkom, K.F.; Petroianu, G.; Azimullah, S.; Nurulain, S.M.; Singh, S.; Fuchsjäger, M.

    2012-01-01

    Aim and objective: Nephrogenic systemic fibrosis (NSF) has been reported in humans to be most likely induced by gadolinium based contrast agents (GBCA), namely by gadodiamide, gadopentetate dimeglumine, and gadoversetamide, rarely by other GBCA. The pathogenesis of NSF remains unclear; different hypotheses are under discussion. The objective of the study is to assess if in the animal model human-like NSF changes can be induced by high-dose, intraperitoneal GBCA injections over four weeks. Materials and methods: After approval by the institutional animal ethics committee, six rats each were randomly assigned to groups, and treated with seven different GBCA. Intraperitoneal (IP) injections – proven in the animal model to be effective – were chosen to prolong the animals’ exposure to the respective GBCA. GBCA doses of previous intravenous (IV) animal studies were applied. After five weeks all rats were sacrificed. Sham controls were treated with IP saline injections, employing the same regimen. Results: No findings comparable with human NSF were observed in all animals after IP treatment with all seven GBCA at daily doses of 2.5 and 5.0 mmol/kg body weight (BW). No histopathological abnormalities of all examined organs were noted. Weight loss was stated in weeks three and four with GBCA injections at doses of 5.0 mmol/kg BW, but rats regained weight after cessation of GBCA treatment. Conclusions: NSF-comparable pathological findings could not be induced by high dose intraperitoneal injection of seven GBCA

  6. In an animal model nephrogenic systemic fibrosis cannot be induced by intraperitoneal injection of high-dose gadolinium based contrast agents

    Energy Technology Data Exchange (ETDEWEB)

    Langer, R.D., E-mail: rlanger@uaeu.ac.ae [Faculty of Medicine and Health Sciences (FMHS), United Arab Emirates University, Al Ain (United Arab Emirates); Lorke, D.E. [Florida International University, Miami, FL (United States); Neidl van Gorkom, K.F. [Faculty of Medicine and Health Sciences (FMHS), United Arab Emirates University, Al Ain (United Arab Emirates); Petroianu, G. [Florida International University, Miami, FL (United States); Azimullah, S.; Nurulain, S.M.; Singh, S. [Faculty of Medicine and Health Sciences (FMHS), United Arab Emirates University, Al Ain (United Arab Emirates); Fuchsjäger, M. [Al Ain Hospital, MUV-VAMED, Al Ain (United Arab Emirates)

    2012-10-15

    Aim and objective: Nephrogenic systemic fibrosis (NSF) has been reported in humans to be most likely induced by gadolinium based contrast agents (GBCA), namely by gadodiamide, gadopentetate dimeglumine, and gadoversetamide, rarely by other GBCA. The pathogenesis of NSF remains unclear; different hypotheses are under discussion. The objective of the study is to assess if in the animal model human-like NSF changes can be induced by high-dose, intraperitoneal GBCA injections over four weeks. Materials and methods: After approval by the institutional animal ethics committee, six rats each were randomly assigned to groups, and treated with seven different GBCA. Intraperitoneal (IP) injections – proven in the animal model to be effective – were chosen to prolong the animals’ exposure to the respective GBCA. GBCA doses of previous intravenous (IV) animal studies were applied. After five weeks all rats were sacrificed. Sham controls were treated with IP saline injections, employing the same regimen. Results: No findings comparable with human NSF were observed in all animals after IP treatment with all seven GBCA at daily doses of 2.5 and 5.0 mmol/kg body weight (BW). No histopathological abnormalities of all examined organs were noted. Weight loss was stated in weeks three and four with GBCA injections at doses of 5.0 mmol/kg BW, but rats regained weight after cessation of GBCA treatment. Conclusions: NSF-comparable pathological findings could not be induced by high dose intraperitoneal injection of seven GBCA.

  7. Correlation between γ-ray-induced DNA double-strand breakage and cell killing after biologically relevant doses: analysis by pulsed-field gel electrophoresis

    International Nuclear Information System (INIS)

    Murray, D.

    1994-01-01

    We examined the degree of correlation between γ-ray-induced lethality and DNA double-strand breaks (dsbs) after biologically relevant doses of radiation. Radiation lethality was modified by treating 14 C-labelled Chinese hamster ovary cells with either of two aminothiols (WR-1065 or WR-255591) and the associated effect on dsb induction was determined by pulsed-field gel electrophoresis (PFGE). The use of phosphorimaging to analyse the distribution of 14 C-activity in the gel greatly improved the low-dose resolution of the PFGE assay. Both WR-1065 and WR-255591 protected against dsb induction and lethality to a similar extent after low doses of radiation. although this correlation broke down when supralethal doses were used to induce dsbs. Thus, the level of dsbs induced in these cells as measured by PFGE after survival-curve doses of γ-radiation is consistently predictive of the degree of lethality obtained, implying a cause-effect relationship between these two parameters and confirming previous results obtained using the neutral filter elution assay for dsbs. (author)

  8. Low-Dose Radiation Induces Cell Proliferation in Human Embryonic Lung Fibroblasts but not in Lung Cancer Cells

    Directory of Open Access Journals (Sweden)

    Xinyue Liang

    2016-01-01

    Full Text Available Hormesis and adaptive responses are 2 important biological effects of low-dose ionizing radiation (LDR. In normal tissue, LDR induces hormesis as evinced by increased cell proliferation; however, whether LDR also increases tumor cell proliferation needs to be investigated. In this study, cell proliferation was assayed by total cell numbers and the Cell Counting Kit 8 assay. Mitogen-activated protein kinases (MAPK/extracellular signal-regulated kinase (ERK and phosphatidylinositol 3′ -kinase(PI3K-Akt (PI3K/AKT phosphorylation were determined by Western blot analysis. Human embryonic lung fibroblast 2BS and lung cancer NCI-H446 cell lines were irradiated with LDR at different doses (20-100 mGy. In response to 20 to 75 mGy X-rays, cell proliferation was significantly increased in 2BS but not in NCI-H446 cells. In 2BS cells, LDR at 20 to 75 mGy also stimulated phosphorylation of MAPK/ERK pathway proteins including ERK, MEK, and Raf and of the PI3K/AKT pathway protein AKT. To test whether ERK1/2 and AKT pathway activation was involved in the stimulation of cell proliferation in 2BS cells, the MAPK/ERK and PI3K/AKT pathways were inhibited using their specific inhibitors, U0126 and LY294002. U0126 decreased the phosphorylation of ERK1/2, and LY294002 decreased the phosphorylation of AKT; each could significantly inhibit LDR-induced 2BS cell proliferation. However, LDR did not stimulate these kinases, and kinase inhibitors also did not affect cell proliferation in the NCI-H446 cells. These results suggest that LDR stimulates cell proliferation via the activation of both MAPK/ERK and PI3K/AKT signaling pathways in 2BS but not in NCI-H446 cells. This finding implies the potential for applying LDR to protect normal tissues from radiotherapy without diminishing the efficacy of tumor therapy.

  9. High-dose metoclopramide + lorazepam versus low-dose metoclopramide + lorazepam + dehydrobenzperidol in the treatment of cisplatin-induced nausea and vomiting

    DEFF Research Database (Denmark)

    Herrstedt, Jørn; Hannibal, J; Hallas, Jesper

    1991-01-01

    In a randomized double-blind, cross-over trial of 34 patients receiving cisplatin-based chemotherapy (20-100 mg/m2), the antiemetic effect of high-dose metoclopramide (HDM) (10 mg/kg iv. loading dose + 7 hours continuous infusion) + lorazepam (L) (2.5 mg x 4 po) was compared with low......-dose metoclopramide (LDM) (70 mg) + L (2.5 mg x 2 po) + dehydrobenzperidol (5 mg x 2 im). Among the 29 patients who completed the cross-over, HDM significantly reduced the number of vomiting episodes (p = 0.002) and the degree of nausea (p = 0.004). Seventeen patients preferred the HDM and 4 the LDM regimen (p = 0.......01). Sedation was seen in all but 1 patient, and was graded as severe in 6 patients receiving the HDM and in 2 patients receiving the LDM regimen. No extrapyramidal adverse reactions were seen. We conclude that high-dose metoclopramide + lorazepam is a safe antiemetic regimen and significantly superior to low...

  10. High-dose stabilized chlorite matrix WF10 prolongs cardiac xenograft survival in the hamster-to-rat model without inducing ultrastructural or biochemical signs of cardiotoxicity

    DEFF Research Database (Denmark)

    Hansen, A; Kemp, K; Kemp, E

    2001-01-01

    of high dose WF10 as a single drug regimen in the hamster-to-rat xenotransplantation model and searched for possible cardiotoxic side effects. WF10 prolonged cardiac xenograft survival, but did not induce tolerence or inhibit pathological signs of acute rejection. Hamsters from the donor population...

  11. A randomized, dose-response study of sugammadex given for the reversal of deep rocuronium- or vecuronium-induced neuromuscular blockade under sevoflurane anesthesia

    DEFF Research Database (Denmark)

    Duvaldestin, Philippe; Kuizenga, Karel; Saldien, Vera

    2010-01-01

    Sugammadex is the first of a new class of selective muscle relaxant binding drugs developed for the rapid and complete reversal of neuromuscular blockade induced by rocuronium and vecuronium. Many studies have demonstrated a dose-response relationship with sugammadex for reversal of neuromuscular...

  12. Number and ultrastructure of CD4+ cells (Helpe/inducers) in the blood of patients subjected to low doses of irradiation after Chernobylsk accident

    International Nuclear Information System (INIS)

    Komissarenko, S.V.; Zak, K.P.; Khomenko, B.M.; Karlova, N.P.; Lukinov, D.I.; Semionova, T.A.; Chernyak, S.I.

    1991-01-01

    Chromic low dose irradiation (up to 25 ber) resulted in no statistically reliable changes of CD4 + -lymphocyte content in the blood of healthy people and induced violation of ratio of morphologically various types of CD4 + -cells and their submicroscopic organization. Thus breakage of subpopulation composition within the T-cell class and their functions was stated

  13. No indications of an enhanced UV-light-induced unscheduled DNA synthesis in splenocytes of mice following a low-dose irradiation in vivo or in vitro

    International Nuclear Information System (INIS)

    Wojcik, A.; Seemayer, C.A.; Mueller, W.U.; Streffer, C.

    1995-01-01

    One of the open questions regarding the adaptive response to ionizing radiation is whether it can be induced in G 0 lymphocytes. In the majority of experiments in which an adaptive response in G 0 lymphocytes was observed, the adapting dose was applied in vivo. In order to investigate whether there is some in vivo component of adaptive response, mouse splenocytes of the C57BL/6 strain were irradiated with 0.1 Gy x-rays either in vivo or in vitro, and their UV-light-induced unscheduled DNA synthesis (UDS) levels were determined autoradiographically. An augmented UV-light-induced UDS following an adapting dose applied in vivo has previously been described by several authors in splenocytes of C57BL/6 mice, indicating that the adapting dose enhanced the DNA repair capacity of lymphocytes. In the present investigation, however, no evidence of an adaptive response could be seen regardless of whether the adapting dose was given in vivo or in vitro. Those results present a further indication for the fact that the adaptive response to ionizing radiation is not always inducible, even in lymphocytes of an inbred mouse strain in which its existence has been reported before. (orig.)

  14. Short term high dose atorvastatin for the prevention of contrast-induced nephropathy in patients undergoing computed tomography angiography

    Directory of Open Access Journals (Sweden)

    Hamid Sanei

    2014-09-01

    Full Text Available BACKGROUND: Statins are shown effective by some studies in preventing contrast-induced nephropathy (CIN. We evaluated the effectiveness of atorvastatin in the prevention of CIN in computed tomography angiography (CTA candidates. METHODS: This study was conducted on patients referring for elective CTA with normal renal function. Patients received atorvastatin (80 mg/day or placebo from 24 h before to 48 h after administration of the contrast material. Serum creatinine was measured before and 48 h after contrast material injection. CIN was defined as an increase in serum creatinine level of ≥ 0.5 mg/dl or ≥ 25% of the baseline creatinine. RESULTS: A total of 236 patients completed the study; 115 atorvastatin, 121 placebo, mean age = 58.40 ± 9.80 year, 68.6% male. Serum creatinine increased after contrast material injection in both the atorvastatin (1.00 ± 0.16-1.02 ± 0.15 mg/dl, P = 0.017 and placebo groups (1.03 ± 0.17-1.08 ± 0.18 mg/dl, P < 0.001. Controlling for age, gender, comorbidities, drug history, and baseline serum creatinine level, patients who received atorvastatin experienced less increase in serum creatinine after contrast material injection (beta = 0.127, P = 0.034. However, there was no difference between the atorvastatin and placebo groups in the incidence of CIN (4.3 vs. 5.0%, P = 0.535. CONCLUSION: In patients undergoing CTA, a short-term treatment with high dose atorvastatin is effective in preventing contrast-induced renal dysfunction, in terms of less increase in serum creatinine level after contrast material injection. Further trials including larger sample of patients and longer follow-ups are warranted.   Keywords: Kidney Diseases, Multidetector Computed Tomography, Contrast Media, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Atorvastatin 

  15. Low-dose Norfloxacin-treated leptospires induce less IL-1β release in J774A.1 cells following discrepant leptospiral gene expression.

    Science.gov (United States)

    Cao, Yongguo; Xie, Xufeng; Zhang, Wenlong; Wu, Dianjun; Tu, Changchun

    2018-06-01

    Currently, accumulating evidence is challenging subtherapeutic therapy. Low-dose Norfloxacin (Nor) has been reported to suppress the immune response and worsen leptospirosis. In this study, we investigated the influence of low-dose Nor (0.03 μg/ml, 0.06 μg/ml, 0.125 μg/ml) on leptospiral gene expression and analyzed the immunomodulatory effects of low-dose Nor-treated leptospires in J774A.1 cells. To study the expression profiles of low-dose Nor-treated leptospires, we chose LipL71/LipL21 as reference genes determined by the geNorm applet in this experiment. The results showed that low-dose Nor up-regulated the expression of FlaB and inhibited the expression of 16S rRNA, LipL32, LipL41, Loa22, KdpA, and KdpB compared with the untreated leptospires. These results indicated that low-dose Nor could regulate leptospiral gene expression. Using RT-PCR, the gene expression of IL-1β and TNF-α in J774A.1 cells was detected. Nor-treated leptospires induced higher expression levels of both IL-1β and TNF-α. However, when analyzed by ELISA, the release of mature IL-1β was reduced compared with that observed in cells induced with no Nor-treated leptospires, although the TNF-α protein level showed no significant change. Our study indicated that the gene expression of leptospires could be modulated by low-dose Nor, which induced less IL-1β release in J774A.1 cells. Copyright © 2018 Elsevier Ltd. All rights reserved.

  16. Different dose-dependent effects of hydrogen sulfide on ischemia-reperfusion induced acute kidney injury in rats

    Directory of Open Access Journals (Sweden)

    Fateme Azizi

    2017-12-01

    Conclusion: Our study demonstrates that different doses of Sodium hydrosulfide (NaHS can play diverse role in renal ischemia reperfusion injury. However, NaHS in the low-doses could protect the kidney from the RIR injury, in a higher dose NaHS exaggerated the renal function by increases plasma creatinine and BUN. Therefore, determining of the therapeutic doses of NaHS may be important in the protection of kidney from the RIR injury.

  17. Radiation-chemical discussion on inverse dose-rate effect observed in radiation-induced strand breaks of plasmid DNA

    International Nuclear Information System (INIS)

    Masuda, Takahiro

    1994-01-01

    Experimental results of inverse dose-rate effect, so-called Kada Effects, which was published by Takakura and her coworkers on radiation-induced strand breaks of plasmid DNA in aerated aqueous solution, have been kinetically analyzed and discussed on the basis of radiation chemistry. the kinetic analysis indicates that there are two possible mechanisms; 1) equilibrium mixture of O 2 - and HO 2 is responsible for strand breaks of DNA, and 2) peroxyl radical produced from citrate is effective for the strand breaks. However, the detailed kinetic analysis revealed that the latter is improbable because unimolecular decay of the peroxyl radical must be assumed to be negligible for its participation despite fast decay of analogous organic peroxyl radicals. The analysis has also given 9.93±0.10 dm 3 mol -1 s -1 per nucleotide unit, which corresponds to 7.62 x 10 4 dm 3 mol -1 s -1 per DNA molecule, as the rate constant for the reaction of the equilibrium mixture with plasmid pBR 322 DNA. Furthermore the probability that the reaction of the mixture with a nucleotide unit of DNA leads to strand breaks was obtained to be 3.36 x 10 -3 for gamma-irradiated system and 1.98 x 10 -3 for beta-irradiated system, respectively. (author)

  18. The dose, temperature, and projectile-mass dependence for irradiation-induced amorphization of CuTi

    International Nuclear Information System (INIS)

    Koike, J.; Okamoto, P.R.; Rehn, L.E.; Meshii, M.

    1989-01-01

    CuTi was irradiated with 1-MeV Ne + , Kr + , and Xe + in the temperature range from 150 to 563 K. The volume fraction of the amorphous phase produced during room temperature irradiation with Ne + and Kr + ions was determined as a function of ion dose from measurements of the integrated intensity of the diffuse ring in electron diffraction patterns. The results, analyzed by Gibbons' model, indicate that direct amorphization occurs along a single ion track with Kr + , but the overlapping of three ion tracks is necessary for amorphization with Ne + . The critical temperature for amorphization increases with increasing projectile mass from electron to Ne + to Kr + . However, the critical temperatures for Kr + and Xe + irradiations were found to be identical, and very close to the thermal crystallization temperature of an amorphous zone embedded in the crystalline matrix. Using the present observations, relationships between the amorphization kinetics and the displacement density along the ion track, and between the critical temperature and the stability of the irradiation-induced damage, are discussed

  19. Visualizing and quantifying dose distribution in a UV reactor using three-dimensional laser-induced fluorescence.

    Science.gov (United States)

    Gandhi, Varun N; Roberts, Philip J W; Kim, Jae-Hong

    2012-12-18

    Evaluating the performance of typical water treatment UV reactors is challenging due to the complexity in assessing spatial and temporal variation of UV fluence, resulting from highly unsteady, turbulent nature of flow and variation in UV intensity. In this study, three-dimensional laser-induced fluorescence (3DLIF) was applied to visualize and quantitatively analyze a lab-scale UV reactor consisting of one lamp sleeve placed perpendicular to flow. Mapping the spatial and temporal fluence delivery and MS2 inactivation revealed the highest local fluence in the wake zone due to longer residence time and higher UV exposure, while the lowest local fluence occurred in a region near the walls due to short-circuiting flow and lower UV fluence rate. Comparing the tracer based decomposition between hydrodynamics and IT revealed similar coherent structures showing the dependency of fluence delivery on the reactor flow. The location of tracer injection, varying the height and upstream distance from the lamp center, was found to significantly affect the UV fluence received by the tracer. A Lagrangian-based analysis was also employed to predict the fluence along specific paths of travel, which agreed with the experiments. The 3DLIF technique developed in this study provides new insight on dose delivery that fluctuates both spatially and temporally and is expected to aid design and optimization of UV reactors as well as validate computational fluid dynamics models that are widely used to simulate UV reactor performances.

  20. Radiation dose rate affects the radiosensitization of MCF-7 and HeLa cell lines to X-rays induced by dextran-coated iron oxide nanoparticles.

    Science.gov (United States)

    Khoshgard, Karim; Kiani, Parvaneh; Haghparast, Abbas; Hosseinzadeh, Leila; Eivazi, Mohammad Taghi

    2017-08-01

    The aim of radiotherapy is to deliver lethal damage to cancerous tissue while preserving adjacent normal tissues. Radiation absorbed dose of the tumoral cells can increase when high atomic nanoparticles are present in them during irradiation. Also, the dose rate is an important aspect in radiation effects that determines the biological results of a given dose. This in vitro study investigated the dose-rate effect on the induced radiosensitivity by dextran-coated iron oxide in cancer cells. HeLa and MCF-7 cells were cultured in vitro and incubated with different concentrations of dextran-coated iron oxide nanoparticles. They were then irradiated with 6 MV photons at dose rates of 43, 185 and 370 cGy/min. The MTT test was used to obtain the cells' survival after 48 h of irradiations. Incubating the cells with the nanoparticles at concentrations of 10, 40 and 80 μg/ml showed no significant cytotoxicity effect. Dextran-coated iron oxide nanoparticles showed more radiosensitivity effect by increasing the dose rate and nanoparticles concentration. Radiosensitization enhancement factors of MCF-7 and HeLa cells at a dose-rate of 370 cGy/min and nanoparticles' concentration of 80 μg/ml were 1.21 ± 0.06 and 1.19 ± 0.04, respectively. Increasing the dose rate of 6 MV photons irradiation in MCF-7 and HeLa cells increases the radiosensitization induced by the dextran-coated iron nanoparticles in these cells.

  1. Comparison of sedation and mechanical antinociception induced by intravenous administration of acepromazine and four dose rates of dexmedetomidine in donkeys.

    Science.gov (United States)

    Lizarraga, Ignacio; Castillo-Alcala, Fernanda; Robinson, Lauren S

    2017-05-01

    To assess and compare the sedative and antinociceptive effects of four dosages of dexmedetomidine in donkeys. Randomized, controlled, crossover, Latin-square, blinded study. Six healthy, castrated, adult, standard donkeys. Dexmedetomidine (2, 3, 4 and 5 μg kg -1 ; D2, D3, D4 and D5), acepromazine (0.1 mg kg -1 ) and saline were administered intravenously to each donkey and a 1 week interval was allowed between successive trials on each animal. Sedation scores (SS) and head heights above ground (HHAG) were used to assess sedation and mechanical nociceptive threshold (MNT) testing to assess antinociception over 120 minutes post-treatment. Areas under the curve (AUC) for 0-30, 30-60 and 60-120 minutes were computed to compare the effect of treatments. SS-AUC 0-30 values were larger for D4 and D5, and SS-AUC 30-60 values were larger for D5 than for saline. All dexmedetomidine treatments produced lower HHAG-AUC 0-30 and HHAG-AUC 30-60 values, and acepromazine produced lower HHAG AUC 60-120 values than did saline. For MNT, D3, D4 and D5 increased AUC 0-30 and AUC 30-60 values compared with saline and also AUC 0-30 values compared with D2 and acepromazine. Smaller MNT-AUC 30-60 values were obtained with D2 than with D4 and D5, with D3 than with D5, and with acepromazine than with D4 and D5. Dexmedetomidine induced sedation and dosage-dependent mechanical antinociception. Larger dexmedetomidine dose rates were required to induce antinociception than sedation. Furthermore, the antinociception induced by dexmedetomidine was of shorter duration than its sedation. For minor painful procedures on standing donkeys, D5 may be clinically useful to provide sedation and analgesia. Copyright © 2017 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.

  2. Radiation-induced temporary partial epilation in the pig: a biological indicator of radiation dose and dose distribution to the skin

    International Nuclear Information System (INIS)

    Sieber, V.K.; Hopewell, J.W.

    1990-01-01

    Radiation damage to the matrix cells of actively growing hairs can result in transient epilation in the pig, the severity of which can be assessed using a visual scoring system. The extent of hair loss was found to be dose-dependent for single doses in the range 6 - 14 Gy for 250 kV X rays. The ED 50 for detectable hair loss was 9.83 ± 0.58 Gy whilst that for the loss of > 50% of hairs was 13.78 ± 0.90 Gy. The system is simple, non-invasive and would appear to have considerable potential for use in biological dosimetry for high exposures that are likely to require local treatment. (author)

  3. Chronic low-dose UVA irradiation induces local suppression of contact hypersensitivity, Langerhans cell depletion and suppressor cell activation in C3H/HeJ mice

    International Nuclear Information System (INIS)

    Bestak, Rosa; Halliday, G.M.

    1996-01-01

    It has previously been demonstrated that chronic low-dose solar-simulated UV radiation could induce both local and systemic immunosuppression as well as tolerance to a topically applied hapten. In this study, we have used a chronic low-dose UV-irradiation protocol to investigate the effects of UVA on the skin immune system of C3H/HeJ mice. Irradiation with UVA+B significantly suppressed the local and systemic primary contact hypersensitivity (CHS) response to the hapten 2,4,6-trinitrochlorobenzene. Furthermore, UVA+B reduced Langerhans cell (LC) and dendritic epidermal T cell (DETC) densities in chronically UV-irradiated mice. Ultraviolet A irradiation induced local, but not systemic, immunosuppression and reduced LC (32%) but not DETC from the epidermis compared to the shaved control animals. Treatment of mice with both UVA+B and UVA radiation also induced an impaired secondary CHS response, and this tolerance was transferable with spleen cells. (Author)

  4. A double-blind, randomized, pilot dose-finding study of maca root (L. meyenii) for the management of SSRI-induced sexual dysfunction.

    Science.gov (United States)

    Dording, Christina M; Fisher, Lauren; Papakostas, George; Farabaugh, Amy; Sonawalla, Shamsah; Fava, Maurizio; Mischoulon, David

    2008-01-01

    We sought to determine whether maca, a Peruvian plant, is effective for selective-serotonin reuptake inhibitor (SSRI)-induced sexual dysfunction. We conducted a double-blind, randomized, parallel group dose-finding pilot study comparing a low-dose (1.5 g/day) to a high-dose (3.0 g/day) maca regimen in 20 remitted depressed outpatients (mean age 36+/-13 years; 17 women) with SSRI-induced sexual dysfunction. The Arizona Sexual Experience Scale (ASEX) and the Massachusetts General Hospital Sexual Function Questionnaire (MGH-SFQ) were used to measure sexual dysfunction. Ten subjects completed the study, and 16 subjects (9 on 3.0 g/day; 7 on 1.5 g/day) were eligible for intent-to-treat (ITT) analyses on the basis of having had at least one postbaseline visit. ITT subjects on 3.0 g/day maca had a significant improvement in ASEX (from 22.8+/-3.8 to 16.9+/-6.2; z=-2.20, P=0.028) and in MGH-SFQ scores (from 24.1+/-1.9 to 17.0+/-5.7; z=-2.39, P=0.017), but subjects on 1.5 g/day maca did not. Libido improved significantly (PMaca was well tolerated. Maca root may alleviate SSRI-induced sexual dysfunction, and there may be a dose-related effect. Maca may also have a beneficial effect on libido.

  5. Evaluation of the potential inhibitor of Ix (Pp-Ix) protoporphyrin of the genetic damage induced by gamma rays administered to different dose reasons in Drosophila melanogaster

    International Nuclear Information System (INIS)

    Flores A, J. A.

    2016-01-01

    Ionizing radiation can damage in DNA directly or indirectly by free radicals (Rl), characterized by unstable and highly reactive. To avoid damage by Rl the cell has endogenous antioxidants such as Sod, Cat, GSH or exogenous as some vitamins, but if with these mechanisms does not reach the cell homeostasis, the consequence may be the generation of chronic-disease degenerative such as cancer. This study was conducted in order to test the inhibitory role of Rl protoporphyrin Ix (Pp-Ix), induced by 20 Gy of gamma rays administered at different dose ratios using the assay of somatic mutation and recombination in the Drosophila wing. The results indicated that 20 Gy delivered at a rate of low dose (6.659 Gy/h), caused elevated frequencies of genetic damage (p <0.001), compared with those that induced a high dose reason (1111.42 Gy/h) in larvae of 48 h old. The difference is probably due to an indirect damage by Rl; when this hypothesis was approved with the possible inhibitor role of Pp-Ix (0.69 m M), damage was increased with the two reasons of tested doses. This result may be due to: 1) the Pp-Ix is not a good inhibitor of Rl, 2) the difference in the frequency of mutation found with both dose reasons, not due to Rl so that this compound did not reduce the genetic damage, and 3) that Pp-Ix acts as pro oxidant. (Author)

  6. The influence of non-radiation induced ESR background signal from paraffin-alanine probes for dosimetry in the radiotherapy dose range

    International Nuclear Information System (INIS)

    Wieser, A.; Lettau, C.; Fill, U.; Regulla, D.F.

    1993-01-01

    The yield of radicals induced by ionizing radiation in the amino acid alanine and its quantification by ESR spectroscopy has proven excellent reproducibility. Those radicals trapped in the crystal lattice are prevented from recombination providing a thermally very stable system. This allows alanine to be applied as a transfer dosemeter. With paraffin-alanine probes ESR dosimetry can be performed with a standard deviation of ± 0.5% in the dose range from 20 Gy up to 100 kGy. At 1 Gy dose level the error increases to ± 6%. This dose level is three orders of magnitude higher than the calculated detection threshold for alanine with modern X-band ESR spectrometers. It was found that the poor standard deviation at the 1 Gy dose level, is not mainly produced by a bad signal-to-noise ratio but by a variable non-radiation induced ESR background signal from the alanine probes within a batch. In the present study the main sources of error for ESR dosimetry in the dose range below 20 Gy were analyzed. The influences of the production process, UV light and humidity upon the ESR background signal from paraffin-alanine probes were investigated. Measurements are shown indicating a second stable structure of the alanine radical at room temperature. (author)

  7. Evaluation of the Effect of Different Doses of Low Energy Shock Wave Therapy on the Erectile Function of Streptozotocin (STZ-Induced Diabetic Rats

    Directory of Open Access Journals (Sweden)

    Zhong-Cheng Xin

    2013-05-01

    Full Text Available To investigate the therapeutic effect of different doses of low energy shock wave therapy (LESWT on the erectile dysfunction (ED in streptozotocin (STZ induced diabetic rats. SD rats (n = 75 were randomly divided into 5 groups (normal control, diabetic control, 3 different dose LESWT treated diabetic groups. Diabetic rats were induced by intra-peritoneal injection of STZ (60 mg/kg and rats with fasting blood glucose ≥ 300 mg/dL were selected as diabetic models. Twelve weeks later, different doses of LESWT (100, 200 and 300 shocks each time treatment on penises were used to treat ED (7.33 MPa, 2 shocks/s three times a week for two weeks. The erectile function was evaluated by intracavernous pressure (ICP after 1 week washout period. Then the penises were harvested for histological study. The results showed LESWT could significantly improve the erectile function of diabetic rats, increase smooth muscle and endothelial contents, up-regulate the expression of α-SMA, vWF, nNOS and VEGF, and down- regulate the expression of RAGE in corpus cavernosum. The therapeutic effect might relate to treatment dose positively, and the maximal therapeutic effect was noted in the LESWT300 group. Consequently, 300 shocks each time might be the ideal LESWT dose for diabetic ED treatment.

  8. Half dose sugammadex combined with neostigmine is non-inferior to full dose sugammadex for reversal of rocuronium-induced deep neuromuscular blockade: a cost-saving strategy.

    Science.gov (United States)

    Aouad, Marie T; Alfahel, Waseem S; Kaddoum, Roland N; Siddik-Sayyid, Sahar M

    2017-04-11

    Sugammadex reverses the effect of rocuronium more rapidly and effectively than neostigmine, at all levels of neuromuscular blockade (NMB). However, its cost is prohibitive. The combination of half dose sugammadex with neostigmine would be non-inferior to full dose sugammadex for the reversal of deep NMB. This approach would reduce the cost of sugammadex while preserving its efficacy. Patients were randomly allocated to receive sugammadex 4 mg/kg (Group S) or sugammadex 2 mg/kg with neostigmine 50 μg/kg and glycopyrrolate 10 μg/kg (Group NS) for reversal of rocuronium deep NMB. The primary outcome was the percentage of patients who recovered to 90% Train of Four (TOF) ratio within 5 min. The non-inferiority margin was set at 10%. Twenty eight patients were enrolled in each group. The number of patients who reached 90% TOF ratio within 5 min was 27 out of 28 (96%) in group S versus 25 out of 28 (89%) in group NS by intention-to-treat (difference: 7%, 95% CI of the difference: -9% to 24%). The number of patients who reached 90% TOF ratio within 5 min was 26 out of 26 (100%) in group S versus 23 out of 25 (92%) in group NS by per-protocol (difference: 8%, 95% CI of the difference: -6% to 25%). Sugammadex 2 mg/kg with neostigmine 50 μg/kg was at worst 9% and 6% less effective than sugammadex 4 mg/kg by intention-to-treat and by per-protocol analysis respectively. Hence, the combination is non-inferior to the recommended dose of sugammadex. Clinicaltrials.gov NCT 02375217 , registered on February 11, 2015.

  9. Tumor control induced by Boron Neutron Capture Therapy (BNCT) as a function of dose in an experimental model of liver metastases at 5 weeks follow-up

    International Nuclear Information System (INIS)

    Pozzi, E C C; Trivillin, V A; Colombo, L L; Monti Hughes, A; Thorp, S; Cardoso, J E; Garabalino, M A; Molinari, A J; Heber, E M; Curotto, Paula; Miller, M; Itoiz, M E; Aromando, R F; Nigg, D W; Schwint, A E

    2012-01-01

    BNCT has been proposed for the treatment of multifocal, non-resectable, bilobar colorectal liver metastases that do not respond to chemotherapy. We recently reported that BNCT mediated by boronophenylalanine (BPA) induced significant remission of experimental colorectal tumor nodules in rat liver at 3 weeks follow-up with no contributory liver toxicity (Pozzi et al.,2012). The aim of the present study was to evaluate tumor control and potential liver toxicity of BPA-BNCT at 5 weeks follow-up. Prescribed dose was retrospectively evaluated based on blood boron values, allowing for assessment of response over a range of delivered dose values (author)

  10. Assessment of prior image induced nonlocal means regularization for low-dose CT reconstruction: Change in anatomy.

    Science.gov (United States)

    Zhang, Hao; Ma, Jianhua; Wang, Jing; Moore, William; Liang, Zhengrong

    2017-09-01

    Repeated computed tomography (CT) scans are prescribed for some clinical applications such as lung nodule surveillance. Several studies have demonstrated that incorporating a high-quality prior image into the reconstruction of subsequent low-dose CT (LDCT) acquisitions can either improve image quality or reduce data fidelity requirements. Our proposed previous normal-dose image induced nonlocal means (ndiNLM) regularization method for LDCT is an example of such a method. However, one major concern with prior image based methods is that they might produce false information when the prior image and the current LDCT image show different structures (for example, if a lung nodule emerges, grows, shrinks, or disappears over time). This study aims to assess the performance of the ndiNLM regularization method in situations with change in anatomy. We incorporated the ndiNLM regularization into the statistical image reconstruction (SIR) framework for reconstruction of subsequent LDCT images. Because of its patch-based search mechanism, a rough registration between the prior image and the current LDCT image is adequate for the SIR-ndiNLM method. We assessed the performance of the SIR-ndiNLM method in lung nodule surveillance for two different scenarios: (a) the nodule was not found in a baseline exam but appears in a follow-up LDCT scan; (b) the nodule was present in a baseline exam but disappears in a follow-up LDCT scan. We further investigated the effect of nodule size on the performance of the SIR-ndiNLM method. We found that a relatively large search-window (e.g., 33 × 33) should be used for the SIR-ndiNLM method to account for misalignment between the prior image and the current LDCT image, and to ensure that enough similar patches can be found in the prior image. With proper selection of other parameters, experimental results with two patient datasets demonstrated that the SIR-ndiNLM method did not miss true nodules nor introduce false nodules in the lung nodule

  11. Clinical study on the adriamycin induced cardiomyopathy using the cardiac magnetic resonance imaging. Total dose and cardiac dysfunction

    International Nuclear Information System (INIS)

    Yamaguchi, Kyoko; Teraoka, Kunihiko; Hirano, Masaharu

    2001-01-01

    We studied cardiac functional disorders caused by Adoriamycin using gadolinium (Gd) contrast cine MRI. Forty-eight patients were given ACT (31 men and 17 women; mean age, 52±15 years). First, the relationship between dose and the left ventricular volume, cardiac function, left ventricular cardiac mass and localized wall motion were examined in all patients. Patients given a total dose of 300 mg/m 2 or higher were assigned to the high dose group and those given doses under 300 mg/m 2 to the low dose group. The same parameters were studied in both groups and compared. A 1.5-Tesla superconductive MRI was used for all studies. Cine images of the long and short axes at the papillary muscle level were obtained by ECG R-wave synchronized Gd contrast cine MRI. Left ventricular volume and cardiac function were analyzed using the long-axis cine images and the wall thickness in diastole and systole was measured at each site using the short-axis cine images. The percentage of wall thickness was calculated at each site. The mean ACT dose was 273.3±218.2 mg/m 2 . In all patients the total dose directly correlated with ESVI and inversely correlated with the ejection fraction (EF). In the high dose group, the total dose and EF were inversely correlated, but no significant differences were observed in the low dose group. In the high dose group, the ESVI was significantly greater and the SVI and EF were more significantly reduced than in the low dose group. In the high dose group, the thickness of the anterior, lateral and posterior walls, excluding the septum, was significantly lower than in the low dose group. However, changes in wall thickness were not significantly different between the groups. Gd contrast cine MRI was useful in examining cardiac functional disorders caused by anthracyclines. The total dose of anthracycline correlated directly with the ESVI, and inversely with the EF. A total dose of 300 mg/m 2 appeared to be the borderline dose beyond which there were

  12. Clinical study on the adriamycin induced cardiomyopathy using the cardiac magnetic resonance imaging. Total dose and cardiac dysfunction

    Energy Technology Data Exchange (ETDEWEB)

    Yamaguchi, Kyoko; Teraoka, Kunihiko; Hirano, Masaharu [Tokyo Medical Coll. (Japan)

    2001-05-01

    We studied cardiac functional disorders caused by Adoriamycin using gadolinium (Gd) contrast cine MRI. Forty-eight patients were given ACT (31 men and 17 women; mean age, 52{+-}15 years). First, the relationship between dose and the left ventricular volume, cardiac function, left ventricular cardiac mass and localized wall motion were examined in all patients. Patients given a total dose of 300 mg/m{sup 2} or higher were assigned to the high dose group and those given doses under 300 mg/m{sup 2} to the low dose group. The same parameters were studied in both groups and compared. A 1.5-Tesla superconductive MRI was used for all studies. Cine images of the long and short axes at the papillary muscle level were obtained by ECG R-wave synchronized Gd contrast cine MRI. Left ventricular volume and cardiac function were analyzed using the long-axis cine images and the wall thickness in diastole and systole was measured at each site using the short-axis cine images. The percentage of wall thickness was calculated at each site. The mean ACT dose was 273.3{+-}218.2 mg/m{sup 2}. In all patients the total dose directly correlated with ESVI and inversely correlated with the ejection fraction (EF). In the high dose group, the total dose and EF were inversely correlated, but no significant differences were observed in the low dose group. In the high dose group, the ESVI was significantly greater and the SVI and EF were more significantly reduced than in the low dose group. In the high dose group, the thickness of the anterior, lateral and posterior walls, excluding the septum, was significantly lower than in the low dose group. However, changes in wall thickness were not significantly different between the groups. Gd contrast cine MRI was useful in examining cardiac functional disorders caused by anthracyclines. The total dose of anthracycline correlated directly with the ESVI, and inversely with the EF. A total dose of 300 mg/m{sup 2} appeared to be the borderline dose beyond

  13. Ovulation time and ovulated eggs count of sneakehead Channa striata induced by prostaglandin 2α with different doses

    Directory of Open Access Journals (Sweden)

    Frits Jamlaay

    2016-02-01

    Full Text Available ABSTRACT Snakehead fish Channa striata is one of freshwater commodity which has high economic value. Nowadays, snakehead fish stock mostly comes from wild capture. Artificial spawning with hormonal induction is usually used to improve broodstock efficiency, as well as the quality and quantity of fish seed production. Purpose of this study was to determine the effectiveness of prostaglandin 2α (PGF2α hormone on ovulation time and count of ovulated eggs. This experiment used 30–40 cm broodstock with 600–900 g body weight. Fishes were acclimated for one week in a container and then injected with different doses of PGF2α, namely: control without PGF2α (P1, 0.5 mL/kg (P2; 0.7mL/kg (P3; and 0.9 mL/kg (P4. Each treatment consisted of three fishes as replication. Ovulation time was observed until 72 hours post injection. The results showed that PGF2α injected broodstoks ovulated faster (9.17–12.24 hours post injection than control P1 (22.67 hours, while among PGF2α injected fishes were the same. Furthermore, count of ovulated eggs from PGF2α induced broodstocks were higher than control P1, and the highest (2,860 eggs was obtained in treatment 0.9 mL/kg. Thus, PGF2α at dose of 0.9 mL/kg can be used to induce eggs ovulation of snakehead fish and to increase count of ovulated eggs. Keywords: PGF2α, ovulation time, ovulated eggs count, Channa striata  ABSTRAK Ikan gabus Channa striata merupakan salah satu komoditas air tawar yang mempunyai nilai ekonomi tinggi. Saat ini, pemenuhan kebutuhan hanya bergantung pada hasil penangkapan di alam. Cara pemijahan buatan dengan induksi hormon biasanya digunakan untuk efisiensi penggunaan induk serta peningkatan kualitas dan kuantitas benih ikan yang dihasilkan. Tujuan dari penelitian ini adalah untuk menguji efektivitas hormon prostaglandin 2α (PGF2α terhadap waktu ovulasi dan jumlah telur ikan gabus yang diovulasikan. Penelitian ini menggunakan induk ikan gabus berukuran 30–40 cm dengan bobot

  14. Regeneration of pancreatic non-β endocrine cells in adult mice following a single diabetes-inducing dose of streptozotocin.

    Directory of Open Access Journals (Sweden)

    Yanqing Zhang

    Full Text Available The non-β endocrine cells in pancreatic islets play an essential counterpart and regulatory role to the insulin-producing β-cells in the regulation of blood-glucose homeostasis. While significant progress has been made towards the understanding of β-cell regeneration in adults, very little is known about the regeneration of the non-β endocrine cells such as glucagon-producing α-cells and somatostatin producing δ-cells. Previous studies have noted the increase of α-cell composition in diabetes patients and in animal models. It is thus our hypothesis that non-β-cells such as α-cells and δ-cells in adults can regenerate, and that the regeneration accelerates in diabetic conditions. To test this hypothesis, we examined islet cell composition in a streptozotocin (STZ-induced diabetes mouse model in detail. Our data showed the number of α-cells in each islet increased following STZ-mediated β-cell destruction, peaked at Day 6, which was about 3 times that of normal islets. In addition, we found δ-cell numbers doubled by Day 6 following STZ treatment. These data suggest α- and δ-cell regeneration occurred rapidly following a single diabetes-inducing dose of STZ in mice. Using in vivo BrdU labeling techniques, we demonstrated α- and δ-cell regeneration involved cell proliferation. Co-staining of the islets with the proliferating cell marker Ki67 showed α- and δ-cells could replicate, suggesting self-duplication played a role in their regeneration. Furthermore, Pdx1(+/Insulin(- cells were detected following STZ treatment, indicating the involvement of endocrine progenitor cells in the regeneration of these non-β cells. This is further confirmed by the detection of Pdx1(+/glucagon(+ cells and Pdx1(+/somatostatin(+ cells following STZ treatment. Taken together, our study demonstrated adult α- and δ-cells could regenerate, and both self-duplication and regeneration from endocrine precursor cells were involved in their regeneration.

  15. Reversal of profound, high-dose rocuronium-induced neuromuscular blockade by sugammadex at two different time points - An international, multicenter, randomized, dose-finding, safety assessor-blinded, phase II trial

    DEFF Research Database (Denmark)

    Puhringer, F.K.; Rex, C.; Sielenkamper, A.W.

    2008-01-01

    Background: Sugammadex (Org 25969), a novel, selective relaxant binding agent, was specifically designed to rapidly reverse rocuronium-induced neuromuscular blockade. The efficacy and safety of sugammadex for the reversal of profound, high-dose rocuronium-induced neuromuscular blockade...... was evaluated. Methods: A total of 176 adult patients were randomly assigned to receive sugammadex (2, 4, 8, 12, or 16 mg/kg) or placebo at 3 or 15 min after high-dose rocuronium (1.0 or 1.2 mg/kg) during propofol anesthesia. The primary endpoint was time to recovery of the train-of-four ratio to 0.......9. Neuromuscular monitoring was performed using acceleromyography. Results: Sugammadex administered 3 or 15 min after injection of 1 mg/kg rocuronium decreased the median recovery time of the train-of-four ratio to 0.9 in a dose-dependent manner from 111.1 min and 91.0 min (placebo) to 1.6 min and 0.9 min (16 mg...

  16. Comparison of the dose-response relationship of radiation-induced apoptosis in the hippocampal dentate gyrus and intestinal crypt of adult mice

    International Nuclear Information System (INIS)

    Kim, J. S.; Yang, M.; Kim, J.; Lee, D.; Kim, J. C.; Shin, T.; Kim, S. H.; Moon, C.

    2012-01-01

    The present study compared the dose-response curves for the frequency of apoptosis in mouse hippocampal dentate gyrus (DG) and intestinal crypt using whole-body gamma irradiation. The incidence of gamma-ray-induced apoptosis was measured using the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end-labelling (TUNEL) method. TUNEL-positive apoptotic nuclei in the DG and intestinal crypt were increased in a dose-dependent pattern (0-2 Gy). The dose-response curves were linear-quadratic, with a significant relationship between the appearance of apoptosis and irradiation dose. The slopes of the dose-response curves in the DG were much steeper (∼5-6-fold) than those in the intestinal crypt within the range of 0-1 Gy exposure. Hippocampal DG might be a more effective and sensitive evaluation structure than the intestinal crypt to estimate the degree of radiation exposure in damaged organs of adult mice exposed to low irradiation dose. copy; The Author 2011. Published by Oxford Univ. Press. All rights reserved. (authors)

  17. Study of gamma radiation induced damages and variation of oxygen enhancement ratio with radiation dose using Saccharomyces cerevisiae

    International Nuclear Information System (INIS)

    Nairy, R.K.; Yerol Narayana; Bhat, N.N.; Anjaria, K.B.; Sreedevi, B.; Sapra, B.K.

    2014-01-01

    In the present study, an attempt has been made to quantify Oxygen Enhancement Ratio (OER) and variation of OER as a function of dose with experimental and theoretical formulations using Saccharomyces cerevisiae D7, X2180 and rad 52. The study confirms that, the variation of OER with dose depends upon type of cell and repair proficiency of cells. A theoretical model has been formulated to estimate OER values. With the help of this model, OER value for any dose can be calculated in the exponential region of the survival curve without actually extending the experiment in that dose region. (author)

  18. Human hepatocytes support the hypertrophic but not the hyperplastic response to the murine nongenotoxic hepatocarcinogen sodium phenobarbital in an in vivo study using a chimeric mouse with humanized liver.

    Science.gov (United States)

    Yamada, Tomoya; Okuda, Yu; Kushida, Masahiko; Sumida, Kayo; Takeuchi, Hayato; Nagahori, Hirohisa; Fukuda, Takako; Lake, Brian G; Cohen, Samuel M; Kawamura, Satoshi

    2014-11-01

    High doses of sodium phenobarbital (NaPB), a constitutive androstane receptor (CAR) activator, have been shown to produce hepatocellular tumors in rodents by a mitogenic mode of action (MOA) involving CAR activation. The effect of 1-week dietary treatment with NaPB on liver weight and histopathology, hepatic CYP2B enzyme activity and CYP2B/3A mRNA expression, replicative DNA synthesis and selected genes related to cell proliferation, and functional transcriptomic and metabolomic analyses was studied in male CD-1 mice, Wistar Hannover (WH) rats, and chimeric mice with human hepatocytes. The treatment of chimeric mice with 1000-1500-ppm NaPB resulted in plasma levels around 3-5-fold higher than those observed in human subjects given therapeutic doses of NaPB. NaPB produced dose-dependent increases in hepatic CYP2B activity and CYP2B/3A mRNA levels in all animal models. Integrated functional metabolomic and transcriptomic analyses demonstrated that the responses to NaPB in the human liver were clearly different from those in rodents. Although NaPB produced a dose-dependent increase in hepatocyte replicative DNA synthesis in CD-1 mice and WH rats, no increase in replicative DNA synthesis was observed in human hepatocyte-originated areas of chimeric mice. In addition, treatment with NaPB had no effect on Ki-67, PCNA, GADD45β, and MDM2 mRNA expression in chimeric mice, whereas significant increases were observed in CD-1 mice and/or WH rats. However, increases in hepatocyte replicative DNA synthesis were observed in chimeric mice both in vivo and in vitro after treatment epidermal growth factor. Thus, although NaPB could activate CAR in both rodent and human hepatocytes, NaPB did not increase replicative DNA synthesis in human hepatocytes of chimeric mice, whereas it was mitogenic to rat and mouse hepatocytes. As human hepatocytes are refractory to the mitogenic effects of NaPB, the MOA for NaPB-induced rodent liver tumor formation is thus not relevant for humans. © The

  19. TU-F-CAMPUS-T-01: Dose and Energy Spectra From Neutron Induced Radioactivity in Medical Linear Accelerators Following High Energy Total Body Irradiation

    International Nuclear Information System (INIS)

    Keehan, S; Taylor, M; Franich, R; Smith, R; Dunn, L; Kron, T

    2015-01-01

    Purpose: To assess the risk posed by neutron induced activation of components in medical linear accelerators (linacs) following the delivery of high monitor unit 18 MV photon beams such as used in TBI. Methods: Gamma spectroscopy was used to identify radioisotopes produced in components of a Varian 21EX and an Elekta Synergy following delivery of photon beams. Dose and risk estimates for TBI were assessed using dose deliveries from an actual patient treatment. A 1 litre spherical ion chamber (PTW, Germany) has been used to measure the dose at the beam exit window and at the total body irradiation (TBI) treatment couch following large and small field beams with long beam-on times. Measurements were also made outside of the closed jaws to quantify the benefit of the attenuation provided by the jaws. Results: The radioisotopes produced in the linac head have been identified as 187 W, 56 Mn, 24 Na and 28 Al, which have half-lives from between 2.3 min to 24 hours. The dose at the beam exit window following an 18 MV 2197 MU TBI beam delivery was 12.6 µSv in ten minutes. The dose rate at the TBI treatment couch 4.8 m away is a factor of ten lower. For a typical TBI delivered in six fractions each consisting of four beams and an annual patient load of 24, the annual dose estimate for a staff member at the treatment couch for ten minutes is 750 µSv. This can be further reduced by a factor of about twelve if the jaws are closed before entering the room, resulting in a dose estimate of 65 µSv. Conclusion: The dose resulting from the activation products for a representative TBI workload at our clinic of 24 patients per year is 750 µSv, which can be further reduced to 65 µSv by closing the jaws

  20. The impact of assumptions regarding vaccine-induced immunity on the public health and cost-effectiveness of hepatitis A vaccination: Is one dose sufficient?

    Science.gov (United States)

    Curran, Desmond; de Ridder, Marc; Van Effelterre, Thierry

    2016-01-01

    ABSTRACT Hepatitis A vaccination stimulates memory cells to produce an anamnestic response. In this study, we used a mathematical model to examine how long-term immune memory might convey additional protection against clinical/icteric infections. Dynamic and decision models were used to estimate the expected number of cases, and the costs and quality-adjusted life-years (QALYs), respectively. Several scenarios were explored by assuming: (1) varying duration of vaccine-induced immune memory, (2) and/or varying levels of vaccine-induced immune memory protection (IMP), (3) and/or varying levels of infectiousness in vaccinated individuals with IMP. The base case analysis assumed a time horizon of 25 y (2012 – 2036), with additional analyses over 50 and 75 y. The analyses were conducted in the Mexican public health system perspective. In the base case that assumed no vaccine-induced IMP, the 2-dose hepatitis A vaccination strategy was cost-effective compared with the 1-dose strategy over the 3 time horizons. However, it was not cost-effective if we assumed additional IMP durations of at least 10 y in the 25-y horizon. In the 50- and 75-y horizons, the 2-dose strategy was always cost-effective, except when 100% reduction in the probability of icteric Infections, 75% reduction in infectiousness, and mean durations of IMP of at least 50 y were assumed. This analysis indicates that routine vaccination of toddlers against hepatitis A virus would be cost-effective in Mexico using a single-dose vaccination strategy. However, the cost-effectiveness of a second dose depends on the assumptions of additional protection by IMP and the time horizon over which the analysis is performed. PMID:27428611

  1. Radiation-induced strand-breaks and DNA-protein crosslinks depend predominantly on the dose, oxygen concentration and repair time

    International Nuclear Information System (INIS)

    Wheeler, K.T.; Miyagi, Y.; Zhang, H.

    1995-01-01

    It has been known for many years that the DNA damage produced by ionizing radiation depends upon the oxygen concentration around the DNA. For example, the number of DNA strand-breaks (SBs) formed per unit dose decreases at low oxygen concentrations, and the number of DNA-protein crosslinks formed per unit dose increases at low oxygen concentrations. If radiation-induced SBs and DPCs are to be useful for detecting and/or quantifying hypoxic cells in solid tumors, the formation of these lesions must depend predominantly on the oxygen concentration around the DNA. All other physical, biological, and physiological factors must either be controllable or have little influence on the assay used to measure these lesions. This paper is a summary of the authors' recent experiments to determine if the radiation-induced SBs and DPCs measured by alkaline elution may be used to estimate the hypoxic fraction or fractional hypoxic volume of solid tumors

  2. Quantitative and qualitative changes induced by low-dose gamma irradiation in essential oil of Cymbopogon martinii var. motia

    International Nuclear Information System (INIS)

    Gupta, R.S.; Verma, Sheela; Trivedi, K.C.; Gangrade, S.K.

    1981-01-01

    Seeds of palmarosa grass were exposed to low doses of gamma-rays. The effects on quantitative and qualitative characters were studied in M 1 generation for two years. Highest response in quantitative and qualitative characters was observed in 10 Kr and 15 Kr doses. (author)

  3. The repair of low dose UV light-induced damage to human skin DNA in condition of trace amount Mg 2+

    Science.gov (United States)

    Gao, Fang; Guo, Zhouyi; Zheng, Changchun; Wang, Rui; Liu, Zhiming; Meng, Pei; Zhai, Juan

    2008-12-01

    Ultraviolet light-induced damage to human skin DNA was widely investigated. The primary mechanism of this damage contributed to form cyclobutane pyrimidine dimmers (CPDs). Although the distribution of UV light-induced CPDs within a defined sequence is similar, the damage in cellular environment which shields the nuclear DNA was higher than that in organism in apparent dose. So we use low UVB light as main study agent. Low dose UV-irradiated HDF-a cells (Human Dermal Fibroblasts-adult cells) which is weaker than epidermic cells were cultured with DMEM at different trace amount of Mg2+ (0mmol/L , 0.1mmol/L , 0.2mmol/L, 0.4mmol/L, 0.8mmol/L, 1.2mmol/L) free-serum DMEM and the repair of DNA strands injured were observed. Treat these cells with DNA strand breaks detection, photoproducts detection and the repair of photoproducts detection. Then quantitate the role of trace amount Mg2+ in repair of UV light-induced damage to human skin. The experiment results indicated that epidermic cells have capability of resistance to UV-radiation at a certain extent. And Mg2+ can regulate the UV-induced damage repair and relative vitality. It can offer a rationale and experiment data to relieve UV light-induced skin disease.

  4. Effects of subcutaneous, low-dose glucagon on insulin-induced mild hypoglycaemia in patients with insulin pump treated type 1 diabetes

    DEFF Research Database (Denmark)

    Ranjan, Ajenthen; Schmidt, S; Madsbad, Sten

    2016-01-01

    AIM: To investigate the dose-response relationship of subcutaneous glucagon administration on plasma glucose and on counterregulatory hormone responses during subcutaneous insulin induced mild hypoglycaemia in patients with type 1 diabetes treated with insulin pumps. MATERIALS AND METHODS: Eight...... hypoglycaemia in patients with type 1 diabetes....... insulin pump treated patients completed a blinded, randomized, placebo-controlled study. Hypoglycaemia was induced in the fasting state by a subcutaneous insulin bolus and when plasma glucose reached 3.4 mmol/l (95%CI 3.2-3.5), a subcutaneous bolus of either 100, 200, 300 µg glucagon or saline...

  5. Regional changes in brain 2-14C-deoxyglucose uptake induced by convulsant and non-convulsant doses of lindane

    International Nuclear Information System (INIS)

    Sanfeliu, C.; Sola, C.; Camon, L.; Martinez, E.; Rodriguez-Farre, E.

    1990-01-01

    Lindane-induced dose- and time-related changes in regional 2-14C-deoxyglucose (2-DG) uptake were examined in 59 discrete rat brain structures using the 2-DG autoradiographic technique. At different times (0.5-144 hr) after administration of a seizure-inducing single dose of lindane (60 mg/kg), 2-DG uptake was significantly increased in 18 cortical and subcortical regions mainly related to the limbic system (e.g., Ammon's horn, dentate gyrus, septal nuclei, nucleus accumbens, olfactory cortex) and extrapyramidal and sensory-motor areas (e.g., cerebellar cortex, red nucleus, medial vestibular nucleus). There was also a significant increase in superior colliculus layer II. In addition, significant decreases occurred in a group of 6 regions (e.g., auditory and motor cortices). Non-convulsing animals treated with the same dose of lindane showed a regional pattern of 2-DG uptake less modified than the convulsant group. A non-convulsant single dose of lindane (30 mg/kg) also modified significantly the 2-DG uptake (0.5-24 hr) in some brain areas. Although the various single doses of lindane tested produced different altered patterns of brain 2-DG uptake, some structures showed a similar trend in their modification (e.g., superior colliculi and accumbens, raphe and red nuclei). Repeated non-convulsant doses of lindane produced defined and long-lasting significant elevations of 2-DG uptake in some subcortical structures. Considering the treated groups all together, 2-DG uptake increased significantly in 26 of the 59 regions examined but only decreased significantly in 9 of them during the course of lindane effects. This fact can be related to the stimulant action described for this neurotoxic agent. The observed pattern provides a descriptive approach to the functional alterations occurring in vivo during the course of lindane intoxication

  6. Therapeutic doses of doxorubicin induce premature senescence of human mesenchymal stem cells derived from menstrual blood, bone marrow and adipose tissue.

    Science.gov (United States)

    Kozhukharova, Irina; Zemelko, Victoria; Kovaleva, Zoya; Alekseenko, Larisa; Lyublinskaya, Olga; Nikolsky, Nikolay

    2018-03-01

    Doxorubicin (Dox) is an effective anticancer drug with known activity against a wide spectrum of malignancies, hematologic malignancies in particular. Despite extensive clinical use, the mechanisms of its side effects and negative action on normal cells remain under study. The aim of this study was to investigate the effect of Dox on cultured human mesenchymal stem cells (MSCs) derived from menstrual blood (eMSCs), bone marrow (BMSCs) and adipose tissue (AMSCs). Dox treatment in high doses decreased the survival of MSCs in a dose-dependent manner. Clinically relevant low doses of Dox induced premature senescence of eMSCs, BMSCs and AMSCs, but did not kill the cells. Dox caused cell cycle arrest and formation of γ-H2AX foci, and increased the number of SA-β-gal-positive cells. BMSCs entered premature senescence earlier than other MSCs. It has been reported that neural-like cells differentiated from MSCs of various origins are more sensitive to Dox than their parent cells. Dox-treated differentiated MSCs exhibited lower viability and earlier generation of γ-H2AX foci. Dox administration inhibited secretory activity in neural-like cells. These findings suggest that a clinically relevant Dox dose damages cultured MSCs, inducing their premature senescence. MSCs are more resistant to this damage than differentiated cells.

  7. Analgesia induced by repeated exposure to low dose X-rays in mice, and involvement of the accessory olfactory system in modulation of the radiation effects

    International Nuclear Information System (INIS)

    Miyachi, Yukihisa; Yamada, Takeshi

    1997-01-01

    The effects of low-dose X-rays on mouse nociceptive behavior were examined using a formalin injected test which rated the amount of time the animals spent licking the injected hind-paw. Male ICR White Swiss mice showed a marked suppression of licking behavior after repeated low-dose X-irradiation (5 cGy/day, 6 consecutive days). The most profound effect was observed on the day 30 after irradiation. The decline of licking behavior, however, was not observed at all following olfactory bulbectomy or vomeronasal tract cut. The analgesic effects could be observed in writhing animals administered acetic-acid intraperitoneally. Moreover, analgesia was totally blocked by the administration of N-nitro-L-arginine, a nitric oxide synthase inhibitor, to accessory olfactory bulbs prior to the exposure. The present results indicate that the olfactory system plays an important role in modulation of radiation-induced analgesia, and a possible involvement of nitric oxide in the formation of recognition memory subjected to repeated X-rays. Relatively higher doses (5 cGy x 9 days, 5 cGy x 12 days), however, did not induce such effects, namely, the decline of nociceptive response was limited to the animals irradiated with the smaller dose. (author)

  8. Hypophosphatemic osteomalacia and renal Fanconi syndrome induced by low-dose adefovir dipivoxil: a case report and literature review suggesting ethnic predisposition.

    Science.gov (United States)

    Wu, C; Zhang, H; Qian, Y; Wang, L; Gu, X; Dai, Z

    2013-08-01

    Adefovir dipivoxil (ADV) is one of the commonly used antiviral agents in the treatment of chronic hepatitis B (CHB) infection. Safety of a daily dose of 10 mg ADV is advocated by the registration trials. We report a case of severe hypophosphatemic osteomalacia and renal Fanconi syndrome induced by low-dose ADV in a CHB-related cirrhosis patient, and discuss the case through a thorough review of other cases reported in the literature. A 48-yr-old Chinese man with CHB-related cirrhosis developed severe progressive generalized bone pain and muscle weakness after receiving ADV 10 mg daily for 54 months. The laboratory results showed severe hypophosphatemia and features of proximal renal tubule dysfunction. Imaging studies were consistent with osteomalacia. After discontinuation of ADV, his symptoms resolved, laboratory abnormalities normalized and imaging studies showed improvement. In addition to our case, 12 other patients have been reported to have developed hypophosphatemic osteomalacia induced by low-dose ADV. Most of the reported cases were of subjects of East-Asian ethnicity. After discontinuation or reduction of ADV, serum phosphate level increased and clinical symptoms significantly improved in all cases. Hypophosphatemic osteomalacia and renal Fanconi syndrome can be associated with low-dose ADV. Clinicians treating CHB patients with ADV 10 mg daily over long periods of time should be aware of this infrequent but serious complication. © 2013 John Wiley & Sons Ltd.

  9. Low and high dose rate heavy ion radiation-induced intestinal and colonic tumorigenesis in APC1638N/+ mice

    Science.gov (United States)

    Suman, Shubhankar; Kumar, Santosh; Moon, Bo-Hyun; Fornace, Albert J.; Datta, Kamal

    2017-05-01

    Ionizing radiation (IR) is a recognized risk factor for colorectal cancer (CRC) and astronauts undertaking long duration space missions are expected to receive IR doses in excess of permissible limits with implications for colorectal carcinogenesis. Exposure to IR in outer space occurs at low doses and dose rates, and energetic heavy ions due to their high linear energy transfer (high-LET) characteristics remain a major concern for CRC risk in astronauts. Previously, we have demonstrated that intestinal tumorigenesis in a mouse model (APC1638N/+) of human colorectal cancer was significantly higher after exposure to high dose rate energetic heavy ions relative to low-LET γ radiation. The purpose of the current study was to compare intestinal tumorigenesis in APC1638N/+ mice after exposure to energetic heavy ions at high (50 cGy/min) and relatively low (0.33 cGy/min) dose rate. Male and female mice (6-8 weeks old) were exposed to either 10 or 50 cGy of 28Si (energy: 300 MeV/n; LET: 70 keV/μm) or 56Fe (energy: 1000 MeV/n; LET: 148 keV/μm) ions at NASA Space Radiation Laboratory in Brookhaven National Laboratory. Mice (n = 20 mice/group) were euthanized and intestinal and colon tumor frequency and size were counted 150 days after radiation exposure. Intestinal tumorigenesis in male mice exposed to 56Fe was similar for high and low dose rate exposures. Although male mice showed a decreasing trend at low dose rate relative to high dose rate exposures, the differences in tumor frequency between the two types of exposures were not statistically significant after 28Si radiation. In female mice, intestinal tumor frequency was similar for both radiation type and dose rates tested. In both male and female mice intestinal tumor size was not different after high and low dose rate radiation exposures. Colon tumor frequency in male and female mice after high and low dose rate energetic heavy ions was also not significantly different. In conclusion, intestinal and colonic tumor

  10. Comparative studies of the dose-response relationship of radiation-induced chromosomal aberrations in human lymphocytes induced by low radiation doses, using Feulgen orcein glacial acetic acid and FPG staining

    International Nuclear Information System (INIS)

    Wagner, R.

    1982-01-01

    Peripheral lymphocytes were exposed in vitro to 220 kV X-radiation, with doses of 0.05, 0.1, 0.2, 0.4, and 0.5 Gy, their culture and preparation was made under standardized conditions. The slides were stained using two different methods, namely FPG staining (fluorescence plus giemsa), and the conventional Feulgen orcein glacial acetic acid method. Compared to the conventional method, FPG staining achieved absolute yields of acentric fragments three times higher, and of dicentric chromosomes twice as high. A linear dose-response relationship in acentric fragments was found by the two staining methods alike, which agrees with the theory. Both staining methods revealed a linear-square dose-response relationship in dicentric chromosomes. Using FPG staining, preparing only M 1 cells for evaluation, the linear component was found to be dominant over the whole dose range applied. The conventional method, analysing M 1 and M 2 cells, revealed the square component to be the most important one. The dose-response relationships determined after FPG staining can be used for biological dosimetry. Calibration can be improved by increasing the number of cells analysed at doses [de

  11. Investigation of J-shaped dose-responses induced by exposure to the alkylating agent N-methyl-N-nitrosourea.

    Science.gov (United States)

    Chapman, Katherine E; Hoffmann, George R; Doak, Shareen H; Jenkins, Gareth J S

    2017-07-01

    Hormesis is defined as a biphasic dose-response where biological effects of low doses of a stressor demonstrate the opposite effect to high-dose effects of the same stressor. Hormetic, or J-shaped, dose-response relationships are relatively rarely observed in toxicology, resulting in a limited understanding and even some skepticism of the concept. Low dose-response studies for genotoxicity endpoints have been performed at Swansea University for over a decade. However, no statistically significant decreases below control genotoxicity levels have been detected until recently. A hormetic-style dose-response following a 24h exposure to the alkylating agent N-methyl-N-nitrosourea (MNU) was observed in a previous study for HPRT mutagenesis in the human lymphoblastoid cell line AHH-1. A second recent study demonstrated a J-shaped dose-response for the induction of micronuclei by MNU in a 24h treatment in a similar test system. Following mechanistic investigations, it was hypothesized that p53 may be responsible for the observed hormetic phenomenon. As genotoxic carcinogens are a major causative factor of many cancers, consideration of hormesis in carcinogenesis could be important in safety assessment. The data examined here offer possible insights into hormesis, including its estimated prevalence, underlying mechanisms and lack of generalizability. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. From personnel dose to personal dose

    International Nuclear Information System (INIS)

    Hoefert, M.; Raffnsoe, R.C.; Tuyn, J.W.N.; Wittekind, D.

    1985-01-01

    From following the development of personnel doses at CERN over the past six years it has become evident that work in areas of induced radioactivity is the principal cause of exposure. The results of photon dose measurements free-in-air and around a phantom are presented and discussed in the light of new quantities in individual monitoring. The importance of these results, with respect to the practical situation, is discussed and the problem of phantom size is mentioned. Finally, the results of dose measurements in the phantom are presented, since such information is important in cases where it becomes necessary to transform personnel doses into personal doses. (author)

  13. Predicting radiation effects on the development of leukemic stem cells based on studies of leukemias induced by high- and low-dose-rate radiation

    International Nuclear Information System (INIS)

    Hirouchi, Tokuhisa

    2012-01-01

    One of the most important causes of radiation-induced cancers, particularly leukemia, is gene mutations resulting from single and double strand breaks in the DNA. Tanaka et al. (2003) reported life shortening in specific pathogen free male and female B6C3F1 mice continuously exposed to γ rays at a low dose rate of 20 mGy/22 h/d for 400 days from 8 weeks of age. Early death due to cancer, mostly malignant lymphomas, was observed in both sexes. A significant increase in the incidence of myeloid leukemia, resulting in early death, was also reported in males. It is expected however, that at 20 mGy/22 h/d, which is equivalent to a dose of 15 μGy/min, DNA strand breaks induced in these cells are repaired soon after they occur. Murine leukemias induced by high-dose-rate radiation were also found in males, and 80% of the mice with leukemia had hemizygous deletions in chromosome 2 around the PU.1 gene and they appeared to be derived from DNA strand breaks. Majority of these leukemia showing hemizygous deletions in chromosome 2 revealed point mutations in the remaining alleles resulting in PU.1 inactivation, which was reported to be related to leukemogenesis. These point mutations are assumed to be independent of DNA strand breaks that occur immediately after irradiation, as they appear at later time after irradiation. This review discusses the effect of radiation-induced DNA strand breaks and also mutagenesis induced independently of DNA strand breaks in hematopoietic cells contributing to the development of the first leukemic stem cell. (author)

  14. Single visit rabies pre-exposure priming induces a robust anamnestic antibody response after simulated post-exposure vaccination: results of a dose-finding study.

    Science.gov (United States)

    Jonker, Emile F F; Visser, Leonardus G

    2017-09-01

    The current standard 3-dose intramuscular rabies PrEP schedule suffers from a number of disadvantages that severely limit accessibility and availability. The cost of is often prohibitive, it requires 3 visits to the clinic, and there are regular vaccine shortages. Volunteers ( N  = 30) were randomly assigned to 4 study arms: 1 standard dose intramuscular (IM) dose of PVRV (purified Vero cell rabies vaccine, Verorab), and 1/5th, 2/5th or 3/5th- fractional intradermal (ID) dose of PVRV in a single visit. All subjects received a simulated rabies post-exposure prophylaxis (D0, D3) 1 year later. Rabies virus neutralizing antibodies (RVNA) were determined by virus neutralization microtest (FAVN) on D0, D7, D28, Y1 and Y1 + D7. 28 out of 30 subjects (93%) seroconverted 1 month after primary vaccination; 1 subject in the 1-dose IM arm and 1 in the 1/5th-fractional dose ID arm did not. After 1 year, 22 out of 30 subjects (73%) no longer had RVNA above 0.5 IU/ml, with no discernible difference between study groups. After 1 year, all 30 subjects mounted a booster response within 7 days after simulated PEP, with the highest titers found in the single dose IM group ( P  rabies vaccine was sufficient to induce an adequate anamnestic antibody response to rabies PEP in all subjects 1 year later, even in those in whom the RVNA threshold of 0.5 IU/ml was not reached after priming. © International Society of Travel Medicine, 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

  15. Multiple low-dose radiation prevents type 2 diabetes-induced renal damage through attenuation of dyslipidemia and insulin resistance and subsequent renal inflammation and oxidative stress.

    Directory of Open Access Journals (Sweden)

    Minglong Shao

    Full Text Available Dyslipidemia and lipotoxicity-induced insulin resistance, inflammation and oxidative stress are the key pathogeneses of renal damage in type 2 diabetes. Increasing evidence shows that whole-body low dose radiation (LDR plays a critical role in attenuating insulin resistance, inflammation and oxidative stress.The aims of the present study were to investigate whether LDR can prevent type 2 diabetes-induced renal damage and the underlying mechanisms.Mice were fed with a high-fat diet (HFD, 40% of calories from fat for 12 weeks to induce obesity followed by a single intraperitoneal injection of streptozotocin (STZ, 50 mg/kg to develop a type 2 diabetic mouse model. The mice were exposed to LDR at different doses (25, 50 and 75 mGy for 4 or 8 weeks along with HFD treatment. At each time-point, the kidney weight, renal function, blood glucose level and insulin resistance were examined. The pathological changes, renal lipid profiles, inflammation, oxidative stress and fibrosis were also measured.HFD/STZ-induced type 2 diabetic mice exhibited severe pathological changes in the kidney and renal dysfunction. Exposure of the mice to LDR for 4 weeks, especially at 50 and 75 mGy, significantly improved lipid profiles, insulin sensitivity and protein kinase B activation, meanwhile, attenuated inflammation and oxidative stress in the diabetic kidney. The LDR-induced anti-oxidative effect was associated with up-regulation of renal nuclear factor E2-related factor-2 (Nrf-2 expression and function. However, the above beneficial effects were weakened once LDR treatment was extended to 8 weeks.These results suggest that LDR exposure significantly prevented type 2 diabetes-induced kidney injury characterized by renal dysfunction and pathological changes. The protective mechanisms of LDR are complicated but may be mainly attributed to the attenuation of dyslipidemia and the subsequent lipotoxicity-induced insulin resistance, inflammation and oxidative stress.

  16. A threshold in the dose-response relationship for X-ray induced somatic mutation frequency in drosophila melanogaster

    International Nuclear Information System (INIS)

    Koana, Takao; Sakai, Kazuo; Okada, M.O.

    2004-01-01

    The dose-response relationship of ionizing radiation and its stochastic effects has been thought to be linear without any thresholds for a long time. The basic data for this model was obtained from mutational assays using germ cells of male fruit fly Drosophila melanogaster. However, cancer-causing activity should be examined more appropriately in somatic cells than in germ cells. In this paper, we examined the dose-response relationship of X-ray irradiation and somatic mutation in drosophila, and found a threshold at approximately 1 Gy in the DNA repair proficient flies. In the repair deficient siblings, the threshold was smaller and the inclination of the dose-response curve was five times steeper. These results suggest that the dose-response relationship between X-ray irradiation and somatic mutation has a threshold, and that the DNA repair function contributes to its formation. (author)

  17. Methanolic extract of Moringa oleifera leaf and low doses of gamma radiation alleviated amiodarone-induced lung toxicity in albino rats

    Directory of Open Access Journals (Sweden)

    Hasan Hesham F.

    2016-01-01

    Full Text Available This study aimed to evaluate the effects of methanolic extract of Moringa oleifera (MO and/or low doses of gamma radiation (LDR on amiodarone (AMD-induced lung toxicity in rats. AMD administered to female albino rats (100 mg/kg body weight for 10 consecutive days. Rats received methanolic extract of MO (250 mg/kg bwt for 15 successive days and/or were exposed to whole body LDR (0.25Gy on the 1st and 10th days, up to a total dose of 0.5Gy. MO administration induced a significant decrease in serum tumor necrosis factor-alpha (TNF-α and transforming growth factor-beta (TGF-β levels as well as lactate dehydrogenase (LDH activity. Also, the content of malondialdehyde (MDA and hydroxyproline (HYP was significantly decreased in lung tissue. Furthermore, MO significantly increased reduced glutathione (GSH content in lung tissue as compared with AMD. The histopathological investigation of lung tissue revealed the appearance of interstitial pneumonia in rats treated with AMD. The oral administration of MO and/or exposure to LDR reversed the biochemical and histopathological alterations induced by AMD. It can be posited that MO and LDR might have a considerable role in the prevention of lung toxicity induced by AMD.

  18. Chronic Low Dose Rate Ionizing Radiation Exposure Induces Premature Senescence in Human Fibroblasts that Correlates with Up Regulation of Proteins Involved in Protection against Oxidative Stress

    Directory of Open Access Journals (Sweden)

    Olga Loseva

    2014-07-01

    Full Text Available The risks of non-cancerous diseases associated with exposure to low doses of radiation are at present not validated by epidemiological data, and pose a great challenge to the scientific community of radiation protection research. Here, we show that premature senescence is induced in human fibroblasts when exposed to chronic low dose rate (LDR exposure (5 or 15 mGy/h of gamma rays from a 137Cs source. Using a proteomic approach we determined differentially expressed proteins in cells after chronic LDR radiation compared to control cells. We identified numerous proteins involved in protection against oxidative stress, suggesting that these pathways protect against premature senescence. In order to further study the role of oxidative stress for radiation induced premature senescence, we also used human fibroblasts, isolated from a patient with a congenital deficiency in glutathione synthetase (GS. We found that these GS deficient cells entered premature senescence after a significantly shorter time of chronic LDR exposure as compared to the GS proficient cells. In conclusion, we show that chronic LDR exposure induces premature senescence in human fibroblasts, and propose that a stress induced increase in reactive oxygen species (ROS is mechanistically involved.

  19. Suppressor of cytokine signaling 2 (SOCS2) deletion protects against multiple low dose streptozotocin-induced type 1 diabetes in adult male mice

    DEFF Research Database (Denmark)

    Alkharusi, Amira; Mirecki-Garrido, Mercedes; Ma, Zuheng

    2016-01-01

    Background: Diabetes type 1 is characterized by the failure of beta cells to produce insulin. Suppressor of cytokine signaling (SOCS) proteins are important regulators of the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway. Previous studies have shown that GH can...... prevent the development of type I diabetes in mice and that SOCS2 deficiency mimics a state of increased GH sensitivity. Methodology: The elevated sensitivity of SOCS2-/- mice to GH and possibly to PRL was the rationale to analyze the effects of multiple low dose streptozotocin (MLDSTZ)-induced diabetes...... in SOCS2-/- mice. Results: We show that 6-month-old SOCS2-/- mice, but not 2-month-old mice, were less sensitive to MLDSTZ-induced diabetes, compared to controls. MLDSTZ treatment induced glucose intolerance in both SOCS2+/+ and SOCS2-/- mice, as shown by glucose tolerance tests, with SOCS2+/+ mice...

  20. Magnetic-field-induced dose effects in MR-guided radiotherapy systems: dependence on the magnetic field strength.

    Science.gov (United States)

    Raaijmakers, A J E; Raaymakers, B W; Lagendijk, J J W

    2008-02-21

    Several institutes are currently working on the development of a radiotherapy treatment system with online MR imaging (MRI) modality. The main difference between their designs is the magnetic field strength of the MRI system. While we have chosen a 1.5 Tesla (T) magnetic field strength, the Cross Cancer Institute in Edmonton will be using a 0.2 T MRI scanner and the company Viewray aims to use 0.3 T. The magnetic field strength will affect the severity of magnetic field dose effects, such as the electron return effect (ERE): considerable dose increase at tissue air boundaries due to returning electrons. This paper has investigated how the ERE dose increase depends on the magnetic field strength. Therefore, four situations where the ERE occurs have been simulated: ERE at the distal side of the beam, the lateral ERE, ERE in cylindrical air cavities and ERE in the lungs. The magnetic field comparison values were 0.2, 0.75, 1.5 and 3 T. Results show that, in general, magnetic field dose effects are reduced at lower magnetic field strengths. At the distal side, the ERE dose increase is largest for B = 0.75 T and depends on the irradiation field size for B = 0.2 T. The lateral ERE is strongest for B = 3 T but shows no effect for B = 0.2 T. Around cylindrical air cavities, dose inhomogeneities disappear if the radius of the cavity becomes small relative to the in-air radius of the secondary electron trajectories. At larger cavities (r > 1 cm), dose inhomogeneities exist for all magnetic field strengths. In water-lung-water phantoms, the ERE dose increase takes place at the water-lung transition and the dose decreases at the lung-water transition, but these effects are minimal for B = 0.2 T. These results will contribute to evaluating the trade-off between magnetic field dose effects and image quality of MR-guided radiotherapy systems.

  1. Magnetic-field-induced dose effects in MR-guided radiotherapy systems: dependence on the magnetic field strength

    International Nuclear Information System (INIS)

    Raaijmakers, A J E; Raaymakers, B W; Lagendijk, J J W

    2008-01-01

    Several institutes are currently working on the development of a radiotherapy treatment system with online MR imaging (MRI) modality. The main difference between their designs is the magnetic field strength of the MRI system. While we have chosen a 1.5 Tesla (T) magnetic field strength, the Cross Cancer Institute in Edmonton will be using a 0.2 T MRI scanner and the company Viewray aims to use 0.3 T. The magnetic field strength will affect the severity of magnetic field dose effects, such as the electron return effect (ERE): considerable dose increase at tissue air boundaries due to returning electrons. This paper has investigated how the ERE dose increase depends on the magnetic field strength. Therefore, four situations where the ERE occurs have been simulated: ERE at the distal side of the beam, the lateral ERE, ERE in cylindrical air cavities and ERE in the lungs. The magnetic field comparison values were 0.2, 0.75, 1.5 and 3 T. Results show that, in general, magnetic field dose effects are reduced at lower magnetic field strengths. At the distal side, the ERE dose increase is largest for B = 0.75 T and depends on the irradiation field size for B = 0.2 T. The lateral ERE is strongest for B = 3 T but shows no effect for B = 0.2 T. Around cylindrical air cavities, dose inhomogeneities disappear if the radius of the cavity becomes small relative to the in-air radius of the secondary electron trajectories. At larger cavities (r > 1 cm), dose inhomogeneities exist for all magnetic field strengths. In water-lung-water phantoms, the ERE dose increase takes place at the water-lung transition and the dose decreases at the lung-water transition, but these effects are minimal for B = 0.2 T. These results will contribute to evaluating the trade-off between magnetic field dose effects and image quality of MR-guided radiotherapy systems

  2. Dose-responsiveness and persistence of microRNA expression alterations induced by cigarette smoke in mouse lung

    International Nuclear Information System (INIS)

    Izzotti, Alberto; Larghero, Patrizia; Longobardi, Mariagrazia; Cartiglia, Cristina; Camoirano, Anna; Steele, Vernon E.; De Flora, Silvio

    2011-01-01

    Our previous studies demonstrated that exposure to cigarette smoke (CS), either mainstream or environmental, results in a remarkable downregulation of microRNA expression in the lung of both mice and rats. The goals of the present study were to evaluate the dose responsiveness to CS and the persistence of microRNA alterations after smoking cessation. ICR (CD-1) neonatal mice were exposed whole-body to mainstream CS, at the doses of 119, 292, 438, and 631 mg/m 3 of total particulate matter. Exposure started within 12 h after birth and continued daily for 4 weeks. The levels of bulky DNA adducts and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodGuo) were measured by 32 P postlabeling procedures, and the expression of 697 mouse microRNAs was analyzed by microarray. The highest CS dose was lethal. Exposure to CS caused a dose-dependent increase of DNA alterations. DNA adducts and, even more sharply, 8-oxodGuo were reverted 1 and 4 weeks after smoking cessation. Exposure to CS resulted in an evident dysregulation of microRNA expression profiles, mainly in the sense of downregulation. The two lowest doses were not particularly effective, while the highest nonlethal dose produced extensive microRNA alterations. The expression of most downregulated microRNAs, including among others 7 members of the let-7 family, was restored one week after smoking cessation. However, the recovery was incomplete for a limited array of microRNAs, including mir-34b, mir-345, mir-421, mir-450b, mir-466, and mir-469. Thus, it appears that microRNAs mainly behave as biomarkers of effect and that exposure to high-dose, lasting for an adequate period of time, is needed to trigger the CS-related carcinogenesis process in the experimental animal model used.

  3. Radiation-induced changes in breathing frequency and lung histology of C57BL/6J mice are time- and dose-dependent

    Energy Technology Data Exchange (ETDEWEB)

    Eldh, T.; Heinzelmann, F.; Velalakan, A. [Univ. Hospital of Tuebingen (Germany). Dept. of Radiation Oncology; Budach, W. [Duesseldorf Univ. (Germany). Dept. of Radiation Oncology; Belka, C. [Univ. Hospital of Tuebingen (Germany). Dept. of Radiation Oncology; Muenchen Univ. (Germany). Dept. of Radiation Oncology; Jendrossek, V. [Univ. Hospital of Tuebingen (Germany). Dept. of Radiation Oncology; Duisburg-Essen Univ., Essen (DE). Inst. of Cell Biology (Cancer Research)

    2012-03-15

    Pneumonitis and fibrosis constitute serious adverse effects of radiotherapy in the thoracic region. In this study, time-course and dose-dependence of clinically relevant parameters of radiation-induced lung injury in C57BL/6J mice were analyzed. A well-characterized disease model is necessary for the analysis of the cellular and molecular mechanisms using genetically modified mice. C57BL/6J mice received single dose right hemithorax irradiation with 12.5 or 22.5 Gy. Body weight and breathing frequency were recorded as parameters for health impairment. Lung tissue was collected over 24 weeks for histological analysis. Hemithorax irradiation with 12.5 or 22.5 Gy induced biphasic breathing impairment with the first increase between days 7 and 70. Although breathing impairment was more pronounced in the 22.5 Gy group, it was accompanied in both dose groups by pneumonitis-associated histological changes. A second rise in breathing frequency ratios became visible starting on day 70 with a steady increase until day 210. Again, breathing wa