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Sample records for hepatocarcinogenic dose induces

  1. Repeated-dose liver micronucleus assay: an investigation with 2-nitropropane, a hepatocarcinogen.

    Science.gov (United States)

    Kawakami, Satoru; Araki, Tetsuro; Nakajima, Mikio; Kusuoka, Osamu; Uchida, Keisuke; Sato, Norihiro; Tanabe, Yoko; Takahashi, Kaori; Wako, Yumi; Kawasako, Kazufumi; Tsurui, Kazuyuki

    2015-03-01

    The utility of the repeated-dose liver micronucleus (RDLMN) assay in the detection of a genotoxic hepatocarcinogen was evaluated. In this paper, a rat hepatocarcinogen, 2-nitropropane (2-NP), was administered orally to young adult rats for 14 and 28 days without a partial hepatectomy or a mitogen, and the micronucleus induction in liver was examined using a simple method to isolate hepatocytes. In addition, a bone marrow micronucleus assay was conducted concomitantly. The frequency of micronucleated hepatocytes induced by 2-NP increased significantly in both the 14- and 28-day repeated-dose studies, while the bone marrow micronucleus assays were negative in each study. These results indicate that the RDLMN assay is useful for detecting a genotoxic hepatocarcinogen that is negative in bone marrow micronucleus assays and is a suitable in vivo genotoxicity test method for integration into a repeated-dose general toxicity study. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. Relationship of hepatocarcinogenicity and hepatocellular proliferation induced by mutagenic noncarcinogens vs carcinogens. II. 1- vs 2-nitropropane.

    Science.gov (United States)

    Cunningham, M L; Matthews, H B

    1991-09-15

    2-Nitropropane (2-NP) is mutagenic in a number of short-term mutagenicity assays in vitro and in vivo, and is a potent hepatocarcinogen in rats. A structural isomer, 1-nitropropane (1-NP), is mutagenic in V79 cells and can induce unscheduled DNA synthesis in rat hepatocytes, yet did not induce tumors in rats following chronic exposure. We examined the correlation of cell proliferation and hepatocarcinogenesis induced by this mutagenic noncarcinogen-carcinogen pair in a rat liver proliferation model. Rats were exposed to gavage doses of 0.5, 1, or 2 mmol/kg of 1-NP or 2-NP daily for 10 days; the highest two dose groups were similar to the doses used in the carcinogenesis bioassay. Cell proliferation was quantitated by incorporation of bromodeoxyuridine, detected immunohistochemically, into newly synthesized DNA. Animals exposed to the vehicle exhibited a labeling index (LI) of approximately 1.9% and animals exposed to CCL4 had a LI of approximately 30%. Rats exposed to the hepatocarcinogen 2-NP exhibited a dose-related increase in LI to 6.3 and 11% at the 1 and 2 mmol/kg doses, respectively, and no increase above control at the 0.5 mmol/kg exposure level. Animals exposed to the noncarcinogenic isomer 1-NP showed no statistically significant increase in LI above controls at any dose level tested. Serum chemistries were consistent with mild to moderate decreases in hepatocellular function, cholestasis, and necrosis following 2-NP exposure, but only minimal effects were observed, probably due to slight dehydration resulting from 1-NP exposure. These data indicate a positive association between increased cell proliferation and hepatocarcinogenesis induced by these two nitropropane isomers.

  3. Aberrant DNA methylation and gene expression in livers of newborn mice transplacentally exposed to a hepatocarcinogenic dose of inorganic arsenic

    Science.gov (United States)

    Xie, Yaxiong; Liu, Jie; Benbrahim-Tallaa, Lamia; Ward, Jerry M.; Logsdon, Daniel; Diwan, Bhalchandra A.; Waalkes, Michael P.

    2008-01-01

    Our prior work showed that brief exposure of pregnant C3H mice to inorganic arsenic-induced hepatocellular carcinoma (HCC) formation in adult male offspring. The current study examined the early hepatic events associated with this oncogenic transformation. Pregnant mice were exposed to a known carcinogenic dose of arsenic (85 ppm) in the drinking water from gestation days 8 to 18. The dams were allowed to give birth and liver samples from newborn males were analyzed for arsenic content, global DNA methylation and aberrant expression of genes relevant to the carcinogenic process. Arsenic content in newborn liver reached 57 ng/g wet weight, indicating arsenic had crossed the placenta, reached the fetal liver and that significant amounts remained after birth. Global methylation status of hepatic DNA was not altered by arsenic in the newborn. However, a significant reduction in methylation occurred globally in GC-rich regions. Microarray and real-time RT-PCR analysis showed that arsenic exposure enhanced expression of genes encoding for glutathione production and caused aberrant expression of genes related to insulin growth factor signaling pathways and cytochrome P450 enzymes. Other expression alterations observed in the arsenic-treated male mouse newborn liver included the overexpression of cdk-inhibitors and stress response genes including increased expression of metallothionein-1 and decreased expression of betaine-homocysteine methyltransferase and thioether S-methyltransferase. Thus, transplacental exposure to arsenic at a hepatocarcinogenic dose induces alterations in DNA methylation and a complex set of aberrant gene expressions in the newborn liver, a target of arsenic carcinogenesis. PMID:17451858

  4. 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

  5. Oxidative DNA and RNA damage in the livers of Sprague-Dawley rats treated with the hepatocarcinogen 2-nitropropane.

    Science.gov (United States)

    Fiala, E S; Conaway, C C; Mathis, J E

    1989-10-15

    2-Nitropropane (2-NP), a widely used industrial chemical, is a mutagen in bacteria and a powerful hepatocarcinogen in Sprague-Dawley rats. In contrast, 1-nitropropane (1-NP) is not mutagenic and does not appear to be carcinogenic. Thus far, the mechanism of carcinogenicity of 2-NP has not been examined. We report in the present work that i.p. treatment of male Sprague-Dawley rats with 100 mg/kg 2-NP results in a 3.6-fold increase (P less than 0.01) in the levels of 8-hydroxydeoxyguanosine as well as in the appearance of an additional electrochemically active species, presumably a modified deoxynucleoside, in liver DNA hydrolysates 6 h after dosing. Treatment with 2-NP also induces an 11-fold increase (P less than 0.0001) in the levels of 8-hydroxyguanosine in rat liver RNA, and results in the appearance of two new electrochemically active species (RX1 and RX2), presumably modified nucleosides. Small, statistically not significant increases of 8-hydroxyguanosine in RNA and of 8-hydroxydeoxyguanosine in DNA, as well as the induction of much smaller amounts of RX2 (but apparently not RX1) in rat liver RNA, are also observed following analogous treatment with 1-NP. Since the presence of 8-hydroxyguanine, a product of the attack of hydroxyl radicals (or other reactive oxygen species) on guanine, can cause DNA misreplication [Kuchino et al., Nature (Lond.), 327: 77-79, 1987], our findings are consistent with a mechanism of hepatocarcinogenicity of 2-NP based on damage to nucleic acids from the intracellular generation of reactive forms of oxygen and/or the 2-NP free radical.

  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

    Science.gov (United States)

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

    2009-01-01

    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 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. PMID:17350061

  7. Anti-hepatocarcinogenic and Anti-oxidant Effects of Mangrove Plant Scyphiphora hydrophyllacea.

    Science.gov (United States)

    Samarakoon, Sameera R; Shanmuganathan, Chanthirika; Ediriweera, Meran K; Piyathilaka, Poorna; Tennekoon, Kamani H; Thabrew, Ira; Galhena, Prasanna; De Silva, E Dilip

    2017-01-01

    Scyphiphora hydrophyllacea is a shrub mangrove plant of the family Rubiaceae and not yet been studied for anti-hepatocarcinogenic effects. We investigated possible in vitro anti-hepatocarcinogenic and antioxidant properties of S. hydrophyllacea. Dried leaves of S. hydrophyllacea were sequentially extracted into hexane, chloroform, ethyl acetate, and methanol and tested for cytotoxicity on HepG2 cells by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and sulforhodamine B assays, and for antioxidant activities by the free radical 1,1-diphenyl-2-picryl-hydrazyl (DPPH) and 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulfonic acid (ABTS) assays. Total phenolic and flavonoid contents were estimated in all four extracts. The hexane and chloroform extracts were tested for pro-apoptotic properties in HepG2 cells, and bioactive components were identified by gas chromatography-mass spectrometry (GC-MS) analysis. The hexane and chloroform extracts showed dose-dependent and time-dependent cytotoxic effects. Morphological changes observed under fluorescence microscope related to apoptosis, and significant (P hydrophyllacea concluded that these two extracts are good source for isolation of possible anticarcinogenic compounds. The hexane and chloroform extracts of Scyphiphora hydrophyllacea showed dose-dependent and time-dependent cytotoxic effects.Morphological changes related to apoptosis and significant (P < 0.001) increases in caspase 3 and 9 levels were observed in hexane and chloroform extract-treated cells.mRNA expressions of p53 and Bax were significantly upregulated by low doses of hexane and chloroform extracts.Highest antioxidant activity was observed in the methanol extract.GC-MS profiles identified 24 and four major compounds in the hexane and chloroform extracts, respectively. Abbreviation used: DPPH: 1,1-diphenyl-2-picryl-hydrazyl, ABTS: 2,2'-azinobis-3-ethylbenzthiazoline-6-sulfonic acid, GC-MS: gas chromatography-mass spectrometry, DNA: deoxyribonucleic

  8. Anti-hepatocarcinogenic and Anti-oxidant Effects of Mangrove Plant Scyphiphora hydrophyllacea

    OpenAIRE

    Samarakoon, Sameera R.; Shanmuganathan, Chanthirika; Ediriweera, Meran K.; Piyathilaka, Poorna; Tennekoon, Kamani H.; Thabrew, Ira; Galhena, Prasanna; De Silva, E Dilip

    2017-01-01

    Context: Scyphiphora hydrophyllacea is a shrub mangrove plant of the family Rubiaceae and not yet been studied for anti-hepatocarcinogenic effects. Objectives: We investigated possible in vitro anti-hepatocarcinogenic and antioxidant properties of S. hydrophyllacea. Materials and Methods: Dried leaves of S. hydrophyllacea were sequentially extracted into hexane, chloroform, ethyl acetate, and methanol and tested for cytotoxicity on HepG2 cells by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetra...

  9. 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.

  10. Transcriptomic responses generated by hepatocarcinogens in a battery of liver-based in vitro models.

    Science.gov (United States)

    Doktorova, Tatyana Y; Yildirimman, Reha; Vinken, Mathieu; Vilardell, Mireia; Vanhaecke, Tamara; Gmuender, Hans; Bort, Roque; Brolen, Gabriella; Holmgren, Gustav; Li, Ruoya; Chesne, Christophe; van Delft, Joost; Kleinjans, Jos; Castell, Jose; Bjorquist, Petter; Herwig, Ralf; Rogiers, Vera

    2013-06-01

    As the conventional approach to assess the potential of a chemical to cause cancer in humans still includes the 2-year rodent carcinogenicity bioassay, development of alternative methodologies is needed. In the present study, the transcriptomics responses following exposure to genotoxic (GTX) and non-genotoxic (NGTX) hepatocarcinogens and non-carcinogens (NC) in five liver-based in vitro models, namely conventional and epigenetically stabilized cultures of primary rat hepatocytes, the human hepatoma-derived cell lines HepaRG and HepG2 and human embryonic stem cell-derived hepatocyte-like cells, are examined. For full characterization of the systems, several bioinformatics approaches are employed including gene-based, ConsensusPathDB-based and classification analysis. They provide convincingly similar outcomes, namely that upon exposure to carcinogens, the HepaRG generates a gene classifier (a gene classifier is defined as a selected set of characteristic gene signatures capable of distinguishing GTX, NGTX carcinogens and NC) able to discriminate the GTX carcinogens from the NGTX carcinogens and NC. The other in vitro models also yield cancer-relevant characteristic gene groups for the GTX exposure, but some genes are also deregulated by the NGTX carcinogens and NC. Irrespective of the tested in vitro model, the most uniformly expressed pathways following GTX exposure are the p53 and those that are subsequently induced. The NGTX carcinogens triggered no characteristic cancer-relevant gene profiles in all liver-based in vitro systems. In conclusion, liver-based in vitro models coupled with transcriptomics techniques, especially in the case when the HepaRG cell line is used, represent valuable tools for obtaining insight into the mechanism of action and identification of GTX carcinogens.

  11. Biological Networks for Predicting Chemical Hepatocarcinogenicity Using Gene Expression Data from Treated Mice and Relevance across Human and Rat Species

    Science.gov (United States)

    Thomas, Reuben; Thomas, Russell S.; Auerbach, Scott S.; Portier, Christopher J.

    2013-01-01

    Background Several groups have employed genomic data from subchronic chemical toxicity studies in rodents (90 days) to derive gene-centric predictors of chronic toxicity and carcinogenicity. Genes are annotated to belong to biological processes or molecular pathways that are mechanistically well understood and are described in public databases. Objectives To develop a molecular pathway-based prediction model of long term hepatocarcinogenicity using 90-day gene expression data and to evaluate the performance of this model with respect to both intra-species, dose-dependent and cross-species predictions. Methods Genome-wide hepatic mRNA expression was retrospectively measured in B6C3F1 mice following subchronic exposure to twenty-six (26) chemicals (10 were positive, 2 equivocal and 14 negative for liver tumors) previously studied by the US National Toxicology Program. Using these data, a pathway-based predictor model for long-term liver cancer risk was derived using random forests. The prediction model was independently validated on test sets associated with liver cancer risk obtained from mice, rats and humans. Results Using 5-fold cross validation, the developed prediction model had reasonable predictive performance with the area under receiver-operator curve (AUC) equal to 0.66. The developed prediction model was then used to extrapolate the results to data associated with rat and human liver cancer. The extrapolated model worked well for both extrapolated species (AUC value of 0.74 for rats and 0.91 for humans). The prediction models implied a balanced interplay between all pathway responses leading to carcinogenicity predictions. Conclusions Pathway-based prediction models estimated from sub-chronic data hold promise for predicting long-term carcinogenicity and also for its ability to extrapolate results across multiple species. PMID:23737943

  12. Biological networks for predicting chemical hepatocarcinogenicity using gene expression data from treated mice and relevance across human and rat species.

    Directory of Open Access Journals (Sweden)

    Reuben Thomas

    Full Text Available BACKGROUND: Several groups have employed genomic data from subchronic chemical toxicity studies in rodents (90 days to derive gene-centric predictors of chronic toxicity and carcinogenicity. Genes are annotated to belong to biological processes or molecular pathways that are mechanistically well understood and are described in public databases. OBJECTIVES: To develop a molecular pathway-based prediction model of long term hepatocarcinogenicity using 90-day gene expression data and to evaluate the performance of this model with respect to both intra-species, dose-dependent and cross-species predictions. METHODS: Genome-wide hepatic mRNA expression was retrospectively measured in B6C3F1 mice following subchronic exposure to twenty-six (26 chemicals (10 were positive, 2 equivocal and 14 negative for liver tumors previously studied by the US National Toxicology Program. Using these data, a pathway-based predictor model for long-term liver cancer risk was derived using random forests. The prediction model was independently validated on test sets associated with liver cancer risk obtained from mice, rats and humans. RESULTS: Using 5-fold cross validation, the developed prediction model had reasonable predictive performance with the area under receiver-operator curve (AUC equal to 0.66. The developed prediction model was then used to extrapolate the results to data associated with rat and human liver cancer. The extrapolated model worked well for both extrapolated species (AUC value of 0.74 for rats and 0.91 for humans. The prediction models implied a balanced interplay between all pathway responses leading to carcinogenicity predictions. CONCLUSIONS: Pathway-based prediction models estimated from sub-chronic data hold promise for predicting long-term carcinogenicity and also for its ability to extrapolate results across multiple species.

  13. Single dose regorafenib-induced hypertensive crisis.

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    Yilmaz, B; Kemal, Y; Teker, F; Kut, E; Demirag, G; Yucel, I

    2014-06-01

    Gastrointestinal stromal tumors (GISTs) are uncommon tumors of the gastrointestinal (GI) tract. Regorafenib is a new multikinase inhibitor and is approved for the treatment of GISTs in patients who develop resistance to imatinib and sunitinib. The most common drug-related adverse events with regorafenib are hypertension, hand-foot skin reactions, and diarrhea. Grade IV hypertensive side effect has never been reported after a single dose. In this report, we present a case of Grade IV hypertensive side effect (hypertensive crisis and seizure) after a single dose of regorafenib. A 54-year-old male normotensive GIST patient was admitted to the emergency department with seizure and encephalopathy after the first dosage of regorafenib. His blood pressure was 240/140 mmHg upon admission. After intensive treatment with nitrate and nitroprusside, his blood pressure returned to normal levels in five days. Regorafenib was discontinued, and he did not experience hypertension again. This paper reports the first case of Grade IV hypertension after the first dosage of regorafenib. We can suggest that hypertension is an idiosyncratic side effect unrelated to the dosage.

  14. Low doses of neutrons induce changes in gene expression

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    Woloschak, G.E.; Chang-Liu, C.M. (Argonne National Lab., IL (United States)); Panozzo, J.; Libertin, C.R. (Loyola Univ., Maywood, IL (United States))

    1993-01-01

    Studies were designed to identify genes induced following low-dose neutron but not following [gamma]-ray exposure in fibroblasts. Our past work had shown differences in the expression of [beta]-protein kinase C and c-fos genes, both being induced following [gamma]-ray but not neutron exposure. We have identified two genes that are induced following neutron, but not [gamma]-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 [gamma] 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.

  15. Low doses of neutrons induce changes in gene expression

    Energy Technology Data Exchange (ETDEWEB)

    Woloschak, G.E.; Chang-Liu, C.M. [Argonne National Lab., IL (United States); Panozzo, J.; Libertin, C.R. [Loyola Univ., Maywood, IL (United States)

    1993-06-01

    Studies were designed to identify genes induced following low-dose neutron but not following {gamma}-ray exposure in fibroblasts. Our past work had shown differences in the expression of {beta}-protein kinase C and c-fos genes, both being induced following {gamma}-ray but not neutron exposure. We have identified two genes that are induced following neutron, but not {gamma}-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 {gamma} 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.

  16. Dose-Dependent Amelioration of Gentamicin-Induced ...

    African Journals Online (AJOL)

    increase in serum urea and creatine while 3ml/kg of the same drug completely prevented the increase in serum urea and creatine in this model. Conclusion: Vitamin B-complex dose-dependently ameliorated gentamicin-induced nephrotoxicity in adult Swiss albino rats when given intramuscularly. This finding may have ...

  17. Downregulation of TMEM70 in Rat Liver Cells After Hepatocarcinogen Treatment Related to the Warburg Effect in Hepatocarcinogenesis Producing GST-P-Expressing Proliferative Lesions.

    Science.gov (United States)

    Mizukami, Sayaka; Watanabe, Yousuke; Nakajima, Kota; Hasegawa-Baba, Yasuko; Jin, Meilan; Yoshida, Toshinori; Shibutani, Makoto

    2017-09-01

    We previously observed downregulation of mitochondrial oxidative phosphorylation-related protein, TMEM70, which is suggestive of disrupted cellular senescence, in GST-P-expressing (+) proliferative lesions from early hepatocarcinogenesis stages in rats. The present study investigated the immunohistochemical relationship between TMEM70 downregulation and cellular metabolic changes in carcinogenic processes, as well as the onset of the liver cell respiratory changes after repeated hepatocarcinogen treatment in rats. At the early hepatocarcinogenesis stage in a 2-stage model, GST-P+ preneoplastic lesions showing TMEM70 downregulation also downregulated the mitochondrial ATPase, ATPB, but upregulated glycolysis-related glucose transporter member 1 (GLUT1) and glucose-6-phosphate dehydrogenase, suggesting a metabolic shift from oxidative phosphorylation to glycolysis, known as the Warburg effect. Combined downregulation of TMEM70 and ATPB increased proliferation activity in GST-P+ preneoplastic lesions, suggesting cell proliferation facilitation by reducing mitochondrial respiration. Concurrent GLUT1-upregulation and TMEM70-downregulation increased nuclear phosphorylated c-MYC+ cells in GST-P+ preneoplastic lesions, suggesting c-MYC-mediated transcription facilitation to promote glycolysis and cell proliferation. The TMEM70-related metabolic shift was enhanced in GST-P+ neoplastic lesions, suggesting a contribution to tumor progression. Conversely, the TMEM70-related metabolic shift was lacking in peroxisome proliferator-activated receptor-α agonist-induced hepatocarcinogenesis, as well as in carcinogenic processes targeting other organs. Transcript expression analysis following 28- and 90-day repeated hepatocarcinogen treatment showed downregulation of Tmem70 from day 28 and upregulation of Pkm and Myc at day 90, suggesting early onset of a catastrophic cellular senescence-related metabolic shift beginning from depressed mitochondrial respiration in the liver. These

  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 IR Creates an Oncogenic Microenvironment by Inducing Premature

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    Yuan, Zhi-Min [Harvard School of Public Health

    2013-04-28

    Introduction Much of the work addressing ionizing radiation-induced cellular response has been carried out mainly with the traditional cell culture technique involving only one cell type, how cellular response to IR is influenced by the tissue microenvironment remains elusive. By use of a three-dimensional (3D) co-culture system to model critical interactions of different cell types with their neighbors and with their environment, we recently showed that low-dose IR-induced extracellular signaling via the tissue environment affects profoundly cellular responses. This proposal aims at determining the response of mammary epithelial cells in a tissue-like setting.

  20. N2-amination of guanine to 2-hydrazinohypoxanthine, a novel in vivo nucleic acid modification produced by the hepatocarcinogen 2-nitropropane.

    Science.gov (United States)

    Sodum, R S; Fiala, E S

    1998-12-01

    2-Nitropropane, an industrial chemical and a hepatocarcinogen in rats, induces aryl sulfotransferase-mediated liver DNA and RNA base modifications [Sodum, R. S., Sohn, O. S., Nie, G., and Fiala, E. S. (1994) Chem. Res. Toxicol. 7, 344-351]. Two of these modifications were previously identified as 8-aminoguanine and 8-oxoguanine. We now report that the base moiety of the so far unidentified third nucleic acid modification, namely RX1 in RNA and DX1 in DNA, is 2-hydrazinohypoxanthine (N2-aminoguanine). 2-Hydrazinoinosine and 2-hydrazinodeoxyinosine, synthesized by adapting published procedures, cochromatographed with RX1 and DX1 of liver RNA and DNA, respectively, from 2-nitropropane-treated rats. 2-Hydrazinoinosine and 2-hydrazinodeoxyinosine are unstable in solution like the in vivo products RX1 and DX1. At neutral pH, hypoxanthine nucleoside is the major product of decomposition, while at pH 10 or above, xanthine nucleoside is also formed. RX1 and DX1 could be generated in the anaerobic reactions of hydroxylamine-O-sulfonic acid, an intermediate in the proposed activation pathway of 2-nitropropane, with guanine nucleosides. These results provide further evidence for the activation of 2-nitropropane and other carcinogenic secondary nitroalkanes to a reactive species capable of aminating nucleic acids and proteins.

  1. Dammar resin, a non-mutagen, induces [corrected] oxidative stress and metabolic enzymes in the liver of gpt delta transgenic mouse which is different from a mutagen, 2-amino-3-methylimidazo[4,5-f]quinoline.

    Science.gov (United States)

    Xie, Xiao-Li; Wei, Min; Kakehashi, Anna; Yamano, Shotaro; Okabe, Kyoko; Tajiri, Masaki; Wanibuchi, Hideki

    2012-10-09

    Dammar resin has long been used in foods as either a clouding or a glazing agent. In a recent study, 2% Dammar resin showed significant hepatocarcinogenicity in a rat 2-year bioassay. Therefore, for an accurate estimate of human risk, it is necessary to understand whether Dammar resin induces liver genotoxicity and the underlying mechanisms of its hepatocarcinogenicity. Modifying effects of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), a typical genotoxic carcinogen produced during cooking of protein-rich foods, was also studied in the present study. Exposure of gpt delta mice to Dammar resin at a dose of 2% for 12 weeks did not induce any obvious mutagenicity in the liver. However, the index of cell proliferation, the level of 8-OHdG, and bax, bcl-2, p53, cyp1a2, cyp2e1, gpx1 and gstm2 gene expression were all significantly increased when compared with the control group. In the IQ treatment group, at a dose of 300ppm, mutagenicity was readily detected, the index of cell proliferation increased, and p53, cyp2e1 and gpx1 gene expression was down-regulated in the liver. Down-regulation of p53, P450s, and gpx1 in the livers of IQ treated mice are consistent with its genotoxic mechanism of carcinogenicity observed in a 675-day study. In contrast, our results using gpt delta mice suggest that Dammar resin is not genotoxic. Instead, the Dammar resin-induced hepatocarcinogenicity seen in our previous 2-year study with rats may have been mediated by non-genotoxic mechanisms, including increased P450 enzyme activity, increased oxidative stress, altered gene expression, and promotion of cell proliferation. © 2012 Elsevier B.V. All rights reserved.

  2. 8-Aminoguanine: a base modification produced in rat liver nucleic acids by the hepatocarcinogen 2-nitropropane.

    Science.gov (United States)

    Sodum, R S; Nie, G; Fiala, E S

    1993-01-01

    2-Nitropropane (2-NP), an important industrial chemical and a hepatocarcinogen in rats, had previously been found to produce several modifications of nucleosides in rat liver RNA and DNA that are discernible using HPLC with electrochemical detection. While one of these modifications has been identified as an increase in the levels of 8-oxoguanosine and 8-oxo-2'-deoxyguanosine in RNA and DNA, respectively, the others had not been identified. We now present evidence that a major modification in rat liver nucleic acids due to the administration of 2-NP is the amination of guanine at C8, apparently a completely novel in vivo reaction. 8-Aminoguanosine, isolated from hydrolysates of liver RNA from 2-NP-treated rats, cochromatographed with synthetic or commercially-obtained standard on reverse-phase as well as cation-exchange HPLC, and its UV spectral characteristics at acidic, neutral, and basic pH were identical to those of the standard. Acid hydrolysis produced 8-aminoguanine, which had a retention time and fragmentation pattern identical to that of the standard on gas chromatography-mass spectrometry of the trimethylsilyl derivatives. Evidence for the presence of 8-aminodeoxyguanosine in liver DNA of rats treated with 2-NP was also obtained by cochromatography with synthetic standard on HPLC. Hydroxylamine-O-sulfonic acid was found to react with RNA and DNA to give 8-oxo- and 8-amino-substituted guanines. We propose, as a working hypothesis, that 2-NP may be metabolized to hydroxylamine-O-sulfonate or acetate, which yield the reactive nitrenium ion, NH2+, capable of aminating cellular macromolecules in vivo.

  3. Dose-dependent changes in the locomotor responses to methamphetamine in BALB/c mice: low doses induce hypolocomotion.

    Science.gov (United States)

    Singh, Rana A K; Kosten, Therese A; Kinsey, Berma M; Shen, Xiaoyun; Lopez, Angel Y; Kosten, Thomas R; Orson, Frank M

    2012-12-01

    The overall goal of the present study was to determine the effects of different doses of (+)-methamphetamine (meth) on locomotor activity of Balb/C mice. Four experiments were designed to test a wide range of meth doses in BALB/c female mice. In Experiment 1, we examined locomotor activity induced by an acute administration of low doses of meth (0.01 and 0.03mg/kg) in a 90-min session. Experiment 2 was conducted to test higher meth doses (0.3-10mg/kg). In Experiment 3, separate sets of mice were pre-treated with various meth doses once or twice (one injection/week) prior to a locomotor challenge with a low meth dose. Finally, in Experiment 4, we tested whether locomotor activation would be affected by pretreatment with a low or moderate dose of meth one month prior to the low meth dose challenge. Results show that low doses of meth induce hypolocomotion whereas moderate to high doses induce hyperlocomotion. Prior exposure to either one moderate or high dose of meth or to two, low doses of meth attenuated the hypolocomotor effect of a low meth dose one week later. This effect was also attenuated in mice tested one month after administration of a moderate meth dose. These results show that low and high doses of meth can have opposing effects on locomotor activity. Further, prior exposure to the drug leads to tolerance, rather than sensitization, of the hypolocomotor response to low meth doses. Published by Elsevier Inc.

  4. 2-Nitropropane-induced lipid peroxidation: antitoxic effects of melatonin.

    Science.gov (United States)

    Kim, S J; Reiter, R J; Rouvier Garay, M V; Qi, W; El-Sokkary, G H; Tan, D X

    1998-09-15

    The degree of lipid peroxidation (LPO) as indicated by the levels of thiobarbituric acid reactive substances, malondialdehyde (MDA) and 4-hydroxyalkenals (4-HDA), and the activity of sorbitol dehydrogenase (SDH) in serum as parameters of hepatotoxicity were studied in rats treated with a single intraperitoneal (i.p.) injection of the hepatocarcinogen 2-nitropropane (2-NP). Since melatonin, the main secretory product of the pineal gland, has been shown to protect against a number of toxic agents, it was given 30 min before 2-NP to test its protective effect against 2-NP toxicity. Significant increases in LPO in liver (P<0.0001), lung (P<0.05) and kidney (P<0.0001) were observed 24 h after 4 mmol/kg 2-NP while serum SDH activity was increased 470-fold. All parameters showed time (0, 4, 8, 24 h) and dose (0, 1, 2, 3, 4 mmol/kg) dependency. The induction of LPO by 2-NP was significantly reduced in lung and kidney when melatonin (2.5, 5 or 10 mg/kg) was given prior to 2-NP administration. The elevation in serum SDH caused by 2-NP was also reduced when melatonin was given. These findings show that 2-NP induces LPO and that pharmacological levels of melatonin can reduce the toxicity of this hepatocarcinogen.

  5. Acute Low-Dose Hydralazine-Induced Lupus Pneumonitis

    Directory of Open Access Journals (Sweden)

    Sarah K. Holman

    2017-01-01

    Full Text Available A 35-year-old female was started on hydralazine 10 mg orally three times a day for treatment of postpartum hypertension. Three months later, after multiple unsuccessful courses of prednisone and antibiotics for presumed pneumonia and asthma exacerbations, her respiratory symptoms progressed in severity and she developed resting hypoxia. Previous diagnostic work-up included spirometry with a restrictive pattern, chest CT showing bilateral basilar consolidation, negative BAL, and nonspecific findings on lung biopsy of mild inflammatory cells. Review of systems was positive for arthralgia, lymphadenopathy, paresthesia, and fatigue that began four weeks after starting hydralazine. A clinical diagnosis of hydralazine-induced lupus (HIL with pneumonitis was made. Antihistone antibodies were positive supporting a diagnosis of HIL. Management included cessation of hydralazine and a prolonged steroid taper. Within days, patient began improving symptomatically. Six weeks later, CT chest showed complete resolution of infiltrates. Genetic testing revealed she was heterozygous for N-acetyltransferase 2 (intermediate acetylator. Drug-induced lupus should be considered in patients with lupus-like symptoms taking medications with a known association. While the majority of HIL cases occur with high doses and prolonged treatment, cases of low-dose HIL have been reported in patients who are slow acetylators.

  6. 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.

  7. Supra-physiological dose of testosterone induces pathological cardiac hypertrophy.

    Science.gov (United States)

    Pirompol, Prapawadee; Teekabut, Vassana; Weerachatyanukul, Wattana; Bupha-Intr, Tepmanas; Wattanapermpool, Jonggonnee

    2016-04-01

    Testosterone and androgenic anabolic steroids have been misused for enhancement of physical performance despite many reports on cardiac sudden death. Although physiological level of testosterone provided many regulatory benefits to human health, including the cardiovascular function, supra-physiological levels of the hormone induce hypertrophy of the heart with unclear contractile activation. In this study, dose- and time-dependent effects of high-testosterone treatment on cardiac structure and function were evaluated. Adult male rats were divided into four groups of testosterone treatment for 0, 5, 10, and 20 mg/kg BW for 4, 8, or 12 weeks. Increases in both percentage heart:body weight ratio and cardiomyocyte cross-sectional area in representing hypertrophy of the heart were significantly shown in all testosterone-treated groups to the same degree. In 4-week-treated rats, physiological cardiac hypertrophy was apparent with an upregulation of α-MHC without any change in myofilament contractile activation. In contrast, pathological cardiac hypertrophy was observed in 8- and 12-week testosterone-treated groups, as indicated by suppression of myofilament activation and myocardial collagen deposition without transition of MHC isoforms. Only in 12-week testosterone-treated group, eccentric cardiac hypertrophy was demonstrated with unaltered myocardial stiffness, but significant reductions in the phosphorylation signals of ERK1/2 and mTOR. Results of our study suggest that the outcome of testosterone-induced cardiac hypertrophy is not dose dependent but is rather relied on the factor of exposure to duration in inducing maladaptive responses of the heart. © 2016 Society for Endocrinology.

  8. 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.

  9. Dose-dependent changes in the locomotor responses to methamphetamine in BALB/c mice: Low doses induce hypolocomotion

    OpenAIRE

    Singh, Rana A.K.; Kosten, Therese A.; Berma M Kinsey; Shen, Xiaoyun; Lopez, Angel Y.; Kosten, Thomas R.; Orson, Frank M.

    2012-01-01

    The overall goal of the present study was to determine the effects of different doses of (+)-methamphetamine (meth) on locomotor activity of Balb/C mice. Four experiments were designed to test a wide range of meth doses in BALB/c female mice. In Experiment 1, we examined locomotor activity induced by an acute administration of low doses of meth (0.01 and 0.03 mg/kg) in a 90-min session. Experiment 2 was conducted to test higher meth doses (0.3 – 10 mg/kg). In Experiment 3, separate sets of mi...

  10. Radioactivity of Tobacco Leaves and Radiation Dose Induced from Smoking

    Science.gov (United States)

    Papastefanou, Constantin

    2009-01-01

    The radioactivity in tobacco leaves collected from 15 different regions of Greece and before cigarette production was studied in order to find out any association between the root uptake of radionuclides from soil ground by the tobacco plants and the effective dose induced to smokers from cigarette tobacco due to the naturally occurring primordial radionuclides, such as 226Ra and 210Pb of the uranium series and 228Ra of the thorium series and/or man-made radionuclides, such as 137Cs of Chernobyl origin. Gamma-ray spectrometry was applied using Ge planar and coaxial type detectors of high resolution and high efficiency. It was concluded that the activities of the radioisotopes of radium, 226Ra and 228Ra in the tobacco leaves reflected their origin from the soil by root uptake rather than fertilizers used in the cultivation of tobacco plants. Lead-210 originated from the air and was deposited onto the tobacco leaves and trapped by the trichomes. Potassium-40 in the tobacco leaves was due to root uptake either from soil or from fertilizer. The cesium radioisotopes 137Cs and 134Cs in tobacco leaves were due to root uptake and not due to deposition onto the leaf foliage as they still remained in soil four years after the Chernobyl reactor accident, but were absent from the atmosphere because of the rain washout (precipitation) and gravitational settling. The annual effective dose due to inhalation for adults (smokers) for 226Ra varied from 42.5 to 178.6 μSv/y (average 79.7 μSv/y), while for 228Ra from 19.3 to 116.0 μSv/y (average 67.1 μSv/y) and for 210Pb from 47.0 to 134.9 μSv/y (average 104.7 μSv/y), that is the same order of magnitude for each radionuclide. The sum of the effective doses of the three radionuclides varied from 151.9 to 401.3 μSv/y (average 251.5 μSv/y). The annual effective dose from 137Cs of Chernobyl origin was three orders of magnitude lower as it varied from 70.4 to 410.4 nSv/y (average 199.3 nSv/y). PMID:19440399

  11. Demethylating and anti-hepatocarcinogenic potential of hesperidin, a natural polyphenol of Citrus juices.

    Science.gov (United States)

    Fernández-Bedmar, Zahira; Anter, Jaouad; Alonso-Moraga, Angeles; Martín de Las Mulas, Juana; Millán-Ruiz, Yolanda; Guil-Luna, Silvia

    2017-06-01

    Hepatocellular carcinoma (HCC) is a neoplasia representing the fifth most common malignancy worldwide and the third cause of death from cancer. Diets with high content in fruits and vegetables are widely recommended for their health-promoting properties, among them, the protection against diabetes, cancer, and cardiovascular diseases. Hesperidin is the most important phenol in the orange fruit with well-known health benefits. Diet components have been used as possible modulator agents of DNA methylation in cancer cells and epigenetic therapy against their harmful effects could be a potential tool in chemotherapy. The purpose of the present study was to evaluate the methylation patterns induced by hesperidin in HL60 cell line as an in vitro model in order to analyze its chemopreventive effects in epigenetic cancer therapies. A parallel in vivo pilot experience using a rat diethyl nitrosamine hepatocarcinogenesis-induced model was carried out to validate the therapeutic efficacy of this orange flavonol. Results showed that: (i) Hesperidin is cytotoxic in a dose-dependent manner and the IC 50 was 12.5 mM; (ii) Hesperidin exerts a significant hypomethylating effect on the LINE-1 sequence (up to 47% hypomethylation at 12.5 mM) and on the ALU-M2 repetitive sequences (up to 32% at 6 mM) in HL60 tumor cells. (iii) Hesperidin does not affect the rat body and liver weight and it is able to reduce the diethyl nitrosamine-induced nodules at 1,000, 500, and 250 ppm. In conclusion, hesperidin could be proposed as a candidate molecule in chemoprevention in epigenetic therapy purposes. © 2017 Wiley Periodicals, Inc.

  12. Low dose ionizing radiation induced acoustic neuroma: A putative link?

    Directory of Open Access Journals (Sweden)

    Sachin A Borkar

    2012-01-01

    Full Text Available Although exposure to high dose ionizing radiation (following therapeutic radiotherapy has been incriminated in the pathogenesis of many brain tumors, exposure to chronic low dose ionizing radiation has not yet been shown to be associated with tumorigenesis. The authors report a case of a 50-year-old atomic reactor scientist who received a cumulative dose of 78.9 mSv over a 10-year period and was detected to have an acoustic neuroma another 15 years later. Although there is no proof that exposure to ionizing radiation was the cause for the development of the acoustic neuroma, this case highlights the need for extended follow-up periods following exposure to low dose ionizing radiation.

  13. Low-Dose Bevacizumab Is Effective in Radiation-Induced Necrosis

    Directory of Open Access Journals (Sweden)

    Matheus Alessandretti

    2013-12-01

    Full Text Available Background: Radiation-induced necrosis is a complication of brain irradiation. Treatment options are limited. Methods: The response to treatment with low-dose bevacizumab in 2 patients with radiation-induced necrosis was reported. Results: Both patients with metastatic melanoma, aged 48 and 51 years, had significant symptomatic and radiological improvement with low-dose bevacizumab treatment. Doses as low as 5 mg/kg every 6 weeks and 7.5 mg/kg i.v. every 4 weeks were used and were highly effective. Conclusions: Low-dose bevacizumab is a solid option in the management of edema associated with radiation necrosis.

  14. Medication error - Inadvertent high dose intradermal cloxacillin induced skin necrosis.

    Science.gov (United States)

    Surendiran, Adithan; Kaku, Mayur V; Adithan, Chandrasekaran

    2012-01-01

    Medication error is one of the important causes of preventable adverse drug reactions. It can occur in the form of administration of a wrong drug, in the wrong dose, to the wrong patient, in an unsuitable dosage form, for the wrong duration or by using an inappropriate route of administration. Intradermal skin testing for cloxacillin hypersensitivity is done at low doses to check for drug allergy. In this report, three patients were given 50 times higher dose of cloxacillin than recommended for skin testing, resulting in pain and necrosis at the site of injection. The error occurred due to wrong dilution of the drug as done by a nursing intern. Some reasons for this could be overtime working, under trained staff, unsupervised nursing interns, complicated and unclear protocols, interpersonal communication gap between health care professionals and also poor availability of ideal resources. Pharmacovigilance centers must alert health care professionals about the significance of reporting medication errors through bulletins and journals.

  15. Dapsone-Induced Methemoglobinemia: A Dose Related Occurrence?

    Science.gov (United States)

    Esbenshade, Adam J; Ho, Richard H.; Shintani, Ayumi; Zhao, Zhiguo; Smith, Lesley-Ann; Friedman, Debra L.

    2011-01-01

    Objectives Dapsone, used for Pneumocystis jiroveci (PCP) prophylaxis, is associated with increased risk of methemoglobinemia. Absence of cytochrome b5 reductase enzyme activity (CYB5RA) causes congenital methemoglobinemia, but its role in dapsone-associated methemoglobinemia is unknown. We sought to elucidate drug-related risk factors for dapsone-associated methemoglobinemia in pediatric oncology patients, including contribution of CYB5RA. Patients and Methods Among 167 pediatric patients treated for hematologic malignancies or aplastic anemia who received dapsone for PCP prophylaxis, demographic and dapsone treatment data were retrospectively collected. Drug-related risk factors were evaluated by Cox proportional hazards, and in a cross-sectional subgroup of 40 patients, CYB5RA was assessed. Results Methemoglobinemia (median methemoglobin level = 9.0% [3.5–22.4]) was documented in 32 patients (19.8%). There was a 73% risk reduction in methemoglobinemia with dosing ≥20% below the target dose 2mg/kg/day (HR = 0.27; 95% confidence interval (CI) 0.09, 0.78; p=0.016), while methemoglobinemia risk was increased with dosing ≥20% above the target dose (HR = 6.25; 95% CI 2.45, 15.93; pdapsone. Conclusions Methemoglobinemia occurred in almost 20% of pediatric oncology patients receiving dapsone for PCP prophylaxis. Higher dapsone dosing is associated with increased risk. A cross-sectionally acquired CYB5RA level was not associated with methemoglobinemia risk. Studies are needed to define biologic correlates of methemoglobinemia and evaluate lower dapsone doses for PCP prophylaxis. PMID:21246536

  16. Dapsone-induced methemoglobinemia: a dose-related occurrence?

    Science.gov (United States)

    Esbenshade, Adam J; Ho, Richard H; Shintani, Ayumi; Zhao, Zhiguo; Smith, Lesley-Ann; Friedman, Debra L

    2011-08-01

    Dapsone, used for Pneumocystis jiroveci (PCP) prophylaxis, is associated with increased risk of methemoglobinemia. Absence of cytochrome b5 reductase enzyme activity causes congenital methemoglobinemia, but its role in dapsone-associated methemoglobinemia is unknown. The authors sought to elucidate drug-related risk factors for dapsone-associated methemoglobinemia in pediatric oncology patients, including contribution of cytochrome b5 reductase enzyme activity. Among 167 pediatric patients treated for hematologic malignancies or aplastic anemia who received dapsone for PCP prophylaxis, demographic and dapsone treatment data were retrospectively collected. Drug-related risk factors were evaluated by Cox proportional hazards, and in a cross-sectional subgroup of 40 patients, cytochrome b5 reductase enzyme activity was assessed. Methemoglobinemia (median methemoglobin level = 9.0% [3.5-22.4]) was documented in 32 (19.8%) patients. There was a 73% risk reduction in methemoglobinemia with dosing ≥20% below the target dose of 2 mg/kg/d (hazard ratio [HR], 0.27; 95% confidence interval [CI], 0.09-0.78; P = .016), whereas methemoglobinemia risk was increased with dosing ≥20% above the target dose (HR, 6.25; 95% CI, 2.45-15.93; P dapsone. Methemoglobinemia occurred in almost 20% of pediatric oncology patients receiving dapsone for PCP prophylaxis. Higher dapsone dosing is associated with increased risk. A cross-sectionally acquired cytochrome b5 reductase enzyme activity level was not associated with methemoglobinemia risk. Studies are needed to define biologic correlates of methemoglobinemia and evaluate lower dapsone doses for PCP prophylaxis. Copyright © 2011 American Cancer Society.

  17. 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.

  18. High gamma dose induced damage on two types of discrete JFET transistors

    Energy Technology Data Exchange (ETDEWEB)

    Assaf, J. [Department of Scientific Services, Atomic Energy Commission, P.O. Box 6091, Damascus (Syrian Arab Republic)], E-mail: scientific@aec.org.sy

    2009-01-15

    The effect of high Gamma ray dose on two types of commercial transistors having different DC specifications has been investigated. The transistors were discrete N-JFETs intended as front-end component in nuclear read-out systems. They were exposed to different Gamma doses with a maximum of 10,000 kGy. The irradiation influence was represented by the analysis of the DC and the induced noise characteristics. The results show that the noise was more sensitive to irradiation than the DC parameters, and the radiation effect depends on the original DC specifications. It was also found that the first dose induces noise more than the next doses. Similar effects were observed either if the irradiation is done by one single dose or by many successive accumulated doses.

  19. Cimetidine at therapeutic dose induces derangements in serum ...

    African Journals Online (AJOL)

    Background: Cimetidine is a potent histamine H2-receptor antagonist widely used in treatment of peptic ulcer disease. The aim of this study was to evaluate the effect of chronic cimetidine treatment at therapeutic dose of 30 mg kg-1 on serum levels of testosterone, FSH, LH and estradiol and possible ameliorative effect of ...

  20. 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.

  1. 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.

  2. Can a single dose response predict the effect of montelukast on exercise-induced bronchoconstriction?

    NARCIS (Netherlands)

    Kersten, Elin T. G.; Akkerman-Nijland, Anne M.; Driessen, Jean M. M.; Diamant, Zuzana; Thio, Bernard J.

    RationaleExercise-induced bronchoconstriction (EIB) can be prevented by a single dose of montelukast (MLK). The effect is variable, similar to the variable responsiveness observed after daily treatment with MLK. We hypothesized that the effect of a single MLK-dose (5 or 10mg) on EIB could predict

  3. 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...

  4. Low-Dose UVA Radiation-Induced Adaptive Response in Cultured Human Dermal Fibroblasts

    Directory of Open Access Journals (Sweden)

    Zhongrong Liu

    2012-01-01

    Full Text Available Objective. To investigate the mechanism of the adaptive response induced by low-dose ultraviolet A (UVA radiation. Methods. Cultured dermal fibroblasts were irradiated by a lethal dose of UVA (86.4 J/cm2 with preirradiation of single or repetitive low dose of UVA (7.2 J/cm2. Alterations of cellular morphology were observed by light microscope and electron microscope. Cell cycle and cellular apoptosis were assayed by flow cytometer. The extent of DNA damage was determined by single-cell gel electrophoresis (SCGE. Results. The cultured dermal fibroblasts, with pretreatment of single or repetitive irradiation of 7.2 J/cm2 UVA relieved toxic reaction of cellular morphology and arrest of cell cycle, decreased apoptosis ratio, reduced DNA chain breakage, and accelerated DNA repair caused by subsequent 86.4 J/cm2 UVA irradiation. Compared with nonpretreatment groups, all those differences were significant (P<0.01 or P<0.05. Conclusions. The adaptation reaction might depend on the accumulated dose of low-dose UVA irradiation. Low-dose UVA radiation might induce adaptive response that may protect cultured dermal fibroblasts from the subsequent challenged dose of UVA damage. The duration and protective capability of the adaptive reaction might be related to the accumulated dose of low-dose UVA Irradiation.

  5. DETECTION OF LOW DOSE RADIATION INDUCED DNA DAMAGE USING TEMPERATURE DIFFERENNTIAL FLUORESENCE ASSAY

    Science.gov (United States)

    A rapid and sensitive fluorescence assay for radiation-induced DNA damage is reported. Changes in temperature-induced strand separation in both calf thymus DNA and plasmid DNA (puc 19 plasmid from Escherichia coli) were measured after exposure to low doses of radiation. Exposures...

  6. DETECTION OF LOW DOSE RADIATION INDUCED DNA DAMAGE USING TEMPERATURE DIFFERENTIAL FLUORESCENCE ASSAY

    Science.gov (United States)

    A rapid and sensitive fluorescence assay for radiation-induced DNA damage is reported. Changes in temperature-induced strand separation in both calf thymus DNA and plasmid DNA (puc 19 plasmid from Escherichia coli) were measured after exposure to low doses of radiation. Exposur...

  7. Photonic Activation of Plasminogen induced by low dose UVB

    DEFF Research Database (Denmark)

    Correia, Manuel Guiherme L.P. Marins; Snabe, Torben; Thiagarajan, Viruthachalam

    2015-01-01

    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...... of plasminogen activation has the potential to be used in clinical applications, possibly together with other enzymatic treatments for the elimination of blood clots....

  8. High-dose N-acetylcysteine for the prevention of contrast-induced nephropathy.

    Science.gov (United States)

    Trivedi, Hariprasad; Daram, Sumanth; Szabo, Aniko; Bartorelli, Antonio L; Marenzi, Giancarlo

    2009-09-01

    Whether N-acetylcysteine is beneficial for the prevention of contrast-induced nephropathy is uncertain. We conducted a meta-analysis to evaluate the efficacy of high-dose N-acetylcysteine for the prevention of contrast-induced nephropathy. Our prespecified inclusion criteria were as follows: adult subjects; English language literature; administration of high-dose N-acetylcysteine a priori defined as a daily dose greater than 1200 mg or a single periprocedural dose (within 4 hours of contrast exposure) greater than 600 mg; prospective trials of individuals randomized to N-acetylcysteine, administered orally or intravenously, versus a control group; and trials that included the end point of the incidence of contrast-induced nephropathy. Trials that compared N-acetylcysteine with another active treatment were excluded. Sixteen comparisons of patients randomized to high-dose N-acetylcysteine versus controls met our prespecified inclusion criteria with a total sample size of 1677 subjects (842 assigned to high-dose N-acetylcysteine and 835 assigned to the control arm). The average population age was 68 years, 38.7% were diabetic, and the majority was male (67.8% of reported instances). The weighted mean baseline creatinine of the overall population was 1.58 mg/dL. No significant heterogeneity was detected (P = .09; I(2) = 34%). The overall effect size assuming a common odds ratio revealed an odds ratio of 0.46 (95% confidence interval [CI], 0.33-0.63) for the occurrence of contrast-induced nephropathy with the use of high-dose N-acetylcysteine. The results of the more conservative random effects approach were similar (odds ratio = 0.52; 95% CI, 0.34-0.78). There was no evidence of publication bias (P = .34). Our results suggest that high-dose N-acetylcysteine decreases the incidence of contrast-induced nephropathy.

  9. Steroid induced osteonecrosis: An analysis of steroid dosing risk.

    Science.gov (United States)

    Powell, Christian; Chang, Christopher; Naguwa, Stanley M; Cheema, Gurtej; Gershwin, M Eric

    2010-09-01

    Osteonecrosis is a serious condition involving bone destruction that frequently requires surgical treatment to rebuild the joint. While there is an abundance of literature documenting corticosteroid related osteonecrosis, there is no consensus as to the relative risk of osteonecrosis after administration of steroids via parenteral, oral, topical, inhaled and other routes. This risk is an important prognostic indicator because identification and conservative intervention can potentially reduce morbidity associated with aggressive surgical treatment of osteonecrosis. This paper provides insight into establishing guidelines related to the risk of developing osteonecrosis as a result of corticosteroid use. Case studies, retrospective studies and prospective studies in humans on different corticosteroids and varied dosages were assessed. Most cases of osteonecrosis are secondary to systemically administered corticosteroids and/or high dose daily therapy, particularly in patients with underlying comorbidities including connective tissue diseases, hyperlipidemia, or previous trauma. Previous case reports of osteonecrosis related to inhaled or topical use of steroids are complicated by the fact that in the great majority of cases, the patients are also treated with systemic steroids prior to the development of osteonecrosis. Based on the literature, a set of recommendations regarding the risk of osteonecrosis in patients on steroids was formulated. Copyright 2010 Elsevier B.V. All rights reserved.

  10. Low-dose steroid-induced tumor lysis syndrome in a hepatocellular carcinoma patient

    OpenAIRE

    Jin Ok Kim; Dae Won Jun; Hye Jin Tae; Kang Nyeong Lee; Hang Lak Lee; Oh Young Lee; Ho Soon Choi; Byung Chul Yoon; Joon Soo Hahm

    2015-01-01

    Tumor lysis syndrome is rare in hepatocellular carcinoma (HCC), but it has been reported more frequently recently in response to treatments such as transcatheter arterial chemoembolization (TACE), radiofrequency thermal ablation (RFTA), and sorafenib. Tumor lysis syndrome induced by low-dose steroid appears to be very unusual in HCC. We report a patient with hepatitis-C-related liver cirrhosis and HCC in whom tumor lysis syndrome occurred due to low-dose steroid (10 mg of prednisolone). The p...

  11. Measurements of Ionizing Radiation Doses Induced by High Irradiance Laser on Targets in LCLS MEC Instrument

    Energy Technology Data Exchange (ETDEWEB)

    Bauer, J. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Liu, J. C. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Prinz, A. A. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Rokni, S. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Tran, H. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Woods, M. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Xia, Z. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Galter, e. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Lee, H. -J. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Milathianaki, D. [SLAC National Accelerator Lab., Menlo Park, CA (United States); Nagler, B. [SLAC National Accelerator Lab., Menlo Park, CA (United States)

    2014-01-21

    Comprehensive measurements for photon and neutron radiation doses generated from laser-plasma interaction at SLAC’s MEC laser facility have been conducted. The goals of the measurements were to; determine the radiation dose per laser shot as a function of laser, optic and target parameters that are relevant to the MEC laser operations; validate the RPD-developed analytic model for photon dose calculations; and evaluate the performance of various types of passive and active detectors in the laser-induced radiation fields.

  12. Dose-Response Curve of Chromosome Aberrations in Human Lymphocytes Induced by Gamma-Rays

    Directory of Open Access Journals (Sweden)

    Y. Lusiyanti

    2013-12-01

    Full Text Available Chromosome aberration is a biomarker to predict the level of cell damage caused by exposure to ionizing radiation on human body. Dicentric chromosome is a specific chromosome aberration caused by ionizing radiation and is used as a gold standard biodosimetry of individuals over exposed to ionizing radiation. In radiation accident the dicentric assays has been applied as biological dosimetry to estimate radiation absorbed dose and also to confirm the radiation dose received to radiation workers.The purpose of this study was to generate a dose response curve of chromosome aberration (dicentric in human lymphocyte induced by gamma radiation. Peripheral blood samples from three non smoking healthy volunteers aged between 25-48 years old with informed consent were irradiated with dose between 0.1-4.0 Gy and a control using gamma teletherapy source. The culture procedure was conducted following the IAEA standard procedures with slight modifications. Analysis of dose-response curves used was LQ model Y = a + αD + βD2. The result showed that α and β values of the curve obtained were 0.018 ± 0.006 and 0.013 ± 0.002, respectively. Dose response calibration curve for dicentric chromosome aberrations in human lymphocytes induced by gamma-radiation fitted to linear quadratic model. In order to apply the dose response curve of chromosome aberration disentric for biodosimetry, this standar curve still need to be validated.

  13. Impact of concomitant dexamethasone dosing schedule on bortezomib-induced peripheral neuropathy in multiple myeloma.

    Science.gov (United States)

    Kumar, Shaji K; Laubach, Jacob P; Giove, Thomas J; Quick, Maureen; Neuwirth, Rachel; Yung, Godwin; Rajkumar, S Vincent; Richardson, Paul G

    2017-09-01

    Peripheral neuropathy (PN) is the most troublesome adverse event associated with the proteasome inhibitor bortezomib. Studies suggest an inflammatory aetiology for bortezomib-induced PN (BiPN) and it has been hypothesized that reducing inflammation with concomitant dexamethasone may reduce BiPN incidence and/or severity. We retrospectively analysed PN rates from 32 studies (2697 patients with previously untreated multiple myeloma) incorporating bortezomib and differing dexamethasone schedules: partnered dosing (days of and after bortezomib), weekly dosing, and other dosing schedules (e.g. days 1-4, 8-11). Pooled overall PN rates were 45·5%, 63·9%, and 47·5%, respectively, with 5·3%, 11·0%, and 9·6% grade ≥3. Adjusting for potential confounders (age, gender, presence of thalidomide, bortezomib treatment duration), PN rates in patients on partnered dosing schedules appeared lower than in patients on weekly or other dosing schedules. Analyses conducted using patient-level data suggest that cumulative dexamethasone dose, a potential confounding factor, is unlikely to have influenced the analyses. Findings were similar in a separate pooled analysis excluding data from regimens incorporating thalidomide, when pooled overall PN rates were 50·1%, 63·9%, and 48·3%, respectively, with 4·2%, 11·0%, and 8·6% grade ≥3. These findings suggest that partnered dexamethasone dosing may result in less severe BiPN compared with alternative dexamethasone dosing schedules. © 2017 John Wiley & Sons Ltd.

  14. 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.

  15. Development and Optimization of a Novel Prolonged Release Formulation to Resist Alcohol-Induced Dose Dumping.

    Science.gov (United States)

    Gujjar, Chaitanya Yogananda; Rallabandi, Balaramesha Chary; Gannu, Ramesh; Deulkar, Vallabh Subashrao

    2016-04-01

    Alcohol-induced dose dumping is a serious concern for the orally administered prolonged release dosage forms. The study was designed to optimize the independent variables, propylene glycol alginate (PGA), Eudragit RS PO (ERS) and coating in mucoadhesive quetiapine prolonged release tablets 200 mg required for preventing the alcohol-induced dose dumping. Optimal design based on response surface methodology was employed for the optimization of the composition. The formulations are evaluated for in vitro drug release in hydrochloric acid alone and with 40% v/v ethanol. The responses, dissolution at 120 min without alcohol (R1) and dissolution at 120 min with alcohol (R2), were statistically evaluated and regression equations are generated. PGA as a hydrophilic polymeric matrix was dumping the dose when dissolutions are carried in 0.1 N hydrochloric acid containing 40% v/v ethanol. ERS addition was giving structural support to the swelling and gelling property of PGA, and thus, was reducing the PGA erosion in dissolution media containing ethanol. Among the formulations, four formulations with diverse composition were meeting the target dissolution (30-40%) in both the conditions. The statistical validity of the mathematical equations was established, and the optimum concentration of the factors was established. Validation of the study with six confirmatory runs indicated high degree of prognostic ability of response surface methodology. Further coating with ReadiLycoat was providing an additional resistance to the alcohol-induced dose dumping. Optimized compositions showed resistance to dose dumping in the presence of alcohol.

  16. Identification of specific mRNA signatures as fingerprints for carcinogenesis in mice induced by genotoxic and nongenotoxic hepatocarcinogens

    National Research Council Canada - National Science Library

    Kossler, Nadine; Matheis, Katja A; Ostenfeldt, Nina; Bach Toft, Dorthe; Dhalluin, Stéphane; Deschl, Ulrich; Kalkuhl, Arno

    2015-01-01

    .... In the course of the IMI MARCAR project, a European consortium of EFPIA partners and academics, which aims to identify biomarkers for nongenotoxic carcinogenesis, a toxicogenomic mouse liver database was generated...

  17. 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 cancer...

  18. 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.

  19. Evaluation of Bone Cancer Pain Induced by Different Doses of Walker 256 Mammary Gland Carcinoma Cells.

    Science.gov (United States)

    Dong, Changsheng; Wu, RuiXin; Wu, Jing; Guo, Jing; Wang, Fangyuan; Fu, Yanli; Wang, Qing; Xu, Ling; Wang, Juyong

    2016-01-01

    Cancer pain is a complex medical syndrome. Understanding its underlying mechanisms relies on the use of animal models which can mimic the human condition. A crucial component of this model is the quantity of tumor cells; however, the exact relationship between the doses of tumor cells on bone cancer pain is yet unknown. We explored the relationship of different doses of Walker 256 carcinoma cells using a bone cancer pain model in rats, and evaluated its success and stability. Experimental animal study using a comparative design. Experimental Animal Center and Tumor Institute of Traditional Chinese Medicine. We constructed the bone cancer pain model by implanting Walker 256 carcinoma cells into the right tibia of Sprague-Dawley (SD) rats (150 - 170 g). Spontaneous pain, mechanical threshold, and paw withdrawal latency (PWL) were measured and x-ray, bone mineral density (BMD), histological, interleukin-1 beta (IL-1beta) mRNA, carboxyterminal telopeptide of type I collagen (ICTP), and bone alkaline phosphatase (BAP) were analyzed for bone pain model evaluation. The results showed that: (1) the 3 doses (3×105, 3.5×105, 4×105) of Walker 256 carcinoma cells can induce bone cancer pain from day 7 to day 21 after implantation into the right tibia of SD rats; (2) compared to the control group, 3×105, 3.5×105, and 4×105 Walker 256 carcinoma cells produced different pain manifestations, where the 3.5×105 dose of Walker 256 carcinoma cells resulted in the greatest bone cancer pain response; (3) the 3.5×105 dose induced the lowest mortality rate in rats; (4) Walker 256 carcinoma cells (3×105, 3.5×105, and 4×105) resulted in a significant decrease in the general condition and body weight of rats, where the 3.5×105 and 4×105 doses of carcinoma cells produced a greater effect than 3×105 dose of carcinoma cells; (5) progressive spontaneous pain, PWL, and mechanical threshold were exacerbated by 3.5×105 and 4×105 doses of carcinoma cells; (6) implantation of 3.5×105

  20. Hepatoprotective Effect of Low Doses of Caffeine on CCl4-Induced Liver Damage in Rats.

    Science.gov (United States)

    Cachón, Andrés Uc; Quintal-Novelo, Carlos; Medina-Escobedo, Gilberto; Castro-Aguilar, Gaspar; Moo-Puc, Rosa E

    2017-03-04

    Several studies have shown the hepatoprotective effect of the consumption of coffee and tea, which is mainly attributed to caffeine. Many experimental studies have demonstrated this effect; however, these studies used high caffeine doses that are not related to human consumption. The aim of this study was to evaluate the hepatoprotective effect of low doses of caffeine on carbon tetrachloride (CCl 4 )-treated rats. Low doses of caffeine (CAFF) 5 and 10 mg/kg (CAFF5 and CAFF10) were evaluated in chronic liver damage induced by CCl 4 (0.75 mL/kg) in rats. CAFF treatment was administered once a day and CCl 4 administration was twice weekly for 10 weeks. Liver function tests (biochemical markers) and functional (sleeping time) and histological (hematoxylin-eosin and Masson trichrome stains) parameters were carried out at the end of damage treatment. Daily treatments of CAFF5 and CAFF10 exhibited a hepatoprotective effect supported by a decrease of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (AP) serum activities and bilirubin serum levels compared with control and also restored serum albumin levels and liver glutathione (GSH). Moreover, CAFF prevented CCl 4 -induced prolongation in pentobarbital sleeping time and a decrease of liver fibrosis and cell death. Our results demonstrated that low doses of CAFF exert a hepatoprotective effect against CCl 4 -induced liver damage in rats.

  1. 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.

  2. The Effects of Erythropoietin Dose Titration during High-Fat Diet-Induced Obesity

    Directory of Open Access Journals (Sweden)

    Amanda Foskett

    2011-01-01

    Full Text Available Erythropoietin (Epo is a pleotropic cytokine with several nonhematopoietic tissue effects. High-dose Epo treatment-mediated effects on body weight, fat mass and glucose tolerance have recently been reported, thus extending its pleotropic effects to fat and glucose metabolism. However, the exact dose range of Epo treatment required for such effects remains unidentified to date. We investigated Epo dosage effect (up to 1000 U/kg on hematocrit, body weight, body composition, glucose metabolism, food intake, and physical activity, during high-fat diet-induced obesity. We report that Epo doses (1000, 600, 300, and 150 U/kg significantly reduced body weight gain and fat mass, while, only Epo doses of 300 U/kg and higher significantly affected glucose tolerance. None of the tested Epo doses showed any detectable effects on food intake, and only 1000 U/kg dose significantly increased physical activity, suggesting that these parameters may only be partially responsible for the metabolic effects of Epo treatment.

  3. The effects of erythropoietin dose titration during high-fat diet-induced obesity.

    Science.gov (United States)

    Foskett, Amanda; Alnaeeli, Mawadda; Wang, Li; Teng, Ruifeng; Noguchi, Constance T

    2011-01-01

    Erythropoietin (Epo) is a pleotropic cytokine with several nonhematopoietic tissue effects. High-dose Epo treatment-mediated effects on body weight, fat mass and glucose tolerance have recently been reported, thus extending its pleotropic effects to fat and glucose metabolism. However, the exact dose range of Epo treatment required for such effects remains unidentified to date. We investigated Epo dosage effect (up to 1000 U/kg) on hematocrit, body weight, body composition, glucose metabolism, food intake, and physical activity, during high-fat diet-induced obesity. We report that Epo doses (1000, 600, 300, and 150 U/kg) significantly reduced body weight gain and fat mass, while, only Epo doses of 300 U/kg and higher significantly affected glucose tolerance. None of the tested Epo doses showed any detectable effects on food intake, and only 1000 U/kg dose significantly increased physical activity, suggesting that these parameters may only be partially responsible for the metabolic effects of Epo treatment.

  4. Dose-response model for Listeria monocytogenes-induced stillbirths in nonhuman primates.

    Science.gov (United States)

    Smith, Mary Alice; Takeuchi, Kazue; Anderson, Gary; Ware, Glenn O; McClure, Harold M; Raybourne, Richard B; Mytle, Nutan; Doyle, Michael P

    2008-02-01

    A dose-response model using rhesus monkeys as a surrogate for pregnant women indicates that oral exposure to 10(7) CFU of Listeria monocytogenes results in about 50% stillbirths. Ten of 33 pregnant rhesus monkeys exposed orally to a single dose of 10(2) to 10(10) CFU of L. monocytogenes had stillbirths. A log-logistic model predicts a dose affecting 50% of animals at 10(7) CFU, comparable to an estimated 10(6) CFU based on an outbreak among pregnant women but much less than the extrapolated estimate (10(13) CFU) from the FDA-U.S. Department of Agriculture-CDC risk assessment using an exponential curve based on mouse data. Exposure and etiology of the disease are the same in humans and primates but not in mice. This information will aid in risk assessment, assist policy makers, and provide a model for mechanistic studies of L. monocytogenes-induced stillbirths.

  5. Dose dependency and individual variability of the lipopolysaccharide-induced bovine acute phase protein response

    DEFF Research Database (Denmark)

    Jacobsen, S.; Andersen, P.H.; Tølbøll, T.

    2004-01-01

    In order to investigate the dose dependency and the individual variability of the lipopolysaccharide (LPS)-induced acute phase protein response in cattle, 8 nonlactating, nonpregnant Danish Holstein cows were challenged 3 times each by intravenous injection of increasing doses (10, 100, and 1000 ng....../kg, consecutively) of Escherichia coli LPS with 3-wk intervals. All 3 LPS doses resulted in a rapid increase in serum concentrations of haptoglobin and serum amyloid A (SAA) and a decrease in serum concentrations of albumin in all 8 cows. Serum concentrations of acute phase proteins (APP) remained altered...... not only reflect the magnitude of LPS exposure but are also influenced by the ability of the individual cow to mount an acute phase response. The ability to produce SAA and haptoglobin may be an innate characteristic of the individual, as responses in consecutive challenges were quantitatively similar....

  6. Gamma-radiation-induced corrosion of aluminum alloy: low dose effect

    Science.gov (United States)

    Kanjana, K.; Ampornrat, P.; Channuie, J.

    2017-06-01

    Gamma-radiation-induced corrosion of aluminium alloy 6061 (AA6061) immersed in demineralized water was studied at radiation dose up to 206 kGy using a Co-60 gamma radiation source. The surface morphology and chemical composition of the oxide produced on the post-irradiated samples were investigated using SEM-EDS. The electrochemical corrosion potentials (Ecorr ) of the post-irradiated samples were measured. The corrosion behavior of AA6061 appeared to be dose dependent under the experimental conditions. A dramatic change in surface morphology was observed in the samples exposed to gamma radiation at 206 kGy. At this radiation dose the aluminium oxide scale developed can be clearly seen. The results from electrochemical corrosion tests have shown that the corrosion potentials (Ecorr ) can be undoubtedly decreased by gamma irradiation, giving corrosion rate of 7 × 10-4 mm/yr.

  7. Repeated low-dose intradermal allergen injection suppresses allergen-induced cutaneous late responses.

    Science.gov (United States)

    Rotiroti, Giuseppina; Shamji, Mohamed; Durham, Stephen R; Till, Stephen J

    2012-10-01

    Subcutaneous immunotherapy with high-dose grass pollen was first described more than 100 years ago. This treatment suppresses allergen-induced cutaneous late responses, with lesser effects on early responses. In contrast, low-dose subcutaneous immunotherapy has not shown clinical benefit. Uncontrolled reports from the early 20th century describe low-dose allergen inoculation directly into the dermis, an immunologically active area containing abundant dendritic cells and lymphatics. We sought to investigate the effect of low-dose intradermal grass pollen administration on cutaneous reactivity to allergen. Thirty adults sensitized to grass and tree pollens were randomized to receive (1) 6 repeat intradermal injections at 2-week intervals of grass pollen extract (estimated 7 ng of the major grass allergen Phl p 5 per injection), (2) 2 intradermal injections separated by 10 weeks, or (3) a single intradermal injection at 10 weeks. At the end of the study, cutaneous early and late responses were measured after double-blind intradermal injection with grass and birch pollen. Participants who received 6 fortnightly intradermal grass pollen injections had markedly smaller cutaneous late responses to grass pollen than control subjects who received 2 injections separated by 10 weeks (P pollen-specific IgG antibodies. Suppression was observed whether late responses were measured on the arms or the back. However, early responses were equivalent in all groups. Low-dose intradermal allergen, like conventional subcutaneous high-dose immmunotherapy, suppresses allergen-induced cutaneous late responses in a manner that is allergen specific, systemic, and associated with induction of IgG antibodies. Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

  8. High doses of (-)-epigallocatechin-3-gallate from green tea induces cardiac fibrosis in mice.

    Science.gov (United States)

    Cai, Yi; He, Shu-Qiao; Hong, Hui-Qi; Cai, Yue-Peng; Zhao, Li; Zhang, Mei

    2015-12-01

    Tea is the most consumed beverage in the world. (-)-Epigallocatechin-3-gallate (EGCG), a major green tea polyphenol, is effective in the prevention of several chronic diseases, and is marketed as part of many dietary supplements. We have now examined the myocardiotoxic effect of high doses of EGCG in mice. EGCG (500 and 1000 mg/kg·d) induced cardiac collagen synthesis and fibrosis-related protein expression, such as connective tissue growth factor (CTGF) and fibronectin (FN) in mice. Moreover, EGCG decreased the protein expression of p-AMPK and increased the levels of p-p70S6 K and p-S6. This is the first evidence that high oral doses of EGCG could induce cardiac fibrosis, and shed new light on the understanding of EGCG-mediated myocardiotoxicity.

  9. A Case of Teicoplanin-Induced Pancytopenia Caused by Excessive Dosing.

    Science.gov (United States)

    Choi, Hye Min; Choi, Moon Hee; Yang, Yoo Whooi

    2016-01-01

    Teicoplanin is reported to be as effective as vancomycin but with minimal side effects. We report a case of teicoplanin-induced pancytopenia, which has not been demonstrated previously. A 44-year-old man with tetraplegia was treated with a diagnosis of urinary tract infection and pneumonia, and a high-dose of teicoplanin (400 mg every 12 hours) was administered for 4 days inadvertently. Although the infection rapidly improved, the patient developed pancytopenia by the fourth day of teicoplanin therapy, which was improved after reducing the dose of teicoplanin (200 mg/d). Our patient represents a probable case of teicoplanin-induced pancytopenia with adverse drug reaction probability score of 6.

  10. The Effects of Low Dose {gamma}-Irradiation on MIA Induced Joint Inflammation

    Energy Technology Data Exchange (ETDEWEB)

    Ham, Seok Chan; Lee, Ko Eun; Kim, Eun-hea; Lee, Tae Woong; Lee, Won Ho; Kim, June Sun [Korea University, College of Health Science, Seoul (Korea, Republic of)

    2010-10-15

    Inflammation of the synovial membrane is associated with the progression of cartilage degeneration and unexpected pain in osteoarthritis (OA). Inflammation produces painful sensations which are largely divided into spontaneous (non-evoked) pain and evoked pain depending on the presence of external stimuli and are characterized by hyperalgesia and allodynia Nitric oxide (NO) is related to the pathogenesis of OA as inflammatory mediator. Inducible nitric oxide synthase (iNOS) is marker of enhanced NO production in arthritic pain. In previously, low dose irradiation can suppress pro-inflammatory cytokines. But, ray therapeutic effect is unclear. Thus, present study examined the preemptive effect of low dose irradiation on the development of inflammatory pain in MIA induced OA animal model

  11. Vitamin E Reversed Apoptosis of Cardiomyocytes Induced by Exposure to High Dose Formaldehyde During Mice Pregnancy.

    Science.gov (United States)

    Wu, Dongyuan; Jiang, Zhirong; Gong, Bing; Dou, Yue; Song, Mingxuan; Song, Xiaoxia; Tian, Yu

    2017-10-21

    In this study, we investigated the protection effect of Vitamin E (Vit E) on formaldehyde (FA) exposure during pregnancy induced apoptosis of cardiomyocytes, and used an HL-1 cell line to confirmed the findings in vivo.Pregnant mice received different doses of FA (0.5 mg/kg, 1.0 mg/kg, 1.5 mg/kg, 0.1 μg Vit E, or 1.5 mg/kg + 0.1 μg Vit E). TUNEL staining was used to reveal the apoptosis in cardiomyocytes, and SOD, MDA, GSH, Livin, and Caspase-3 in cardiomyocytes were detected by ELISA, RT-PCR, and Western blot. For in vitro study, HL-1 cells were treated with vehicle, 5 μmol/L FA, 25 μmol/L FA, 50 μmol/L FA, 10 mg/L Vit. E, and 50 μmol/L FA+ 10 mg/L Vit E, respectively. CCK-8 assay and flow cytometry were used to evaluate cell vitality and apoptosis. A high dose of FA exposure led to cytotoxicity in both pregnant mice and offspring, as TUNEL staining revealed a significant apoptosis of cardiomyocytes, and the alternation in SOD, GSH, MDA, Livin, and Caspase-3 was found in cardiomyocytes. 0.1 μg Vit. E could reverse high doses of FA exposure induced apoptosis of cardiomyocytes in both pregnant mice and offspring. The in vitro study revealed that FA exposure induced a decrease of cell viability and increased cell apoptosis, as well as oxidative stress in HL-1 cells with alternation in SOD, GSH, MDA, Livin, and Caspase-3.This study revealed a high dose of FA induced oxidative stress and apoptosis of cardiomyocytes in both pregnant mice and offspring, and Vit E supplement during pregnancy reversed the systemic and myocardial toxicity of FA.

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

    Energy Technology Data Exchange (ETDEWEB)

    Clayton, P.E.; Shalet, S.M. (Christie Hospital and Holt Radium Institute, Manchester (England))

    1991-02-01

    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.

  13. 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.

  14. Drug-Induced Nephrotoxicity and Dose Adjustment Recommendations: Agreement Among Four Drug Information Sources

    Science.gov (United States)

    Bicalho, Millena Drumond; Soares, Danielly Botelho; Botoni, Fernando Antonio; Reis, Adriano Max Moreira; Martins, Maria Auxiliadora Parreiras

    2015-01-01

    Hospitalized patients require the use of a variety of drugs, many of which individually or in combination have the potential to cause kidney damage. The use of potentially nephrotoxic drugs is often unavoidable, and the need for dose adjustment should be evaluated. This study is aimed at assessing concordance in information on drug-induced nephrotoxicity and dose adjustment recommendations by comparing four drug information sources (DRUGDEX®, UpToDate®, Medscape® and the Brazilian Therapeutic Formulary) using the formulary of a Brazilian public hospital. A total of 218 drugs were investigated. The global Fleiss’ kappa coefficient was 0.265 for nephrotoxicity (p < 0.001; CI 95%, 0.211–0.319) and 0.346 for recommendations (p < 0.001; CI 95%, 0.292–0.401), indicating fair concordance among the sources. Anti-infectives and anti-hypertensives were the main drugs cited as nephrotoxic by the different sources. There were no clear definitions for qualitative data or quantitative values for dose adjustments among the four information sources. There was no advice for dosing for a large number of the drugs in the international databases. The National Therapeutic Formulary offered imprecise dose adjustment recommendations for many nephrotoxic drugs. Discrepancies among information sources may have a clinical impact on patient care and contribute to drug-related morbidity and mortality. PMID:26371029

  15. Combination of RGD compound and low-dose paclitaxel induces apoptosis in human glioblastoma cells.

    Directory of Open Access Journals (Sweden)

    Ming-Wei Chang

    Full Text Available BACKGROUND: Integrins are a family of transmembrane adhesion proteins that mediate cell adhesion and intracellular signaling. Integrin-αvβ3 is expressed on the surface of human glioblastoma cells, and can be further induced by chemical stress. The Arg-Gly-Asp (RGD motif-containing peptides are specifically bound to integrin-αvβ3, and to inhibit neovasculature underlying competition to normal extracellular matrix proteins. This study employed two types of RGD peptides, cyclic RGD (c(RGDyK and bi-cyclic RGD (E[c(RGDyK](2 peptide, to human glioblastoma U87MG cells with combination of low dose Paclitaxel (PTX pre-treatment to augment therapeutic activity for RGD peptide-induced apoptosis. PRINCIPAL FINDINGS: Human glioblastoma U87MG cells were treated with RGD peptides in the absence or presence of initial exposure to low-dose 10 nM PTX. Results showed that integrin-αvβ3 expressing on the surface of U87MG cells was induced by 10 nM PTX pre-treatment for 12 hrs. Additionally, the U87MG cells pre-treated with PTX and followed by RGD peptides exhibited greater expression of caspases-3, -8 and -9 than those merely treated with single agent of PTX or RGD peptide. Furthermore, the caspase-3, -8 and -9 inhibitor presented significant protection against E[c(RGDyK](2 peptide induced U87MG programmed cell death. The increased expression of PTX-induced integrin-αvβ3 was correlated with the enhanced apoptosis in U87MG cells. CONCLUSIONS: This study provides a novel concept of targeting integrin-αvβ3 with RGD peptides in combination with low-dose PTX pre-treatment to improve efficiency in human glioblastoma treatment.

  16. Combination of RGD Compound and Low-Dose Paclitaxel Induces Apoptosis in Human Glioblastoma Cells

    Science.gov (United States)

    Chang, Ming-Wei; Lo, Jem-Mau; Juan, Hsueh-Fen; Chang, Hsin-Yi; Chuang, Chun-Yu

    2012-01-01

    Background Integrins are a family of transmembrane adhesion proteins that mediate cell adhesion and intracellular signaling. Integrin-αvβ3 is expressed on the surface of human glioblastoma cells, and can be further induced by chemical stress. The Arg-Gly-Asp (RGD) motif-containing peptides are specifically bound to integrin-αvβ3, and to inhibit neovasculature underlying competition to normal extracellular matrix proteins. This study employed two types of RGD peptides, cyclic RGD (c(RGDyK)) and bi-cyclic RGD (E[c(RGDyK)]2) peptide, to human glioblastoma U87MG cells with combination of low dose Paclitaxel (PTX) pre-treatment to augment therapeutic activity for RGD peptide-induced apoptosis. Principal Findings Human glioblastoma U87MG cells were treated with RGD peptides in the absence or presence of initial exposure to low-dose 10 nM PTX. Results showed that integrin-αvβ3 expressing on the surface of U87MG cells was induced by 10 nM PTX pre-treatment for 12 hrs. Additionally, the U87MG cells pre-treated with PTX and followed by RGD peptides exhibited greater expression of caspases-3, -8 and -9 than those merely treated with single agent of PTX or RGD peptide. Furthermore, the caspase-3, -8 and -9 inhibitor presented significant protection against E[c(RGDyK)]2 peptide induced U87MG programmed cell death. The increased expression of PTX-induced integrin-αvβ3 was correlated with the enhanced apoptosis in U87MG cells. Conclusions This study provides a novel concept of targeting integrin-αvβ3 with RGD peptides in combination with low-dose PTX pre-treatment to improve efficiency in human glioblastoma treatment. PMID:22655084

  17. 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.

  18. Protein expression profile changes in human fibroblasts induced by low dose energetic protons

    Science.gov (United States)

    Zhang, Ye; Clement, Jade Q.; Gridley, Daila S.; Rodhe, Larry H.; Wu, Honglu

    2009-12-01

    Extrapolation of known radiation risks to the risks from low dose and low dose-rate exposures of human population, especially prolonged exposures of astronauts in the space radiation environment, relies in part on the mechanistic understanding of radiation induced biological consequences at the molecular level. While some genomic data at the mRNA level are available for cells or animals exposed to radiation, the data at the protein level are still lacking. Here, we studied protein expression profile changes using Panorama antibody microarray chips that contain antibodies to 224 proteins (or their phosphorylated forms) involved in cell signaling that included mostly apoptosis, cytoskeleton, cell cycle and signal transduction. Normal human fibroblasts were cultured until fully confluent and then exposed to 2 cGy of 150 MeV protons at high-dose rate. The proteins were isolated at 2 or 6 h after exposure and labeled with Cy3 for the irradiated cells and with Cy5 for the control samples before loading onto the protein microarray chips. The intensities of the protein spots were analyzed using ScanAlyze software and normalized by the summed fluorescence intensities and the housekeeping proteins. The results showed that low dose protons altered the expression of more than 10% of the proteins listed in the microarray analysis in various protein functional groups. Cell cycle (24%) related proteins were induced by protons and most of them were regulators of G1/S-transition phase. Comparison of the overall protein expression profiles, cell cycle related proteins, cytoskeleton and signal transduction protein groups showed significantly more changes induced by protons compared with other protein functional groups.

  19. Local factors modify the dose dependence of 56Fe-induced atherosclerosis.

    Science.gov (United States)

    Kucik, Dennis; Gupta, Kiran; Wu, Xing; Yu, Tao; Chang, Polly; Kabarowski, Janusz; Yu, Shaohua

    2012-07-01

    Radiation exposure from a number of terrestrial sources is associated with an increased risk of cardiovascular disease, but evidence establishing whether high-LET radiation has similar effects has been lacking. We recently demonstrated that 600 MeV/n 56Fe induces atherosclerosis as well. Ten-week old male apolipoprotein-E deficient mice, a well-characterized atherosclerosis animal model, were exposed to 0 (control) 2, or 5Gy 56Fe targeted to the chest and neck. In these mice, 56Fe-induced atherosclerosis was similar in character to that induced by X-rays in the same mouse model and to that resulting from therapeutic radiation in cancer patients. Atherosclerosis was exacerbated by 56Fe only in targeted areas, however, suggesting a direct effect of the radiation on the arteries themselves. This is in contrast to some other risk factors, such as high cholesterol or tobacco use, which have systemic effects. The radiation dose required to accelerate development of atherosclerotic plaques, however, differed depending on the vessel that was irradiated and even the location within the vessel. For example, atherosclerosis in the aortic arch was accelerated only by the highest dose (5 Gy), while the carotid arteries and the aortic root showed effects at 2 Gy (a dose four- to eight-fold lower than the dose of X-rays that produces similar effects in this model). Since shear stress is disrupted in the area of the aortic root, it is likely that at least part of the site-specificity is due to additive or synergistic effects of radiation and local hydrodynamics. Other factors, such as local oxidative stress or gene expression may also have been involved. Since the pro-atherogenic effects of 56Fe depend on additional local factors, this suggests that radiation exposure, when unavoidable, might be mitigated by modification of factors unrelated to the radiation itself.

  20. Protective Role of Selenium and High Dose Vitamin E against Cisplatin - Induced Nephrotoxicty in Rats.

    Science.gov (United States)

    Aksoy, Asude; Karaoglu, Aziz; Akpolat, Nusret; Naziroglu, Mustafa; Ozturk, Turkan; Karagoz, Zuhal Karaca

    2015-01-01

    Cisplatin (CDDP) is one of the most active cytotoxic agents in the treatment of cancer. We investigated the effect of selenium (Se) with high dose vitamin E (VE) administration to prevent CDDP-induced nephrotoxicity in rats. In this study, 40 female Wistar rats were randomly divided into five equal groups. The first group, which served as the control, was administered physiological saline (2.5 cc/day, 5 days) intraperitoneally (IP), while group A was administered cisplatin (6 mg/kg BW/ single dose) plus physiological saline IP. Groups B, C, D received IP five doses of Se (1.5 mg/kg BW), and a high dose of VE (1000 mg/kg BW) (Se-VE) in combination before, simultaneously, and after CDDP, respectively. The rats were sacrificed five days after CDDP administration. Plasma malondialdehide (MDA), glutathione peroxidase (GSH-Px), reduced glutathione (GSH), catalase, urea, creatinine levels, renal histopathological changes were measured. The histopathological injury score, plasma levels of MDA, urea, creatinine were found to increase in group A compared to the control (p<0.05), while plasma levels of GSH-Px, GSH and catalase decreased (p<0.05). In contrast, plasma levels of MDA decreased (p<0.05) in groups B, C, D, which were treated with Se- VE, whereas levels of GSH-Px, GSH were found to increase only for group D (p<0.05). Plasma urea, creatinine levels improved in the treatment groups compared to group A (p<0.001). Histopathological changes caused by CDDP were also significantly improved after Se-VE treatment (p<0.05). Oxidative stress increases with CDDP-induced nephrotoxicity in rats. Se-VE supplementation might thus play a role in the prevention of CDDP-induced nephrotoxicity in patients.

  1. Gamma ray radiation induced visible light absorption in P-doped silica fibers at low dose levels

    CERN Document Server

    Lu Ping; Kulkarni, N S; Brown, K

    1999-01-01

    A CCD Fiber Optic Spectrometer has been used to monitor the gamma ray radiation induced loss in P-doped fibers at different dopant concentrations (1, 5 and 10 mol%) with a light source (an incandescent bulb with a temperature of 2800-3000 K). The range of dose rates is limited to that used in medical applications (cancer treatments), that is 0.1 to 1.0 Gray per minute (Gy/min). At low integral dose level (<2.0 Gy) four absorption peaks were observed (470, 502, 540 and 600 nm) within the visible region. It has been observed that the radiation induced loss at 470 and 600 nm depends strongly on dose rate. At dose rates of 0.2 and 0.5 Gy/min the induced loss shows nonlinear relation to the total dose. However, at high dose rate (1.0 Gy/min) and low dose rate (0.1 Gy/min) it seems to have a linear dependence with total dose. The conversion from NBOHCs to GeX centers was observed during gamma radiation at low dose rates (0.1-0.5 Gy/min). At the wavelength of 502 and 540 nm, the radiation induced losses show exce...

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

    Directory of Open Access Journals (Sweden)

    Ilknur Keskin

    2017-01-01

    Full Text Available 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.

  3. Assessment of The Dose-Response Relationship of Radiation-Induced Bystander Effect in Two Cell Lines Exposed to High Doses of Ionizing Radiation (6 and 8 Gy).

    Science.gov (United States)

    Bahreyni Toossi, Mohammad Taghi; Khademi, Sara; Azimian, Hosein; Mohebbi, Shokoufeh; Soleymanifard, Shokouhozaman

    2017-10-01

    The dose-response relationship of radiation-induced bystander effect (RIBE) is controversial at high dose levels. The aim of the present study is to assess RIBE at high dose levels by examination of different endpoints. This experimental study used the medium transfer technique to induce RIBE. The cells were divided into two main groups: QU-DB cells which received medium from autologous irradiated cells and MRC5 cells which received medium from irradiated QU-DB cells. Colony, MTT, and micronucleus assays were performed to quantify bystander responses. The medium was diluted and transferred to bystander cells to investigate whether medium dilution could revive the RIBE response that disappeared at a high dose. The RIBE level in QU-DB bystander cells increased in the dose range of 0.5 to 4 Gy, but decreased at 6 and 8 Gy. The Micronucleated cells per 1000 binucleated cells (MNBN) frequency of QU-DB bystander cells which received the most diluted medium from 6 and 8 Gy QU-DB irradiated cells reached the maximum level compared to the MNBN frequency of the cells that received complete medium (PMRC5 cells which received the most diluted medium from 4 Gy QU-DB irradiated cells reached the maximum level compared to MNBN frequency of cells that received complete medium (P<0.0001). Our results showed that RIBE levels decreased at doses above 4 Gy; however, RIBE increased when diluted conditioned medium was transferred to bystander cells. This finding confirmed that a negative feedback mechanism was responsible for the decrease in RIBE response at high doses. Decrease of RIBE at high doses might be used to predict that in radiosurgery, brachytherapy and grid therapy, in which high dose per fraction is applied, normal tissue damage owing to RIBE may decrease.

  4. Prolonged exposure to low-dose microcystin induces nonalcoholic steatohepatitis in mice: a systems toxicology study.

    Science.gov (United States)

    He, Jun; Li, Guangyu; Chen, Jun; Lin, Juan; Zeng, Cheng; Chen, Jing; Deng, Junliang; Xie, Ping

    2017-01-01

    Microcystin-LR (MCLR), a cyanotoxin widely present in freshwater, has been shown to have potent acute hepatotoxicity. However, the chronic toxicity of low-dose MCLR remains confusing by traditional measurements of toxicity. This has impeded understanding of the chronic liver damage of low-dose MCLR and corresponding safety risks of the human exposure guideline value. Here, iTRAQ-based proteomics and NMR-based metabonomics were used to decipher the molecular toxicological signatures of low doses of MCLR in mice exposed to this agent for 90 days. Low levels of MCLR, even under the reported no observed adverse effect level, significantly altered hepatic protein expression, especially of proteins associated with lipid metabolism, transport, immune and proteolysis. Coherently, MCLR induced marked perturbations in lipid metabolites in both liver and serum. Integrated analysis of proteomic, metabolic, histological and cytokine profiles revealed that MCLR significantly inhibited fatty acid β-oxidation and hepatic lipoprotein secretion and promoted hepatic inflammation, resulting in nonalcoholic steatohepatitis disease (NASH). These findings for the first time provide compelling evidence that chronic exposure to low-level MCLR can induce NASH. These results also indicate that current guidelines for MCs in drinking water may be inadequate and associated with risks to human health.

  5. Dose response of attenuated Bordetella pertussis BPZE1-induced protection in mice.

    Science.gov (United States)

    Mielcarek, Nathalie; Debrie, Anne-Sophie; Mahieux, Severine; Locht, Camille

    2010-03-01

    Despite the availability of efficacious vaccines, the incidence of whooping cough is still high in many countries and is even increasing in countries with high vaccine coverage. Most severe and life-threatening pertussis cases occur in infants who are too young to be sufficiently protected by current vaccine regimens. As a potential solution to this problem, we have developed an attenuated live Bordetella pertussis vaccine strain, named BPZE1. Here, we show that after a single administration, BPZE1 induces dose-dependent protection against challenge with virulent B. pertussis in low-dose and in high-dose intranasal mouse lung colonization models. In addition, we observed BPZE1 dose-dependent antibody titers to B. pertussis antigens, as well as cell-mediated immunity, evidenced by the amounts of gamma interferon (IFN-gamma) released from spleen cells upon stimulation with B. pertussis antigens. These two parameters may perhaps be used as readouts in clinical trials in humans that are currently being planned.

  6. Effective analgesic doses of tramadol or tapentadol induce brain, lung and heart toxicity in Wistar rats.

    Science.gov (United States)

    Faria, Juliana; Barbosa, Joana; Leal, Sandra; Afonso, Luís Pedro; Lobo, João; Moreira, Roxana; Queirós, Odília; Carvalho, Félix; Dinis-Oliveira, Ricardo Jorge

    2017-06-15

    Tramadol and tapentadol are extensively prescribed for the treatment of moderate to severe pain. Although these drugs are very effective in pain treatment, the number of intoxications and deaths due to both opioids is increasing, and the underlying toxic mechanisms are not fully understood. The present work aimed to study the potential biochemical and histopathological alterations induced by acute effective (analgesic) doses of tramadol and tapentadol, in Wistar rats. Forty-two male Wistar rats were divided into different groups: a control, administered with normal saline solution, and tramadol- or tapentadol-treated groups (10, 25 or 50mg/kg - typical effective analgesic dose, intermediate and maximum recommended doses, respectively). 24h after intraperitoneal administration, biochemical and oxidative stress analyses were performed in blood, and specimens from brain, lung and heart were taken for histopathological and oxidative stress studies. Both drugs caused an increase in the AST/ALT ratio, in LDH, CK and CK-MB activities in serum samples, and an increase in lactate levels in serum and brain samples. Oxidative damage, namely protein oxidation, was found in heart and lung tissues. In histological analyses, tramadol and tapentadol were found to cause alterations in cell morphology, inflammatory cell infiltrates and cell death in all tissues under study, although tapentadol caused more damage than tramadol. Our results confirmed the risks of tramadol exposure, and demonstrated the higher risk of tapentadol, especially at high doses. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Mechanistic Modeling of Dose and Dose Rate Dependences of Radiation-Induced DNA Double Strand Break Rejoining Kinetics in Saccharomyces cerevisiae.

    Directory of Open Access Journals (Sweden)

    Igor Shuryak

    Full Text Available Mechanistic modeling of DNA double strand break (DSB rejoining is important for quantifying and medically exploiting radiation-induced cytotoxicity (e.g. in cancer radiotherapy. Most radiation-induced DSBs are quickly-rejoinable and are rejoined within the first 1-2 hours after irradiation. Others are slowly-rejoinable (persist for several hours, and yet others are essentially unrejoinable (persist for >24 hours. The dependences of DSB rejoining kinetics on radiation dose and dose rate remain incompletely understood. We hypothesize that the fraction of slowly-rejoinable and/or unrejoinable DSBs increases with increasing dose/dose rate. This radiation-dependent (RD model was implemented using differential equations for three DSB classes: quickly-rejoinable, slowly-rejoinable and unrejoinable. Radiation converts quickly-rejoinable to slowly-rejoinable, and slowly-rejoinable to unrejoinable DSBs. We used large published data sets on DSB rejoining in yeast exposed to sparsely-ionizing (electrons and γ-rays, single or split-doses, high or low dose rates and densely-ionizing (α-particles radiation to compare the performances of the proposed RD formalism and the established two-lesion kinetic (TLK model. These yeast DSB rejoining data were measured within the radiation dose range relevant for clonogenic cell survival, whereas in mammalian cells DSB rejoining is usually measured only at supra-lethal doses for technical reasons. The RD model described both sparsely-ionizing and densely-ionizing radiation data much better than the TLK model: by 217 and 14 sample-size-adjusted Akaike information criterion units, respectively. This occurred because: the RD (but not the TLK model reproduced the observed upwardly-curving dose responses for slowly-rejoinable/unrejoinable DSBs at long times after irradiation; the RD model adequately described DSB yields at both high and low dose rates using one parameter set, whereas the TLK model overestimated low dose rate

  8. Human lymphocytes exposed to low doses of X-rays are less susceptible to radiation-induced mutagenesis

    Energy Technology Data Exchange (ETDEWEB)

    Kelsey, K.T.; Memisoglu, A.; Frenkel, D.; Liber, H.L. (Harvard School of Public Health, Boston, MA (United States))

    1991-08-01

    Human lymphocytes exposed to low doses of X-rays become refractory to the subsequent induction of chromosomal damage by high doses of radiation. The current study was designed to test the effect of pre-treatment of human T-lymphocytes with a low dose of X-rays on the induction of mutations at the hprt locus by a subsequent challenge dose. When cells were exposed to 1 cGy X-rays 24 h after phytohemag-glutinin stimulation, the yield of mutations induced by a 300 cGy X-ray dose given 16 h later was reduced by approximately 70% from the control level of X-ray-induced mutations. This indicates that this previously described adaptive response to low dose X-rays also results in lymphocytes becoming refractory to the induction of gene mutations. (author). 22 refs.; 2 tabs.

  9. 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)

  10. Radiation-induced biomarkers for the detection and assessment of absorbed radiation doses

    Directory of Open Access Journals (Sweden)

    Sudha Rana

    2010-01-01

    Full Text Available Radiation incident involving living organisms is an uncommon but a very serious situation. The first step in medical management including triage is high-throughput assessment of the radiation dose received. Radiation exposure levels can be assessed from viability of cells, cellular organelles such as chromosome and different intermediate metabolites. Oxidative damages by ionizing radiation result in carcinogenesis, lowering of the immune response and, ultimately, damage to the hematopoietic system, gastrointestinal system and central nervous system. Biodosimetry is based on the measurement of the radiation-induced changes, which can correlate them with the absorbed dose. Radiation biomarkers such as chromosome aberration are most widely used. Serum enzymes such as serum amylase and diamine oxidase are the most promising biodosimeters. The level of gene expression and protein are also good biomarkers of radiation.

  11. [Case of rhabdomyolysis induced by the approved daily dose of a traditional Chinese medicine].

    Science.gov (United States)

    Toyohara, Takafumi; Tanemoto, Masayuki; Uruno, Akira; Abe, Michiaki; Abe, Takaaki; Ito, Sadayoshi

    2008-01-01

    We report a case of a 67-year-old woman with hypokalemic rhabdomyolysis induced by pseudohyperaldosteronism. The pseudohyperaldosteronism in this case was caused by the administration of a traditional Chinese medicine, which contained 2.0 g of licorice in the approved daily dose. She started to suffer from hypertension and general fatigue after taking the medication, but continued it for two years until admission after an episode of diarrhea and vomiting. On admission, severe hypokalemia (1.6 mEq/L) and increased serum creatinine kinase (8,778 IU/L) was noted. With the findings of a high transtubular potassium concentration gradient (TTKG) in spite of low plasma renin activity and a low plasma aldosterone concentration, we suspected licorice-induced pseudohyperaldosteronism as the cause of her hypokalemic rhabdomyolysis. The Chinese medicine was terminated, and she received appropriate hydration and potassium replacement therapy as judged by the value of TTKG with the result that her serum potassium and creatinine kinase levels were normalized without any more adverse events. Since it was only a low dose of licorice (2.0 g/day) that induced hypokalemic rhabdomyolysis in this case, serum electrolytes should be examined in all cases under the possible consumption of licorice.

  12. The effect of radiation dose on the onset and progression of radiation-induced brain necrosis in the rat model.

    Science.gov (United States)

    Hartl, Brad A; Ma, Htet S W; Hansen, Katherine S; Perks, Julian; Kent, Michael S; Fragoso, Ruben C; Marcu, Laura

    2017-07-01

    To provide a comprehensive understanding of how the selection of radiation dose affects the temporal and spatial progression of radiation-induced necrosis in the rat model. Necrosis was induced with a single fraction of radiation exposure, at doses ranging between 20 and 60 Gy, to the right hemisphere of 8-week-old Fischer rats from a linear accelerator. The development and progression of necrosis in the rats was monitored and quantified every other week with T1- and T2-weighted gadolinium contrast-enhanced MRI studies. The time to onset of necrosis was found to be dose-dependent, but after the initial onset, the necrosis progression rate and total volume generated was constant across different doses ranging between 30 and 60 Gy. Radiation doses less than 30 Gy did not develop necrosis within 33 weeks after treatment, indicating a dose threshold existing between 20 and 30 Gy. The highest dose used in this study led to the shortest time to onset of radiation-induced necrosis, while producing comparable disease progression dynamics after the onset. Therefore, for the radiation-induced necrosis rat model using a linear accelerator, the most optimum results were generated from a dose of 60 Gy.

  13. Dose-response analysis of bromate-induced DNA damage and mutagenicity is consistent with low-dose linear, nonthreshold processes.

    Science.gov (United States)

    Spassova, Maria A; Miller, David J; Eastmond, David A; Nikolova, Nadejda S; Vulimiri, Suryanarayana V; Caldwell, Jane; Chen, Chao; White, Paul D

    2013-01-01

    Mutagenic agents have long been inferred to act through low-dose linear, nonthreshold processes. However, there is debate about this assumption, with various studies interpreting datasets as showing thresholds for DNA damage and mutation. We have applied rigorous statistical analyses to investigate the shape of dose-response relationships for a series of in vitro and in vivo genotoxicity studies using potassium bromate (KBrO(3) ), a water ozonation byproduct that is bioactivated to a reactive species causing oxidative damage to DNA. We analyzed studies of KBrO(3) genotoxicity where no-effect/threshold levels were reported as well as other representative datasets. In all cases, the data were consistent with low-dose linear models. In the majority of cases, the data were fit either by a linear (straight line) model or a model which was linear at low doses and showed a saturation-like downward curvature at high doses. Other datasets with apparent upward curvature were still adequately represented by models that were linear at low dose. Sensitivity analysis of datasets showing upward curvature revealed that both low-dose linear and nonlinear models provide adequate fits. Additionally, a simple biochemical model of selected key processes in bromate-induced DNA damage was developed and illustrated a situation where response for early primary events suggested an apparent threshold while downstream events were linear. Overall, the statistical analyses of DNA damage and mutations induced by KBrO(3) are consistent with a low-dose linear response and do not provide convincing evidence for the presence of a threshold. Copyright © 2012 Wiley Periodicals, Inc.

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

    Science.gov (United States)

    Peng, Rui-Rui; Wu, Juan; Zhao, Wei; Qi, Tengfei; Shi, Mei; Guan, Zhifang; Lu, Haikong; Long, Fuquan; Gao, Zixiao; Zhang, Sufang; Zhou, Pingyu

    2017-03-01

    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 patients in

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

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    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

  16. Low-dose steroid-induced tumor lysis syndrome in a hepatocellular carcinoma patient

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    Jin Ok Kim

    2015-03-01

    Full Text Available Tumor lysis syndrome is rare in hepatocellular carcinoma (HCC, but it has been reported more frequently recently in response to treatments such as transcatheter arterial chemoembolization (TACE, radiofrequency thermal ablation (RFTA, and sorafenib. Tumor lysis syndrome induced by low-dose steroid appears to be very unusual in HCC. We report a patient with hepatitis-C-related liver cirrhosis and HCC in whom tumor lysis syndrome occurred due to low-dose steroid (10 mg of prednisolone. The patient was a 90-year-old male who presented at the emergency room of our hospital with general weakness and poor oral intake. He had started to take prednisolone to treat adrenal insufficiency 2 days previously. Laboratory results revealed hyperuricemia, hyperphosphatemia, and increased creatinine. These abnormalities fulfilled the criteria in the Cairo-Bishop definition of tumor lysis syndrome. Although the patient received adequate hydration, severe metabolic acidosis and acute kidney injury progressed unabated. He finally developed multiple organ failure, and died 3 days after admission. This was a case of tumor lysis syndrome caused by administration of low-dose steroid in a patient with HCC.

  17. Low-dose steroid-induced tumor lysis syndrome in a hepatocellular carcinoma patient.

    Science.gov (United States)

    Kim, Jin Ok; Jun, Dae Won; Tae, Hye Jin; Lee, Kang Nyeong; Lee, Hang Lak; Lee, Oh Young; Choi, Ho Soon; Yoon, Byung Chul; Hahm, Joon Soo

    2015-03-01

    Tumor lysis syndrome is rare in hepatocellular carcinoma (HCC), but it has been reported more frequently recently in response to treatments such as transcatheter arterial chemoembolization (TACE), radiofrequency thermal ablation (RFTA), and sorafenib. Tumor lysis syndrome induced by low-dose steroid appears to be very unusual in HCC. We report a patient with hepatitis-C-related liver cirrhosis and HCC in whom tumor lysis syndrome occurred due to low-dose steroid (10 mg of prednisolone). The patient was a 90-year-old male who presented at the emergency room of our hospital with general weakness and poor oral intake. He had started to take prednisolone to treat adrenal insufficiency 2 days previously. Laboratory results revealed hyperuricemia, hyperphosphatemia, and increased creatinine. These abnormalities fulfilled the criteria in the Cairo-Bishop definition of tumor lysis syndrome. Although the patient received adequate hydration, severe metabolic acidosis and acute kidney injury progressed unabated. He finally developed multiple organ failure, and died 3 days after admission. This was a case of tumor lysis syndrome caused by administration of low-dose steroid in a patient with HCC.

  18. Sublethal Dose of Diazinon Induces Pulmonary Toxicity in Rat: Histopathological Evidence

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    Gholamreza Najafi

    2014-02-01

    Full Text Available Objective: Diazinon (DZ is a widely used contact organophosphorous pesticide with broad spectrum insecticide activity. The extensive use of DZ has caused great concern due to the hazardous side effects on human beings as well as wild and domestic animals. The aim of this study was to investigate the effect of sublethal dose of DZ on rat lung. Material and methods: Seven groups of male Wistar rats were used comprising control and test groups. The control group received corn oil (0.3 ml/day for 60 days by oral gavages. The test groups received DZ at a dose of 60 mg/kg body weight orally for 2, 10, 24, 30, 54 and 60 days, respectively. Results: The histopathological analysis of the lungs in DZ-treated groups revealed congestion on day 2, pulmonary edema and emphysema on day 10, congestion and atelectasia on day 24, infiltration of mononuclear cells on day 30 and pulmonary hemorrhage along with bronchial glands hyperplasia on days 54 and 60. DZ administration also caused a significant decrease in serum cholinesterase activity in a time-dependent manner. Conclusion: These findings indicate that sublethal dose of DZ can induce severe lesions in the lung of rat. [J Interdiscipl Histopathol 2014; 2(1.000: 26-31

  19. Low doses of imatinib induce myelopoiesis and enhance host anti-microbial immunity.

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    Ruth J Napier

    2015-03-01

    Full Text Available Imatinib mesylate (Gleevec inhibits Abl1, c-Kit, and related protein tyrosine kinases (PTKs and serves as a therapeutic for chronic myelogenous leukemia and gastrointestinal stromal tumors. Imatinib also has efficacy against various pathogens, including pathogenic mycobacteria, where it decreases bacterial load in mice, albeit at doses below those used for treating cancer. We report that imatinib at such low doses unexpectedly induces differentiation of hematopoietic stem cells and progenitors in the bone marrow, augments myelopoiesis but not lymphopoiesis, and increases numbers of myeloid cells in blood and spleen. Whereas progenitor differentiation relies on partial inhibition of c-Kit by imatinib, lineage commitment depends upon inhibition of other PTKs. Thus, imatinib mimics "emergency hematopoiesis," a physiological innate immune response to infection. Increasing neutrophil numbers by adoptive transfer sufficed to reduce mycobacterial load, and imatinib reduced bacterial load of Franciscella spp., which do not utilize imatinib-sensitive PTKs for pathogenesis. Thus, potentiation of the immune response by imatinib at low doses may facilitate clearance of diverse microbial pathogens.

  20. Protective effect of Genistein against N-nitrosodiethylamine (NDEA)-induced hepatotoxicity in Swiss albino rats.

    Science.gov (United States)

    Ali, Fahad; Rahul; Naz, Falaq; Jyoti, Smita; Hasan Siddique, Yasir

    2015-02-01

    In the present study, we studied the effect of Genistein against the hepatotoxicity induced by N-nitrosodiethylamine (NDEA). NDEA is present in almost all kinds of food stuff and has been reported to be a hepatocarcinogen. The male rats were exposed to NDEA (0.1 mg/mL) dissolved in drinking water separately and along with 25, 50, 100 mg/mL of Genistein for 21 days. The activities of serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) were measured in blood serum. Lipid peroxidation, protein carbonyl content, micronucleus frequency and DNA damage (Comet assay) were performed on rat hepatocytes. The results of the study reveal that the treatment of NDEA along with Genistein showed a significant dose-dependent decrease in the levels of blood serum enzymes i.e., SGOT, SGPT, ALP and LDH ( P <0.05). The HE staining of histological sections of the liver also revealed a protective effect of Genistein. A significant dose-dependent reduction in the lipid peroxidation and protein carbonyl content was observed in rats exposed to NDEA (0.1 mg/mL) along with Genistein ( P <0.05). The results obtained for the comet assay in rat hepatocytes showed a significant dose-dependent decrease in the mean tail length ( P <0.05). Thus the present study supports the hepatoprotective role of Genistein.

  1. Protective effect of Genistein against N-nitrosodiethylamine (NDEA-induced hepatotoxicity in Swiss albino rats

    Directory of Open Access Journals (Sweden)

    Fahad Ali

    2015-02-01

    Full Text Available In the present study, we studied the effect of Genistein against the hepatotoxicity induced by N-nitrosodiethylamine (NDEA. NDEA is present in almost all kinds of food stuff and has been reported to be a hepatocarcinogen. The male rats were exposed to NDEA (0.1 mg/mL dissolved in drinking water separately and along with 25, 50, 100 mg/mL of Genistein for 21 days. The activities of serum glutamic oxaloacetic transaminase (SGOT, serum glutamic pyruvic transaminase (SGPT, alkaline phosphatase (ALP and lactate dehydrogenase (LDH were measured in blood serum. Lipid peroxidation, protein carbonyl content, micronucleus frequency and DNA damage (Comet assay were performed on rat hepatocytes. The results of the study reveal that the treatment of NDEA along with Genistein showed a significant dose-dependent decrease in the levels of blood serum enzymes i.e., SGOT, SGPT, ALP and LDH (P<0.05. The HE staining of histological sections of the liver also revealed a protective effect of Genistein. A significant dose-dependent reduction in the lipid peroxidation and protein carbonyl content was observed in rats exposed to NDEA (0.1 mg/mL along with Genistein (P<0.05. The results obtained for the comet assay in rat hepatocytes showed a significant dose-dependent decrease in the mean tail length (P<0.05. Thus the present study supports the hepatoprotective role of Genistein. Keywords: Genistein, N-nitrosodiethylamine, Serum enzymes, Antigenotoxic, Hepatoprotective

  2. Voxel-based analysis unveils regional dose differences associated with radiation-induced morbidity in head and neck cancer patients.

    Science.gov (United States)

    Monti, Serena; Palma, Giuseppe; D'Avino, Vittoria; Gerardi, Marianna; Marvaso, Giulia; Ciardo, Delia; Pacelli, Roberto; Jereczek-Fossa, Barbara A; Alterio, Daniela; Cella, Laura

    2017-08-03

    The risk of radiation-induced toxicity in patients treated for head and neck (HN) cancer with radiation therapy (RT) is traditionally estimated by condensing the 3D dose distribution into a monodimensional cumulative dose-volume histogram which disregards information on dose localization. We hypothesized that a voxel-based approach would identify correlations between radiation-induced morbidity and local dose release, thus providing a new insight into spatial signature of radiation sensitivity in composite regions like the HN district. This methodology was applied to a cohort of HN cancer patients treated with RT at risk of radiation-induced acute dysphagia (RIAD). We implemented an inter-patient elastic image registration framework that proved robust enough to match even the most elusive HN structures and to provide accurate dose warping. A voxel-based statistical analysis was then performed to test regional dosimetric differences between patients with and without RIAD. We identified a significantly higher dose delivered to RIAD patients in two voxel clusters in correspondence of the cricopharyngeus muscle and cervical esophagus. Our study goes beyond the well-established organ-based philosophy exploring the relationship between radiation-induced morbidity and local dose differences in the HN region. This approach is generally applicable to different HN toxicity endpoints and is not specific to RIAD.

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

    Energy Technology Data Exchange (ETDEWEB)

    Gridley, Daila S.

    2008-10-31

    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

  4. Dose-dependent sickness behavior, abortion and inflammation induced by systemic LPS injection in pregnant mice.

    Science.gov (United States)

    Toyama, Rovana Paludo; Xikota, João Carlos; Schwarzbold, Marcelo L; Frode, Tania Silvia; Buss, Ziliani da Silva; Nunes, Jean Costa; Funchal, Gabriela Di Giunta; Nunes, Fernanda Costa; Walz, Roger; Pires, Maria Marlene de Souza

    2015-03-01

    Clinical and experimental evidences indicate that intrauterine inflammation during pregnancy is associated to brain damage. The objective of this study is to determine the effects of lipopolysaccharide in temperature, cytokine production and sickness behavior of pregnant dams. A single i.p. injection of lipopolysaccharide (LPS) (50, 150 or 300 µg/kg) was administered on E18. Controls received isotonic saline. Body temperature was controlled before and 3 h after injections. Animals' behavior was assessed by the OF test 3 h following treatment. Animals were sacrificed for leukocyte, IL-1β and TNF-α determination. Placental tissue and abortion were also examined. LPS administration elicited hypothermia. Abortion was observed in LPS 150 and 300 µg/kg. Leukocyte levels were significantly lower with LPS 300 µg/kg than in controls. LPS induced dose-dependent impairment in animals' locomotion. IL-1β serum and amniotic fluid were higher than the saline, and TNF-α serum and amniotic fluid increased when compared to controls. Placental histopathologic abnormality was not found. LPS induces dose-dependent sickness behavior and hypothermia in pregnant mice. Our findings suggest that the presence of inflammation may be a causative factor for premature labor and that Escherichia coli antigens modify the concentration of pro-inflammatory agents in circulatory system and intra-uterine environment.

  5. High-Dose Fluoride Induces Apoptosis and Inhibits Ameloblastin Secretion in Primary Rat Ameloblast.

    Science.gov (United States)

    Wang, Lin; Zhu, Yong; Wang, Danyang

    2016-12-01

    The objectives of this study are to establish the in vitro culture system for rat primary ameloblast and to investigate the effects of fluoride on cell viability, apoptosis, and ameloblastin (AMBN) secretion of primary rat ameloblast in vitro. Ameloblast was isolated from the tooth germ of the maxillomandibular molar and cultured in vitro. Cells were treated with NaF at 0.4, 0.8, 1.6, 3.2, and 6.4 mM for 24, 48, and 72 h, respectively. Cell viability was measured by MTT assay and apoptosis was tested by flow cytometry. The activation of Fas ligand (FasL)/Fas pathway was detected using immunoblotting for FasL, Fas, cleaved caspase-8, cleaved caspase-3, and cleaved PARP. Secretion of AMBN in culture medium was measured using ELISA. Primary rat ameloblast was successfully isolated and cultured. The effects of low-dose fluoride on cell viability were bi-phasic, while high-dose fluoride resulted in decreased cell viability uniformly. Fluoride induced ameloblast apoptosis via activation of FasL/Fas signaling pathway and diminished secretion of AMBN by ameloblast. Fluoride could decrease ameloblast viability, induce ameloblast apoptosis via activating FasL/Fas signaling pathway, and reduce AMBN secretion.

  6. Bystander effect between zebrafish embryos in vivo induced by high-dose X-rays.

    Science.gov (United States)

    Choi, V W Y; Ng, C Y P; Kobayashi, A; Konishi, T; Suya, N; Ishikawa, T; Cheng, S H; Yu, K N

    2013-06-18

    We employed embryos of the zebrafish, Danio rerio, for our studies on the in vivo bystander effect between embryos irradiated with high-dose X-rays and naive unirradiated embryos. The effects on the naive whole embryos were studied through quantification of apoptotic signals at 25 h post fertilization (hpf) through the terminal dUTP transferase-mediated nick end-labeling (TUNEL) assay followed by counting the stained cells under a microscope. We report data showing that embryos at 5 hpf subjected to a 4-Gy X-ray irradiation could release a stress signal into the medium, which could induce a bystander effect in partnered naive embryos sharing the same medium. We further demonstrated that this bystander effect (induced through partnering) could be successfully suppressed through the addition of the nitric oxide (NO) scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO) into the medium but not through the addition of the CO liberator tricarbonylchloro(glycinato)ruthenium(II) (CORM-3). This shows that NO was involved in the bystander response between zebrafish embryos induced through X-ray irradiation. We also report data showing that the bystander effect could be successfully induced in naive embryos by introducing them into the irradiated embryo conditioned medium (IECM) alone, i.e., without partnering with the irradiated embryos. The IECM was harvested from the medium that had conditioned the zebrafish embryos irradiated at 5 hpf with 4-Gy X-ray until the irradiated embryos developed into 29 hpf. NO released from the irradiated embryos was unlikely to be involved in the bystander effect induced through the IECM because of the short life of NO. We further revealed that this bystander effect (induced through IECM) was rapidly abolished through diluting the IECM by a factor of 2× or greater, which agreed with the proposal that the bystander effect was an on/off response with a threshold.

  7. Induced Terpene Accumulation in Norway Spruce Inhibits Bark Beetle Colonization in a Dose-Dependent Manner

    Science.gov (United States)

    Zhao, Tao; Krokene, Paal; Hu, Jiang; Christiansen, Erik; Björklund, Niklas; Långström, Bo; Solheim, Halvor; Borg-Karlson, Anna-Karin

    2011-01-01

    Background 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. Methods 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. Results 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. Conclusion/Significance 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. PMID:22028932

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

    Science.gov (United States)

    Zhao, Tao; Krokene, Paal; Hu, Jiang; Christiansen, Erik; Björklund, Niklas; Långström, Bo; Solheim, Halvor; Borg-Karlson, Anna-Karin

    2011-01-01

    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.

  9. 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 BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION/SIGNIFICANCE: 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.

  10. Low dose X-irradiation mitigates diazepam induced depression in rat brain.

    Science.gov (United States)

    Kaur, Amandeep; Singla, Neha; Dhawan, D K

    2016-10-01

    Depression is considered as one of the most prevalent health ailments. Various anti-depressant drugs have been used to provide succour to this ailment, but with little success and rather have resulted in many side effects. On the other hand, low dose of ionizing radiations are reported to exhibit many beneficial effects on human body by stimulating various biological processes. The present study was conducted to investigate the beneficial effects of low doses of X-rays, if any, during diazepam induced depression in rats. Female Sprague Dawley rats were segregated into four different groups viz: Normal control, Diazepam treated, X-irradiated and Diazepam + X-irradiated. Depression model was created in rats by subjecting them to diazepam treatment at a dosage of 2 mg/kg b.wt./day for 3 weeks. The skulls of animals belonging to X-irradiated and Diazepam + X-irradiated rats were X-irradiated with a single fraction of 0.5 Gy, given twice a day for 3 days, thereby delivered dose of 3 Gy. Diazepam treated animals showed significant alterations in the neurobehavior and neuro-histoarchitecture, which were improved after X-irradiation. Further, diazepam exposure significantly decreased the levels of neurotransmitters and acetylcholinesterase activity, but increased the monoamine oxidase activity in brain. Interestingly, X-rays exposure to diazepam treated rats increased the levels of neurotransmitters, acetylcholinesterase activity and decreased the monoamine oxidase activity. Further, depressed rats also showed increased oxidative stress with altered antioxidant parameters, which were normalized on X-rays exposure. The present study, suggests that low dose of ionizing radiations, shall prove to be an effective intervention and a novel therapy in controlling depression and possibly other brain related disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Oxygen requirement to reverse altitude-induced hypoxemia with continuous flow and pulsed dose oxygen.

    Science.gov (United States)

    Blakeman, Thomas C; Rodriquez, Dario; Gerlach, Travis W; Dorlac, Warren C; Johannigman, Jay A; Branson, Richard D

    2015-04-01

    Hypoxemia secondary to reduced barometric pressure is a complication of ascent to altitude. We designed a study to compare the reversal of hypobaric hypoxemia at 14,000 ft with continuous flow oxygen from a cylinder and pulsed dose oxygen from a portable concentrator. There were 30 healthy volunteers who were randomized to one of three study groups, placed in an altitude chamber, and ascended to 14,000 ft. There were 10 subjects in each study group. Subjects breathed room air for 10 min to induce hypoxemia. Oxygen was then delivered via a nasal cannula from a cylinder at 1, 2, or 3 lpm of continuous flow for 10 min. The subjects again breathed room air at altitude for 10 min and were then placed on pulsed dose oxygen and titrated to obtain the continuous flow Spo2 equivalent. Spo2, Etco2, RR, HR, Hgb, and tissue oxygenation (Sto2) were continuously recorded. The 1-lpm group's Spo2 range was 89-99%. The 2-lpm group's Spo2 range was 95-98%, and the 3-lpm group's Spo2 range was 95-99%. The 2-lpm and 3-lpm flows were able to correct hypoxemia in every subject. The mean pulsed dose required to achieve an equivalent Spo2 ranged from 36.8 ml ± 18.9 ml in the 1-lpm arm, and 102.4 ml ± 53.8 in the 3-lpm arm. Portable oxygen concentrators using pulsed dose technology corrected hypoxemia in every subject. Oxygen concentrators may be an alternative to liquid oxygen or cylinders for use during aeromedical evacuation.

  12. Low Dose Radiation Overcomes Diabetes-induced Suppression of Hippocampal Neuronal Cell Proliferation in Rats

    Science.gov (United States)

    Kim, Sang-Ki; Hong, Seong-Eon; Lee, Taeck-Hyun; Kim, Chang-Ju

    2006-01-01

    We investigated the effect of low dose radiation on diabetes induced suppression of neurogenesis in the hippocampal dentate gyrus of rat. After 0.01 Gy, 0.1 Gy, 1 Gy and 10 Gy radiation was delivered, the dentate gyrus of hippocampus of streptozotocin (STZ)-induced diabetic rats were evaluated using immunohistochemistry for 5-bromo-2-deoxyuridine (BrdU), caspase-3, and terminal deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL) staining. The number of BrdU positive cells in the non-diabetic rats, diabetic rats without radiation, diabetic rats with 0.01 Gy radiation, diabetic rats with 0.1 Gy radiation, diabetic rats with 1 Gy radiation and diabetic rats with 10 Gy radiation were 55.4±8.5/mm2, 33.3±6.4/mm2, 67.7±10.5/mm2, 66.6±10.0/mm2, 23.5±6.3/mm2and 14.3±7.2/mm2, respectively. The number of caspase-3 positive cells was 132.6±37.4/mm2, 378.6±99.1/mm2, 15.0±2.8/mm2, 57.1±16.9/mm2, 191.8±44.8/mm2and 450.4±58.3/mm2, respectively. The number of TUNEL-positive cells was 24.5±2.0/mm2, 21.7±4.0/mm2, 20.4±2.0/mm2, 18.96±2.1/mm2, 58.3±7.9/mm2, and 106.0±9.8/mm2, respectively. These results suggest low doses of radiation paradoxically improved diabetes induced neuronal cell suppression in the hippocampal dentate gyrus of rat. PMID:16778397

  13. Kisspeptin-54 at high doses acutely induces testicular degeneration in adult male rats via central mechanisms.

    Science.gov (United States)

    Thompson, E L; Amber, V; Stamp, G W H; Patterson, M; Curtis, A E; Cooke, J H; Appleby, G F; Dhillo, W S; Ghatei, M A; Bloom, S R; Murphy, K G

    2009-02-01

    The kisspeptins are critical regulators of reproduction and a therapeutic target for reproductive disease. Intracerebroventricular (i.c.v.) or peripheral injection of kisspeptin potently stimulates the hypothalamic-pituitary gonadal (HPG) axis via gonadotrophin-releasing hormone (GnRH). However, little is known regarding the effects of kisspeptin administration on testicular function. We investigated the mechanism(s) of kisspeptin-induced testicular degeneration in the rat. Kisspeptin-54 (50 nmol.day(-1)) was continuously administered subcutaneously (6 h to 3 days) to male Wistar rats and reproductive hormones and testicular histology analysed. We also investigated the effects of a single subcutaneous injection of 0.5, 5 or 50 nmol kisspeptin-54. In order to determine whether the testicular degeneration observed is peripherally or centrally mediated, we investigated effects of i.c.v. injections of 5 nmol kisspeptin-54 and pre-administered a GnRH-receptor antagonist (cetrorelix) to rats peripherally treated with kisspeptin-54. Continuous subcutaneous administration of kisspeptin-54 caused testicular degeneration after only 12 h, when gonadotrophins were still markedly raised, suggesting that the degeneration is independent of the desensitization of the HPG axis to kisspeptin-54. Furthermore, a single subcutaneous injection of kisspeptin-54 caused dose-dependent testicular degeneration. Continuous kisspeptin-54 administration is thus not required to cause testicular degeneration. Pretreatment with cetrorelix blocked kisspeptin-induced testicular degeneration, and a single i.c.v. injection of kisspeptin-54 caused testicular degeneration, suggesting it is GnRH-mediated. Kisspeptin-induced testicular degeneration appears to be centrally mediated, and result from acute hyper-stimulation of the HPG axis. Doses must be carefully considered if kisspeptin is to be used therapeutically.

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

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    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

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

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    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.

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

    Science.gov (United States)

    Shim, Hee Jin; Lee, Eun-Mi; Nguyen, Long Duy; Shim, Jaekyung; Song, Young-Han

    2014-01-01

    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.

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

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    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.

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

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    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.

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

    Science.gov (United States)

    Shousha, Hany A; Ahmad, Fawzia

    2012-06-01

    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)).

  20. [Practicing subnarcotic xenon dose inhalation in spa treatment of posttraumatic stress-induced disorders].

    Science.gov (United States)

    Igoshina, T V; Kotrovskaya, T I; Bubeev, Yu A; Schastlivtseva, D V; Potapov, A V

    2014-01-01

    Purpose of the investigation was to compare and contrast effectiveness of xenon therapy of stress-induced neurotic disorders and traditional spa-based therapy. Patients of the experimental and control groups were people of risky professions who received drug therapy, psychotherapy and physiotherapy. The experimental group was additionally treated by inhalation therapeutic doses of medical xenon. Comparative analysis of qualitative and quantitative parameters of electroencephalogram (EEG), blood oxygen level, heart rate and blood pressure were compared in the groups before and after treatment. Recovery of the central nervous system functions, activation of parasympathetic involvement, abatement of main psychopathological and somatovegetative disorders in the experimental group were considered as signs of psychic improvement and return to the gestalt behavior.

  1. Dose-dependent valproate-induced alopecia in patients with mental disorders.

    Science.gov (United States)

    Tomita, Takashi; Goto, Hidekazu; Yoshida, Tadashi; Tanaka, Katsuya; Sumiya, Kenji; Kohda, Yukinao

    2015-01-01

    Drug-induced hair loss may occur as a side effect in patients treated with valproate. However, few studies have reported a relationship between the blood levels of valproate and the occurrence of hair loss. We report three cases of alopecia that occurred in patients who received sodium valproate for mental disorders. In all three cases, alopecia appeared after long-term valproate exposure with a plasma concentration of 100 µg/ml approximately. However, the alopecia resolved in all cases after dose reduction or treatment discontinuation. Therefore, alopecia may develop in patients with chronic exposure to high plasma concentrations of valproate. Based on these findings, we believe that patients with high plasma concentrations of valproate should be closely monitored for the occurrence of side effects, particularly alopecia.

  2. Lipid Emulsions Enhance the Norepinephrine-Mediated Reversal of Local Anesthetic-Induced Vasodilation at Toxic Doses

    Science.gov (United States)

    Lee, Soo Hee; Sung, Hui-Jin; Ok, Seong-Ho; Yu, Jongsun; Choi, Mun-Jeoung; Lim, Jin Soo

    2013-01-01

    Purpose Intravenous lipid emulsions have been used to treat the systemic toxicity of local anesthetics. The goal of this in vitro study was to examine the effects of lipid emulsions on the norepinephrine-mediated reversal of vasodilation induced by high doses of levobupivacaine, ropivacaine, and mepivacaine in isolated endothelium-denuded rat aorta, and to determine whether such effects are associated with the lipid solubility of local anesthetics. Materials and Methods The effects of lipid emulsions (0.30, 0.49, 1.40, and 2.61%) on norepinephrine concentration-responses in high-dose local anesthetic (6×10-4 M levobupivacaine, 2×10-3 M ropivacaine, and 7×10-3 M mepivacaine)-induced vasodilation of isolated aorta precontracted with 60 mM KCl were assessed. The effects of lipid emulsions on local anesthetic- and diltiazem-induced vasodilation in isolated aorta precontracted with phenylephrine were also assessed. Results Lipid emulsions (0.30%) enhanced norepinephrine-induced contraction in levobupivacaine-induced vasodilation, whereas 1.40 and 2.61% lipid emulsions enhanced norepinephrine-induced contraction in both ropivacaine- and mepivacaine-induced vasodilation, respectively. Lipid emulsions (0.20, 0.49 and 1.40%) inhibited vasodilation induced by levobupivacaine and ropivacaine, whereas 1.40 and 2.61% lipid emulsions slightly attenuated mepivacaine (3×10-3 M)-induced vasodilation. In addition, lipid emulsions attenuated diltiazem-induced vasodilation. Lipid emulsions enhanced norepinephrine-induced contraction in endothelium-denuded aorta without pretreatment with local anesthetics. Conclusion Taken together, these results suggest that lipid emulsions enhance the norepinephrine-mediated reversal of local anesthetic-induced vasodilation at toxic anesthetic doses and inhibit local anesthetic-induced vasodilation in a manner correlated with the lipid solubility of a particular local anesthetic. PMID:24142661

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

    Science.gov (United States)

    Warzecha, Zygmunt; Sendur, Paweł; Ceranowicz, Piotr; Cieszkowski, Jakub; Dembiński, Marcin; Sendur, Ryszard; Bonior, Joanna; Jaworek, Jolanta; Ambroży, Tadeusz; Olszanecki, Rafał; Kuśnierz-Cabala, Beata; Tomasz, Kaczmarzyk; Tomaszewska, Romana; Dembiński, Artur

    2017-01-01

    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. PMID:28430136

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

    Science.gov (United States)

    Warzecha, Zygmunt; Sendur, Paweł; Ceranowicz, Piotr; Cieszkowski, Jakub; Dembiński, Marcin; Sendur, Ryszard; Bonior, Joanna; Jaworek, Jolanta; Ambroży, Tadeusz; Olszanecki, Rafał; Kuśnierz-Cabala, Beata; Tomasz, Kaczmarzyk; Tomaszewska, Romana; Dembiński, Artur

    2017-04-21

    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. 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. Treatment with acenocoumarol accelerates the recovery of ischemia/reperfusion-induced acute pancreatitis in rats.

  5. 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.

  6. Nonlinear dynamic characteristics of electroencephalography in a high-dose pilocarpine-induced status epilepticus model.

    Science.gov (United States)

    Jung, Ki-Young; Kim, Jae-Moon; Kim, Dong Wook

    2003-05-01

    We applied nonlinear analysis to the results of electroencephalography (EEG) in a pilocarpine-induced status epilepticus (SE) model to characterize nonlinear dynamics according to SE phase. Nine male Sprague-Dawley rats weighing 150-250 g were used. EEG was classified into four phases in addition to baseline EEG (phase 0) as follows: phase 1, discrete seizures; phase 2, continuous ictal discharges; phase 3, early periodic epileptiform discharges (PEDs); and phase 4, late PEDs. High-dose diazepam was administered at phase 4 to terminate SE. Diazepam controlled SE in five rats (group 1), while it failed to stop SE in the rest (group 2). The presence of nonlinearity was determined by time reversal asymmetry statistics using a surrogate data set. The correlation dimension (D(2)) was calculated to characterize the dimensional complexity of each phase of SE. EEG of later phases of SE showed strong nonlinearity, whereas no or only weak nonlinearity was noted at phases 0 and 1. D(2) showed the highest value at phase 0 and decreased progressively. Considering therapeutic responsiveness, D(2) showed significant differences between the two groups at phases 2 and 4. These results suggest that nonlinear dynamic changes in the later SE phases reflect underlying pathophysiological changes that contribute to determining therapeutic responsiveness in the pilocarpine-induced SE model.

  7. 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.

  8. Comparison of protein expression profile changes in human fibroblasts induced by low doses of gamma rays and energetic protons

    Science.gov (United States)

    Zhang, Ye; Clement, Jade; Gridley, Diala; Rohde, Larry; Wu, Honglu

    Extrapolation of known radiation risks to the risks from low dose and low dose-rate exposures of human population, especially prolonged exposure of astronauts in the space radiation environment, relies in part on the mechanistic understanding of radiation induced biological consequences at the molecular level. While some genomic data at the mRNA level are available for cells or animals exposed to radiation, the data at the protein level are still lacking. Here, we studied protein expression profile changes using Panorama antibody microarray chips that contain antibodies to more than 200 proteins (or modified proteins) involved in cell signaling that included mostly apoptosis, cytoskeleton, cell cycle and signal transduction. Normal human fibroblasts were cultured till fully confluent and then exposed to 2 cGy of gamma rays at either low (1 cGy/hr) or high (0.2 Gy/min) dose-rate, or to 2 cGy of 150 MeV protons at high dose-rate. The proteins were isolated at 2 and 6 hours after exposure and labeled with Cy3 for the irradiated cells and with Cy5 for the control samples before loaded onto the protein microarray chips. The intensities of the protein spots were analyzed using ScanAlyze software and normalized by the summed fluorescence intensities and the housekeeping proteins. Comparison of the overall protein expression profiles in gamma-irradiated cells showed significantly higher inductions at the high dose-rate than at the low dose-rate. The protein profile in cells after the proton exposure showed a much earlier induction pattern in comparison to both the high and low dose-rate gamma exposures. The same expression patterns were also found in individual cell signaling cascades. At 6 hours post irradiation, high dose-rate gamma rays induced cellular protein level changes (ratio to control ˜2) mostly in apoptosis, cell cycle and cytoskeleton, while low dose-rate gamma rays induced similar changes with smaller fold-change values. In comparison, protons induced

  9. 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.

  10. [Profiles of irregular bleeding induced by low-dose hormone therapy and Chinese formulated herbs products].

    Science.gov (United States)

    Wang, Shao-hai; Lin, Shou-qing; Gui, Qi-fang; Jin, Min-juan; Jiang, Ying

    2006-04-01

    To compare profiles and related factors of irregular bleeding induced by different types of low-dose hormone therapy (HT) and a Chinese formulated herbs products. Applied with open-labeled, randomized, and clinical trial design, 136 postmenopausal women were assigned into four groups: group A: estradiol valerate (E2 V) 1 mg/d + medroxyprogesterone acetate (MPA) 2 mg/d; group B: conjugated equine estrogen 0.45 mg/d + MPA 2 mg/d; group C: tibolone 1.25 mg/d; group D: a Chinese formulated herbs product (Kuntai) 4# tid. Each subject took element calcium 400 mg/d and vitamin D 200 IU/d concomitantly. Modified Kupperman scores were assessed on baseline and every 3 months thereafter and irregular bleeding was recorded on menopausal diary every day. The duration of this study was 1 year. Results The efficacies were similar in three HT-managed groups, but was better than in group D, although the latter was also effective in alleviating menopausal symptoms. Hazard ratio (HR) of irregular bleeding was 1.00 in group C, 2.43 in group A (95% CI: 1.08-5.46), 3.12 in group B (95% CI: 1.42-6.88), and 0.73 in group D (95% CI: 0.26-2.04). Most cases initially experienced bleeding in the first 3 months but such initiation was a bit later in group C. Endometrium, as detected by B-mode ultrasound, increased approximately 1 mm in HT groups, while it was a bit thicker in group C. Long periods in reproductive age and short time since menopause were high risk factors for irregular bleeding. Profiles of irregular bleeding in 3 commonly used types of low-dose HT are different and some factors such as long period in reproductive age and short time since menopause may contribute to bleeding initiation.

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

    Science.gov (United States)

    Castilla-Cortázar, Inma; García-Fernández, María; Delgado, Gloria; Puche, Juan E; Sierra, Inma; Barhoum, Rima; González-Barón, Salvador

    2011-07-06

    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. 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. 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. We demonstrate that low doses of IGF-II induce hepatoprotective, neuroprotective and metabolic effects, improving mitochondrial function, without affecting testosterone and IGF-I levels.

  12. "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.

  13. 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

  14. 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

  15. 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

  16. Brief report : enzyme inducers reduce elimination half-life after a single dose of nevirapine in healthy women

    NARCIS (Netherlands)

    L'homme, R.F.A.; Dijkema, T.; Ven, A.J.A.M. van der; Burger, D.M.

    2006-01-01

    OBJECTIVE: Single-dose nevirapine (SD-NVP) to prevent mother-to-child transmission (MTCT) of HIV is associated with development of NVP resistance, probably because of its long half-life in combination with a low genetic barrier to resistance. The objective of this study was to find enzyme inducers

  17. Manipulation of radiation-induced bystander effect in prostate adenocarcinoma by dose and tumor differentiation grade: in vitro study.

    Science.gov (United States)

    Tubin, Slavisa; Valeriani, Maurizio; Salerno, Gerardo; Bracci, Stefano; Stoppacciaro, Antonella; Cardelli, Patrizia; Osti, Mattia Falchetto; De Sanctis, Vitaliana; Minniti, Giuseppe; Maurizi Enrici, Riccardo

    2015-02-01

    This in vitro study evaluated the ability of prostate adenocarcinoma (ADC) cells to induce radiation-induced bystander effect (RIBE) exploring the factors that may be responsible and affect its intensity. The idea was to mimic a strong, clinically applicable RIBE that could lead to the development of innovative approaches in modern radiotherapy of prostate cancer, especially for those patients with hormone-refractory ADC in which radiotherapy might have a limited role. Two human prostate cancer cell lines of different differentiation, PC-3 and DU-145, have been irradiated using wide range of doses to obtain radiation-conditioned medium (RCM), which was used to treat the unirradiated cells and to evaluate the cytokines level. Using a trypan blue dye exclusion method, cell growth was assessed. Prostate ADC cells were able to induce RIBE; intensity depended on dose and cell differentiation. RIBE intensity of DU-145 was not correlated with the cytokines level, while for PC-3 Interleukin-6 (IL-6) correlates with strongest RIBE induced by 20 Gy. RIBE can be manipulated by modifying radiation dose and depends on cell differentiation status. IL-6 correlates with RIBE after exposure of PC-3 to a very high dose of radiation, thus indicates its possible involvement in bystander signaling.

  18. 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

  19. 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. Copyright 2010 S. Karger AG, Basel.

  20. Grand mal seizure induced by low-dose fentanyl and lidocaine in a young child.

    Science.gov (United States)

    Hsieh, Xhang-Xian; Hsu, Yung-Chi; Cherng, Chen-Hwan; Lin, Chun-Chieh; Huang, Go-Shine; Lin, Shinn-Long; Wu, Zhi-Fu; Yeh, Chun-Chang

    2015-09-01

    Surgical procedures require general anesthesia using combinations of drugs including fentanyl and/or lidocaine. Because many of these drugs have bimodal anticonvulsant/proconvulsant effects, they must be administered carefully. We herein report a case of seizure attack during anesthesia induction with low-dose fentanyl and lidocaine in a young child with no history of seizures. A 10-year-old girl was scheduled to receive an elective tenectomy. After a few seconds of fentanyl and lidocaine administration for anesthesia induction, she developed generalized tonic-clonic seizures. Seizures subsided spontaneously after 3 minutes. The patient's blood sugar, serum electrolytes, and arterial blood gas analysis were normal immediately after the event. She remained hemodynamically stable; however, the surgery was postponed after communication and discussion with the surgeon. Postoperatively, there was no evidence of postictal phase, and serum electrolytes and magnetic resonance imaging of the brain were normal. The patient had an uneventful recovery. However, electroencephalogram showed that hyperventilation stimulation test induced isolated epileptiform spikes over O1, suggesting a potential paroxysmal disorder over the left occipital area. This report is on a rare complication likely caused by fentanyl or lidocaine, which suggests that these drugs should be used cautiously in children whose clinical epileptic activities have been verified or are strongly suspected. Copyright © 2015. Published by Elsevier B.V.

  1. [Effects of high dose ambroxol on lung injury induced by paraquat in rats].

    Science.gov (United States)

    Ma, Yu-teng; Tian, Ying-ping; Shi, Han-wen; Lv, Cui-huan; Liu, Jian-hui; Sun, Zhi-ping

    2007-09-01

    To evaluate the protective effect of high dose ambroxol, a mucoactive drug, on acute lung injury caused by paraquat in rats. One hundred and thirty-six healthy male Sprague-Dawley rats were randomly divided into three groups: control group (n = 24) injected with normal saline intraperitoneally, PQ group (n = 56) [(2% paraquat (25 mg/kg) injected into peritoneal cavity on the first day)] and AT group (n = 56) ambroxol 35 mg/kg was injected into peritoneum daily after paraquat intoxication once daily for 7 consecutive days. The arterial gas was determined and the extent of lung injury was assessed by measuring the ratio of wet to dry weight (W/D) and protein content in BALF, the WBC count, the percentage of PMN, the content of malondialdehyde (MDA) and the levels of superoxide dismutase (SOD) in the blood and BALF respectively. Left lung tissue was observed through both light microscope and electron microscope (TEM). The white cell count and the content of protein in the blood and the BALF of PQ group were significantly higher than those of the control group (P ambroxol was administered. Treatment with ambroxol (35 mg/kg) could influence the status of oxidative stress in lung and alleviate lung injury induced by paraquat. Ambroxol has obviously therapeutic effect on paraquat poisoning.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1985-07-01

    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 /sup 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.

  3. Laulimalide induces dose-dependent modulation of microtubule behaviour in the C. elegans embryo.

    Directory of Open Access Journals (Sweden)

    Megha Bajaj

    Full Text Available Laulimalide is a microtubule-binding drug that was originally isolated from marine sponges. High concentrations of laulimalide stabilize microtubules and inhibit cell division similarly to paclitaxel; however, there are important differences with respect to the nature of the specific cellular defects between these two drugs and their binding sites on the microtubule. In this study, we used Caenorhabditis elegans embryos to investigate the acute effects of laulimalide on microtubules in vivo, with a direct comparison to paclitaxel. We observed surprising dose-dependent effects for laulimalide, whereby microtubules were stabilized at concentrations above 100 nM, but destabilized at concentrations between 50 and 100 nM. Despite this behaviour at low concentrations, laulimalide acted synergistically with paclitaxel to stabilize microtubules when both drugs were used at sub-effective concentrations, consistent with observations of synergistic interactions between these two drugs in other systems. Our results indicate that laulimalide induces a concentration-dependent, biphasic change in microtubule polymer dynamics in the C. elegans embryo.

  4. Comparison of the Effects of Low-Dose Midazolam, Magnesium Sulfate, Remifentanil and Low-Dose Etomidate on Prevention of Etomidate-Induced Myoclonus in Orthopedic Surgeries.

    Science.gov (United States)

    Sedighinejad, Abbas; Naderi Nabi, Bahram; Haghighi, Mohammad; Biazar, Gelareh; Imantalab, Vali; Rimaz, Siamak; Zaridoost, Zahra

    2016-04-01

    Etomidate is a potent hypnotic agent with several desirable advantages such as providing a stable cardiovascular profile with minimal respiratory adverse effects and better hemodynamic stability compared with other induction agents. This drug is associated, however, with myoclonic movements which is characterized by a sudden, brief muscle contractions as a disturbing side-effect. The present study was designed to compare the effectiveness of low- dose midazolam, magnesium sulfate, remifentanil and low-dose etomidate to suppress etomidate-induced myoclonus in orthopedic surgery. A double-blind clinical trial study was conducted in an academic hospital from September 2014 to August 2015. Two hundred and eighty-four eligible patients, American society of anesthesiologists class I - II, scheduled for elective orthopedic surgery were randomly allocated into four equal groups (n = 71). They received premedication with intravenous low-dose midazolam 0.015 mg/kg, magnesium sulfate 30 mg/kg, remifentanil 1 μg/kg and low-dose etomidate 0.03 mg/kg two minutes before induction of anesthesia with 0.3 mg/kg intravenous etomidate. Then the incidence and intensity of myoclonus were evaluated on a scale of 0 - 3; 0 = no myoclonus; 1 = mild (movement at wrist); 2 = moderate (movement at arm only, elbow or shoulder); and 3 = severe, generalized response or movement in more than one extremity, within ninety seconds. Any adverse effect due to these premedication agents was recorded. The incidence and intensity of myoclonus were significantly lower in the low-dose etomidate group. The incidence rates of myoclonus were 51 (71.85%), 61 (85.9%), 30 (42.3%) and 41 (57.7%), and the percentages of patients who experienced grade III of myoclonus were 30 (58.8%), 32 (52.5%), 9 (30%) and 14 (34.1%) in the midazolam, magnesium sulfate, etomidate and remifentanil groups, respectively. The incidence and intensity of myoclonus were significantly lower in the low-dose etomidate group (P = 0

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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/m2. 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.

  10. Acute High Dose Lithium-Induced Exacerbation of Obsessive Compulsive Symptoms

    OpenAIRE

    Umesh, Shreekantiah; Sinha, Vinod Kumar

    2014-01-01

    Obsessive compulsive disorder (OCD) is a chronic neuropsychiatric disorder whose pathophysiology is linked to serotonergic dysfunction. More recently, the role of glutamate has also been posited. Lithium is used as an adjunctive for the treatment of OCD which is found to enhance serotonergic transmission. We present a case of OCD who was on stable dose of sertraline developed exacerbation of obsessive compulsive symptoms with acute high dose of lithium but improved after dose reduction.

  11. Radiation-induced heart disease: review of experimental data on dose response and pathogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Schultz-Hector, S. (Institut fuer Strahlenbiologie, Neuherberg (Germany))

    1992-02-01

    Clinical and experimental heart irradiation can cause a variety of sequelae. A single dose of {>=} 15 Gy leads to a reversible exudative pericarditis, occurring in dogs, rabbits or rats at around 100 days. Its time-course is very similar in all species investigated, but there are considerable species and strain differences in severity and incidence. After longer, dose-dependent latency times chronic congestive myocardial failure develops. The paper reviews experimental data concerning dose response and pathogenesis. (author).

  12. Immunological studies in multiple low-dose streptozotocin-induced diabetes in mice

    Energy Technology Data Exchange (ETDEWEB)

    Malik, A.I.

    1988-01-01

    Multiple low doses of streptozotocin (MSZ) treatment successfully induced diabetes in male TO, MF1 and HO lean mice. In contrast however, BALB/c mice failed to develop persistent hyperglycemia. Single streptozotocin (SSZ) treatment also produced diabetes in TO mice. SSZ treatment however, produced severe weight loss and atrophy of the lymphoid organs. MSZ treatment on the other hand, was not cytotoxic towards lymphoid organs and, while there was no loss of body weight, growth rates were reduced in MSZ treated mice. Following sheep red blood cell (SRBC) immunization of MSZ-treated mice, hemagglutination titers, and numbers of antigen reactive cells and plaque forming cells were all significantly lower than control values. In-vitro proliferation of spleen cells in response to phytohemagglutinin (PHA) andconcanavalin and concanavalin A (ConA) was found to be significantly depressed in MSZ treated mice. However, T-lymphocyte responses were intact when the mice were not overtly hyperglycemic. In contrast, however, T cell independent responses to lipopolysaccharide (LPS) were generally intact throughout the study period. Cell mediated immunity, as assessed by measurements of delayed (Type 4) hypersensitivity, was also depressed in MSZ treated mice. Both natural killer cell activity and antibody dependent cell mediated cytotoxicity were found to be significantly increased in MSZ treated mice. Histological examination of the pancreas showed the presence of insulitis, in MSZ treated mice, and cytotoxic effector cells against obese mice islet cells (as assessed by {sup 51}Cr release) and HIT-T15 cells (as assessed by insulin secretion) were found to be significantly increased. Furthermore, these effector cells were also found to show increased proliferation in the presence of homogenates prepared from HIT-T15 cells.

  13. Pretreatment with different doses of dexamethasone in the prevention of docetaxel-induced hypersensitivity.

    Science.gov (United States)

    Zhang, Mingjun; Chen, Zhendong; Yang, Yang; Cheng, Huaidong; Li, Chao; He, Qian

    2017-01-01

    This study aimed to evaluate the efficacy and safety of dexamethasone pretreatment regimen with different doses in the prevention of docetaxel-induced hypersensitivity reaction (HSR). One hundred and sixty-two patients who had malignant tumors as determined by histology and/or cytology and received docetaxel treatments at least 2 cycles, were randomized into two groups. There were 90 patients in the study group and 72 patients in the control group. In the study group, patients received 4.5mg of oral dexamethasone once a day. Patients in the control group received 8 mg of dexamethasone twice a day. All patients received dexamethasone for 3 days, from the day before docetaxel treatment to the day after docetaxel treatment. The endpoints were hypersensitivity reaction (HSR) and other adverse effects, which were determined according to common terminology criteria for adverse event v3.0 (CTCAE 3.0). In the study group, 10 patients had HSRs (11.1%). While in the control group, 7 patients had HSRs (9.7%), and the main clinical symptoms of HSR were rash (3.1%), fever/chill (2.5%), angioedema (1.9%), chest discomfort (1.9%) and hypotension (0.6%). There was no statistically significant difference between these two groups (P=0.774). There was no significant difference in the incidence rate of adverse effect between patients in the study group and in the control group. Those adverse effects included neutropenia, decreased hemoglobin, nausea, vomiting, fatigue and fluid retention. Since no significant difference in the HSR incidence between these two groups has been found, 4.5mg of dexamethasone (qd) is as efficient and safe as 8mg (bid).

  14. Bivalirudin dosing adjustments for reduced renal function with or without hemodialysis in the management of heparin-induced thrombocytopenia.

    Science.gov (United States)

    Tsu, Laura V; Dager, William E

    2011-10-01

    While not approved by the Food and Drug Administration for treatment of heparin-induced thrombocytopenia (HIT), except in patients undergoing percutaneous interventions, the direct thrombin inhibitor bivalirudin is a treatment option that is gaining use. An initial dose of bivalirudin 0.15-0.2 mg/kg/h, adjusted to an activated partial thromboplastin time (aPTT) of 1.5-2.5 times the baseline value, has been suggested. Initial dosing in patients with renal dysfunction, including those on hemodialysis, is unclear. To evaluate initial bivalirudin dosing requirements in patients with and without renal dysfunction, including patients on different forms of dialysis. A retrospective analysis of 135 patients treated with bivalirudin for HIT between June 2004 and October 2009 was conducted at a tertiary care medical center. The patients were divided into groups, based on renal function. Patients receiving dialysis were divided into 3 subgroups based on the mode of hemodialysis: intermittent hemodialysis (IHD, n = 24), sustained low-efficiency daily diafiltration (SLEDD, n = 12), or continuous renal replacement therapy (CRRT, n = 5). Patients not receiving dialysis were separated into 3 subgroups based on calculated creatinine clearance (CrCl): CrCl >60 mL/min (n = 52), CrCl 30-60 mL/min (n = 26), and CrCl 60 mL/min), patients with differing degrees of renal dysfunction (CrCl 30-60 and doses of bivalirudin to achieve aPTT goal (0.13 vs 0.08 vs 0.05 mg/kg/h, respectively; p CRRT) also required dose reductions (0.07, 0.09, and 0.07 mg/kg/h) compared with patients with normal renal function, but higher dosing requirements than patients not receiving dialysis with CrCl dose of bivalirudin to reach a therapeutic aPTT goal. Slightly higher doses may be observed in patients receiving hemodialysis.

  15. Mercuric chloride-induced kidney damage in mice: time course and effect of dose

    DEFF Research Database (Denmark)

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

    1991-01-01

    The rate of elimination of mercury after a single oral or intraperitoneal administration of HgCl2 to male or female mice has recently been demonstrated to be inversely related to the dose size (Nielsen and Andersen, 1989, 1990). The present study demonstrates dose-related induction of renal tubul...

  16. A minimal dose of electrically induced muscle activity regulates distinct gene signaling pathways in humans with spinal cord injury.

    Directory of Open Access Journals (Sweden)

    Michael A Petrie

    Full Text Available Paralysis after a spinal cord injury (SCI induces physiological adaptations that compromise the musculoskeletal and metabolic systems. Unlike non-SCI individuals, people with spinal cord injury experience minimal muscle activity which compromises optimal glucose utilization and metabolic control. Acute or chronic muscle activity, induced through electrical stimulation, may regulate key genes that enhance oxidative metabolism in paralyzed muscle. We investigated the short and long term effects of electrically induced exercise on mRNA expression of human paralyzed muscle. We developed an exercise dose that activated the muscle for only 0.6% of the day. The short term effects were assessed 3 hours after a single dose of exercise, while the long term effects were assessed after training 5 days per week for at least one year (adherence 81%. We found a single dose of exercise regulated 117 biological pathways as compared to 35 pathways after one year of training. A single dose of electrical stimulation increased the mRNA expression of transcriptional, translational, and enzyme regulators of metabolism important to shift muscle toward an oxidative phenotype (PGC-1α, NR4A3, IFRD1, ABRA, PDK4. However, chronic training increased the mRNA expression of specific metabolic pathway genes (BRP44, BRP44L, SDHB, ACADVL, mitochondrial fission and fusion genes (MFF, MFN1, MFN2, and slow muscle fiber genes (MYH6, MYH7, MYL3, MYL2. These findings support that a dose of electrical stimulation (∼10 minutes/day regulates metabolic gene signaling pathways in human paralyzed muscle. Regulating these pathways early after SCI may contribute to reducing diabetes in people with longstanding paralysis from SCI.

  17. Impact of Fractionation and Dose in a Multivariate Model for Radiation-Induced Chest Wall Pain

    Energy Technology Data Exchange (ETDEWEB)

    Din, Shaun U. [Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York (United States); Williams, Eric L.; Jackson, Andrew [Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York (United States); Rosenzweig, Kenneth E. [Department of Radiation Oncology, Mount Sinai Medical Center, New York, New York (United States); Wu, Abraham J.; Foster, Amanda [Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York (United States); Yorke, Ellen D. [Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York (United States); Rimner, Andreas, E-mail: rimnera@mskcc.org [Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York (United States)

    2015-10-01

    Purpose: To determine the role of patient/tumor characteristics, radiation dose, and fractionation using the linear-quadratic (LQ) model to predict stereotactic body radiation therapy–induced grade ≥2 chest wall pain (CWP2) in a larger series and develop clinically useful constraints for patients treated with different fraction numbers. Methods and Materials: A total of 316 lung tumors in 295 patients were treated with stereotactic body radiation therapy in 3 to 5 fractions to 39 to 60 Gy. Absolute dose–absolute volume chest wall (CW) histograms were acquired. The raw dose-volume histograms (α/β = ∞ Gy) were converted via the LQ model to equivalent doses in 2-Gy fractions (normalized total dose, NTD) with α/β from 0 to 25 Gy in 0.1-Gy steps. The Cox proportional hazards (CPH) model was used in univariate and multivariate models to identify and assess CWP2 exposed to a given physical and NTD. Results: The median follow-up was 15.4 months, and the median time to development of CWP2 was 7.4 months. On a univariate CPH model, prescription dose, prescription dose per fraction, number of fractions, D83cc, distance of tumor to CW, and body mass index were all statistically significant for the development of CWP2. Linear-quadratic correction improved the CPH model significance over the physical dose. The best-fit α/β was 2.1 Gy, and the physical dose (α/β = ∞ Gy) was outside the upper 95% confidence limit. With α/β = 2.1 Gy, V{sub NTD99Gy} was most significant, with median V{sub NTD99Gy} = 31.5 cm{sup 3} (hazard ratio 3.87, P<.001). Conclusion: There were several predictive factors for the development of CWP2. The LQ-adjusted doses using the best-fit α/β = 2.1 Gy is a better predictor of CWP2 than the physical dose. To aid dosimetrists, we have calculated the physical dose equivalent corresponding to V{sub NTD99Gy} = 31.5 cm{sup 3} for the 3- to 5-fraction groups.

  18. 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

  19. Recent advances in the investigation of pancreatic inflammation induced by large doses of basic amino acids in rodents.

    Science.gov (United States)

    Kui, Balázs; Balla, Zsolt; Végh, Eszter T; Pallagi, Petra; Venglovecz, Viktória; Iványi, Béla; Takács, Tamás; Hegyi, Péter; Rakonczay, Zoltán

    2014-02-01

    It has been known for approximately 30 years that large doses of the semi-essential basic amino acid L-arginine induce severe pancreatic inflammation in rats. Recently, it has been demonstrated that L-arginine can also induce pancreatitis in mice. Moreover, other basic amino acids like L-ornithine and L-lysine can cause exocrine pancreatic damage without affecting the endocrine parenchyma and the ducts in rats. The utilization of these noninvasive severe basic amino acid-induced pancreatitis models is becoming increasingly popular and appreciated as these models nicely reproduce most laboratory and morphological features of human pancreatitis. Consequently, the investigation of basic amino acid-induced pancreatitis may offer us a better understanding of the pathogenesis and possible treatment options of the human disease.

  20. Efficacy of single-dose ceftriaxone in experimental otitis media induced by penicillin- and cephalosporin-resistant Streptococcus pneumoniae.

    OpenAIRE

    Barry, B.; Muffat-Joly, M; Bauchet, J; Faurisson, F; Gehanno, P; Pocidalo, J J; Carbon, C.

    1996-01-01

    We used a gerbil model of otitis media to assess the efficacy of single-dose ceftriaxone against three Streptococcus pneumoniae strains highly resistant to penicillin (MICs, 4 to 8 micrograms/ml) and with various susceptibilities to ceftriaxone (MICs, 0.5, 4, and 8 micrograms/ml). Middle ear infection was induced by bilateral transbullar challenge with 10(7) bacteria per ear. Antibiotic treatment was administered subcutaneously at 2 h postinfection. Infection status was checked 2 days later b...

  1. 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.

  2. 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...

  3. The effects of pre-emptive low-dose X-ray irradiation on MIA induced inflammatory pain in rats

    Science.gov (United States)

    Hahm, Suk-Chan; Lee, Go-Eun; Kim, Eun-Hye; Kim, Junesun; Lee, Taewoong; Lee, Wonho

    2013-07-01

    This study was performed to determine the effect of pre-emptive low-dose irradiation on the development of inflammatory pain and to characterize the potential mechanisms underlying this effect in osteoarthritis (OA) animal model. Whole-body X-irradiations with 0.1, 0.5, 1 Gy or sham irradiations were performed for 3 days before the induction of ostearthritis with monosodium iodoacetate (MIA) (40 µl, in saline) into the right knee joint in male Sprague Dawley rats. Behavioral tests for arthritic pain including evoked and non-evoked pain were conducted before and after MIA injection and inducible nitric-oxide synthase (iNOS) expression level was measured by western blot. Low-dose radiation significantly prevented the development of mechanical allodynia and thermal hyperalgesia and reduction in weight bearing that is regarded as a behavioral signs of non-evoked pain following MIA injection. Low-dose radiation significantly inhibited the increase in iNOS expression after MIA injection in spinal L3-5 segments in rat. These data suggest that low-dose X-irradiation is able to prevent the development of arthritic pain through modulation of iNOS expression in the spinal cord dorsal horn. Thus, low-dose radiotherapy could be substituted in part for treatment with drugs for patients with chronic inflammatory disease in clinical setting.

  4. 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

    Mercuric chloride is a well-known human and animal nephrotoxicant. Previous studies have demonstrated an inverse relationship between dose size and relative whole-body retention of mercury after oral administration of mercuric chloride to mice. The present study indicates that this inverse...... occurred between days 2 and 3 after administration. The renal damage was followed by regeneration, which was observed between days 3 and 7 at increasing dose levels up to 100 mumole HgCl2/kg. The amount of glutathione and the glutathione peroxidase activity in kidney decreased with increasing doses...

  5. A single dose of inactivated hepatitis A vaccine promotes HAV-specific memory cellular response similar to that induced by a natural infection.

    Science.gov (United States)

    Melgaço, Juliana Gil; Morgado, Lucas Nóbrega; Santiago, Marta Almeida; Oliveira, Jaqueline Mendes de; Lewis-Ximenez, Lia Laura; Hasselmann, Bárbara; Cruz, Oswaldo Gonçalves; Pinto, Marcelo Alves; Vitral, Claudia Lamarca

    2015-07-31

    Based on current studies on the effects of single dose vaccines on antibody production, Latin American countries have adopted a single dose vaccine program. However, no data are available on the activation of cellular response to a single dose of hepatitis A. Our study investigated the functional reactivity of the memory cell phenotype after hepatitis A virus (HAV) stimulation through administration of the first or second dose of HAV vaccine and compared the response to that of a baseline group to an initial natural infection. Proliferation assays showed that the first vaccine dose induced HAV-specific cellular response; this response was similar to that induced by a second dose or an initial natural infection. Thus, from the first dose to the second dose, increase in the frequencies of classical memory B cells, TCD8 cells, and central memory TCD4 and TCD8 cells were observed. Regarding cytokine production, increased IL-6, IL-10, TNF, and IFNγ levels were observed after vaccination. Our findings suggest that a single dose of HAV vaccine promotes HAV-specific memory cell response similar to that induced by a natural infection. The HAV-specific T cell immunity induced by primary vaccination persisted independently of the protective plasma antibody level. In addition, our results suggest that a single dose immunization system could serve as an alternative strategy for the prevention of hepatitis A in developing countries. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Efficacy of single-dose ceftriaxone in experimental otitis media induced by penicillin- and cephalosporin-resistant Streptococcus pneumoniae.

    Science.gov (United States)

    Barry, B; Muffat-Joly, M; Bauchet, J; Faurisson, F; Gehanno, P; Pocidalo, J J; Carbon, C

    1996-09-01

    We used a gerbil model of otitis media to assess the efficacy of single-dose ceftriaxone against three Streptococcus pneumoniae strains highly resistant to penicillin (MICs, 4 to 8 micrograms/ml) and with various susceptibilities to ceftriaxone (MICs, 0.5, 4, and 8 micrograms/ml). Middle ear infection was induced by bilateral transbullar challenge with 10(7) bacteria per ear. Antibiotic treatment was administered subcutaneously at 2 h postinfection. Infection status was checked 2 days later by counting the bacteria in middle ear and cerebrospinal fluid samples. With the cefriaxone-susceptible strain (MIC, 0.5 microgram/ml), we tested doses of 5 to 100 mg/kg of body weight. With a dose of 50 mg/kg, treatment outcome was equivalent to that with amoxicillin, which was used as a reference (25 mg/kg, two injections); no bacteria were recovered from 82% of the middle ear samples, and the rate of cerebrospinal fluid culture positivity was significantly reduced to 6%, relative to 59% for the untreated controls. Similar efficacy was obtained with a dose of 100 mg/kg against the two ceftriaxone-resistant strains. Pharmacokinetic study indicates that the values of the parameters in plasma after the administration of a dose of 100 mg/kg (peak level of total drug, 268 +/- 33 micrograms/ml; elimination half-life, 0.8 h; area under concentration-time curve, 488 micrograms.h.ml-1) were still suboptimal compared with the values of the parameters measured in pediatric patients after intravenous or intramuscular administration of a dose of 50 mg/kg. Our results indicate the efficacy of ceftriaxone against experimental cephalosporin-resistant pneumococcal otitis and provide a basis for the clinical use of single-dose ceftriaxone against pneumococcal otitis media.

  7. 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

  8. 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 avail...... available, and when used with filters as albedo dosimeters in pairs, they provide discrimination of neutron and gamma-ray doses....

  9. Low-dose dynamic myocardial perfusion CT image reconstruction using pre-contrast normal-dose CT scan induced structure tensor total variation regularization

    Science.gov (United States)

    Gong, Changfei; Han, Ce; Gan, Guanghui; Deng, Zhenxiang; Zhou, Yongqiang; Yi, Jinling; Zheng, Xiaomin; Xie, Congying; Jin, Xiance

    2017-04-01

    Dynamic myocardial perfusion CT (DMP-CT) imaging provides quantitative functional information for diagnosis and risk stratification of coronary artery disease by calculating myocardial perfusion hemodynamic parameter (MPHP) maps. However, the level of radiation delivered by dynamic sequential scan protocol can be potentially high. The purpose of this work is to develop a pre-contrast normal-dose scan induced structure tensor total variation regularization based on the penalized weighted least-squares (PWLS) criteria to improve the image quality of DMP-CT with a low-mAs CT acquisition. For simplicity, the present approach was termed as ‘PWLS-ndiSTV’. Specifically, the ndiSTV regularization takes into account the spatial-temporal structure information of DMP-CT data and further exploits the higher order derivatives of the objective images to enhance denoising performance. Subsequently, an effective optimization algorithm based on the split-Bregman approach was adopted to minimize the associative objective function. Evaluations with modified dynamic XCAT phantom and preclinical porcine datasets have demonstrated that the proposed PWLS-ndiSTV approach can achieve promising gains over other existing approaches in terms of noise-induced artifacts mitigation, edge details preservation, and accurate MPHP maps calculation.

  10. Increases in seizure latencies induced by subcutaneous docosahexaenoic acid are lost at higher doses.

    Science.gov (United States)

    Trépanier, Marc-Olivier; Taha, Ameer Y; Mantha, Rebecca L; Ciobanu, Flaviu A; Zeng, Qiudi H; Tchkhartichvili, George M; Domenichiello, Anthony F; Bazinet, Richard P; Burnham, W M

    2012-05-01

    Docosahexaenoic acid (DHA) is a polyunsaturated fatty acid (PUFA) which has been found to have anticonvulsant properties. Our group has previously reported in a pilot study that the acute administration of subcutaneous (s.c.) DHA increases seizure latencies in the maximal pentylenetetrazole (PTZ) seizure test, however it loses its effect at higher doses. The purpose of the present experiments was (1) to confirm that DHA loses its effect at higher doses, (2) to correlate the anticonvulsant properties of DHA with DHA levels in the different lipid pools of serum and (3) to evaluate whether an anticonvulsant dose of DHA resulted in an increase in DHA release from the brain phospholipids following induction of seizure. In the first experiment, male Wistar rats were injected s.c. with 200, 300, 400 or 600 mg/kg of DHA, or 400mg/kg oleic acid (OA, isocaloric control), and seizure tested with the maximal PTZ test 1h post injection (Experiment 1). In a second experiment, subjects received either: (1) an effective dose of DHA (400mg/kg), (2) a higher, non-effective dose (600 mg/kg; based on the findings of Experiment 1), or (3) OA (400mg/kg). Subjects were sacrificed 1h post injection and blood was collected for fatty acid analysis (Experiment 2). In the third experiment, subjects were injected with either the effective dose of DHA (400mg/kg) or OA (400mg/kg). One hour post lipid injection, animals received either PTZ or saline, and animals were euthanized via microwave fixation. Brain were extracted and unesterified fatty acid concentrations were measured (Experiment 3). Experiment 1 confirmed that DHA loses its effects at higher doses in the maximal PTZ test. The 400mg/kg dose was maximally effective but effects were lost at 600 mg/kg. Experiment 2 showed that only the unesterified DHA pool in serum was statistically increased by an acute injection of s.c. DHA (P0.05). Curiously, unesterified DHA levels were similar in both the 400mg/kg and 600 mg/kg dosage groups

  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. 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.

  13. Lamotrigine blocks repeated high-dose methamphetamine-induced behavioral sensitization to dizocilpine (MK-801), but not methamphetamine in rats.

    Science.gov (United States)

    Nakato, Yasuya; Abekawa, Tomohiro; Inoue, Takeshi; Ito, Koki; Koyama, Tsukasa

    2011-10-24

    We recently proposed a new psychostimulant animal model of the progressive pathophysiological changes of schizophrenia. Studies using that model produced a treatment strategy for preventing progression. Lamotrigine (LTG) blocks repeated high-dosage methamphetamine (METH)-induced initiation and expression of prepulse inhibition deficit and development of apoptosis in the medial prefrontal cortex (mPFC). Moreover, it inhibits METH-induced increases in extracellular glutamate levels in the mPFC (Nakato et al., 2011, Neurosci. Lett.). Abnormal behavior induced by METH or NMDA receptor antagonists is regarded as an animal model of schizophrenia. This study examined the effects of LTG on the development of behavioral sensitization to METH and cross-sensitization to dizocilpine (MK-801) by repeated administration of high-dose METH (2.5mg/kg, 10 times s.c.). Rats were injected repeatedly with LTG (30mg/kg) after 120min METH administration (2.5mg/kg). Repeated co-administration of LTG blocked the development of behavioral cross-sensitization to MK-801 (0.15mg/kg), but it did not prevent behavioral sensitization to METH (0.2mg/kg). The LTG-induced prevention of increased glutamate by high-dose METH might be related to the former finding. Combined results of our previous studies and this study suggest that LTG is useful to treat schizophrenia, especially at a critical point in its progression. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  14. 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)

    Pühringer, Friedrich K; Rex, Christopher; Sielenkämper, Andreas W

    2008-01-01

    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....

  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 evalua...

  16. The effects of diazepam or midazolam on the dose of propofol required to induce anaesthesia in cats.

    Science.gov (United States)

    Robinson, Rebecca; Borer-Weir, Kate

    2015-09-01

    Assess effects of benzodiazepine administration on the propofol dose required to induce anaesthesia in healthy cats, investigate differences between midazolam and diazepam, and determine an optimal benzodiazepine dose for co-induction. Prospective, randomised, blinded, placebo-controlled clinical trial. Ninety client-owned cats (ASA I and II) with a median (interquartile range) body mass of 4.0 (3.4-4.9) kg. All cats received 0.01 mg kg(-1) acepromazine and 0.2 mg kg(-1) methadone intravenously (IV). Fifteen minutes later, sedation was scored on a scale of 1-5, with 5 indicating greatest sedation. Propofol, 2 mg kg(-1) , administered IV, was followed by either midazolam or diazepam at 0.2, 0.3, 0.4 or 0.5 mg kg(-1) or saline 0.1 mL kg(-1) . Further propofol was administered until endotracheal intubation was possible. Patient signalment, sedation score, propofol dosage and adverse reactions were recorded. Midazolam and diazepam (all doses) significantly reduced the propofol dose required compared with saline (p diazepam in propofol dose reduction (p = 0.488). All individual doses of midazolam reduced propofol requirement compared with saline (0.2 mg kg(-1) , p = 0.028; 0.3 mg kg(-1) , p = 0.006; 0.4 mg kg(-1) , p Diazepam 0.2 mg kg(-1) did not reduce the propofol dose compared with saline (p = 0.087), but the remaining doses did (0.3 mg kg(-1) , p = 0.001; 0.4 mg kg(-1) , p = 0.032; 0.5 mg kg(-1) , p = 0.041). Cats with sedation scores of 3 required less propofol than cats with scores of 2 (p = 0.008). There was no difference between groups in adverse events. Midazolam (0.2-0.5 mg kg(-1) ) and diazepam (0.3-0.5 mg kg(-1) ) administered IV after 2 mg kg(-1) propofol significantly reduced the propofol dose required for tracheal intubation. © 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

  17. A 12-Month–Interval Dosing Study in Adults Indicates That a Single Dose of the National Institute of Allergy and Infectious Diseases Tetravalent Dengue Vaccine Induces a Robust Neutralizing Antibody Response

    Science.gov (United States)

    Durbin, Anna P.; Kirkpatrick, Beth D.; Pierce, Kristen K.; Carmolli, Marya P.; Tibery, Cecilia M.; Grier, Palmtama L.; Hynes, Noreen; Opert, Kari; Jarvis, Adrienne P.; Sabundayo, Beulah P.; McElvany, Benjamin D.; Sendra, Eli A.; Larsson, Catherine J.; Jo, Matthew; Lovchik, Janece M.; Luke, Catherine J.; Walsh, Mary C.; Fraser, Ellen A.; Subbarao, Kanta; Whitehead, Stephen S.

    2016-01-01

    The ideal dengue vaccine will provide protection against all serotypes of dengue virus and will be economical and uncomplicated in its administration. To determine the ability of a single dose of the live attenuated tetravalent dengue vaccine TV003 to induce a suitable neutralizing antibody response, a placebo-controlled clinical trial was performed in 48 healthy adults who received 2 doses of vaccine or placebo administered 12 months apart. Evaluation of safety, vaccine viremia, and neutralizing antibody response after each dose indicated that the first dose of vaccine was capable of preventing infection with the second dose, thus indicating that multiple doses are unnecessary. Clinical Trials Registration. NCT01782300. PMID:26908742

  18. A 12-Month-Interval Dosing Study in Adults Indicates That a Single Dose of the National Institute of Allergy and Infectious Diseases Tetravalent Dengue Vaccine Induces a Robust Neutralizing Antibody Response.

    Science.gov (United States)

    Durbin, Anna P; Kirkpatrick, Beth D; Pierce, Kristen K; Carmolli, Marya P; Tibery, Cecilia M; Grier, Palmtama L; Hynes, Noreen; Opert, Kari; Jarvis, Adrienne P; Sabundayo, Beulah P; McElvany, Benjamin D; Sendra, Eli A; Larsson, Catherine J; Jo, Matthew; Lovchik, Janece M; Luke, Catherine J; Walsh, Mary C; Fraser, Ellen A; Subbarao, Kanta; Whitehead, Stephen S

    2016-09-15

    The ideal dengue vaccine will provide protection against all serotypes of dengue virus and will be economical and uncomplicated in its administration. To determine the ability of a single dose of the live attenuated tetravalent dengue vaccine TV003 to induce a suitable neutralizing antibody response, a placebo-controlled clinical trial was performed in 48 healthy adults who received 2 doses of vaccine or placebo administered 12 months apart. Evaluation of safety, vaccine viremia, and neutralizing antibody response after each dose indicated that the first dose of vaccine was capable of preventing infection with the second dose, thus indicating that multiple doses are unnecessary. NCT01782300. Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

  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. Radiation-Induced Bystander Effects: Evidence for an Adaptive Response to Low Dose Exposures?

    Science.gov (United States)

    Mothersill, Carmel; Seymour, Colin

    2006-01-01

    This paper reviews our current knowledge of the mechanisms underlying the induction of bystander effects by low dose, low-LET ionizing radiation and discusses how they may be related to observed adaptive responses or other protective effects of low dose exposures. Bystander effects appear to be the result of a generalized stress response in tissues or cells. The signals may be produced by all exposed cells, but the response appears to require a quorum in order to be expressed. The major response involving low LET radiation exposure discussed in the existing literature is a death response. This has many characteristics of apoptosis but is p53 independent. While a death response might appear to be adverse, the position is argued in this paper that it is in fact protective and removes damaged cells from the population. Since many cell populations carry damaged cells without being exposed to radiation, so called “background damage”, it is possible that low doses exposures cause removal of cells damaged by agents other than the test dose of radiation. This mechanism would lead to the production of “U-shaped” dose response curves. In this scenario, the level of “adaptive” or beneficial response will be related to the background damage carried by the cell population. This model may be important when attempting to predict the consequences of mixed exposures involving radiation and other environmental stressors. PMID:18648593

  1. 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.

  2. 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

  3. Dose-volume analysis of radiation-induced trismus in head and neck cancer patients.

    Science.gov (United States)

    Gebre-Medhin, Maria; Haghanegi, Mahnaz; Robért, Lotta; Kjellén, Elisabeth; Nilsson, Per

    2016-11-01

    Trismus is a treatment-related late side effect in patients treated for cancer in the head and neck region (HNC). The condition can have a considerable negative impact on nutrition, dental hygiene, ability to speak and quality of life. We have previously studied trismus within the frame of a randomized phase 3 study of HNC patients treated with mainly three-dimensional (3D) conformal radiotherapy (CRT) and found a strong association to mean radiation dose to the mastication muscles, especially the ipsilateral masseter muscle (iMAS). In the present study we have investigated trismus prevalence and risk factors in a more recent cohort of patients, treated with todays' more updated radiation techniques. Maximal interincisal distance (MID) was measured on 139 consecutive patients. Trismus was defined as MID ≤35 mm. Patient-, disease- and treatment-specific data were retrospectively recorded. Differences between groups were analyzed and mean absorbed dose to mastication structures was evaluated. Dosimetric comparisons were made between this study and our previous results. The prevalence of trismus was 24% at a median of 16 months after completion of radiotherapy. In bivariate analysis treatment technique (3DCRT vs. intensity modulated radiotherapy or helical tomotherapy), tumor site (oropharynx vs. other sites) and mean radiation doses to the ipsilateral lateral pterygoid muscle, the paired masseter muscles and the iMAS were significantly associated with MID ≤35 mm. In multivariable analysis only mean radiation dose to the iMAS was significantly associated to MID ≤35 mm. Mean radiation dose to the ipsilateral masseter muscle is an important risk factor for trismus development. Dose reduction to this structure during radiotherapy should have a potential to diminish the prevalence of trismus in this patient group.

  4. 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.

    2016-09-01

    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.

  5. 2-Nitropropane-induced liver DNA and RNA base modifications: differences between Sprague-Dawley rats and New Zealand white rabbits.

    Science.gov (United States)

    Fiala, E S; Nie, G; Sodum, R; Conaway, C C; Sohn, O S

    1993-10-15

    2-Nitropropane (2-NP), a hepatocarcinogen in male Sprague-Dawley rats but not, under the same conditions, in male New Zealand White rabbits, induces characteristic base modifications in rat liver DNA and RNA including increases in 8-oxoguanine and the formation of 8-aminoguanine. We compared the levels of these modifications in the two animal species at 6, 18 and 42 h after a single i.p. treatment with 1.12 mmol/kg 2-NP. Significantly less nucleic acid base modifications were found to be produced in rabbit liver than in rat liver. Thus, the relative resistance of the rabbit to the hepatocarcinogenicity of 2-NP correlates with decreased levels of 2-NP-induced liver DNA and RNA base damage.

  6. Protection against aflatoxin B1-induced hepatic toxicity as short-term screen of cancer chemopreventive dithiolethiones.

    Science.gov (United States)

    Maxuitenko, Y Y; Curphey, T J; Kensler, T W; Roebuck, B D

    1996-08-01

    Dithiolethiones are an important class of cancer chemopreventive agents. More than 50 new dithiolethione analogs were synthesized for structure-activity studies. Using selected dithiolethiones, studies were designed to measure protection against the hepatotoxicity of aflatoxin B1 (AFB1) and relate it to the protection against carcinogenicity. Young male F344 rats were pretreated with 0.1 or 0.3 mmol dithiolethiones/kg body wt and challenged with toxic doses of AFB1 (50 micrograms/100 g rat/day) on 2 successive days. One day later, the protection from hepatotoxicity was assessed by measuring serum hepatic enzymes, hepatic necrosis, and degree of bile duct cell proliferation. The ability of these dithiolethiones to prevent AFB1-induced tumorigenicity was assessed by quantifying the hepatic burden of putative preneoplastic lesions [placental glutathione S-transferase (GST-P)-positive foci]. Significant correlations (p bile duct cell proliferation, r = 0.933). These results imply that inhibition of hepatotoxicity affords protection against hepatocarcinogenicity. The extent of protection from acute hepatotoxicity offers a simple, short-term biological endpoint to screen dithiolethiones and related compounds for their chemopreventive properties.

  7. Low-dose DHA-induced astrocyte proliferation can be attenuated by insufficient expression of BLBP in vitro.

    Science.gov (United States)

    Li, Haoming; Yang, Qingqing; Han, Xiao; Tan, Xuefeng; Qin, Jianbing; Jin, Guohua

    2017-09-14

    Docosahexaenoic acid (DHA) is an n-3 long chain polyunsaturated fatty acid (PUFA) that is involved in a wide range of cellular processes in human cells. Brain lipid binding protein (BLBP) exhibits a high affinity for n-3 PUFAs, especially DHA, but the precise functional contributions of DHA and BLBP in astrocytes are not clear. We analyzed cell viability and the ratio of Ki67 positive cells after manipulating DHA and/or BLBP levels in cultured astrocytes, and found that low-dose DHA stimulated proliferation of astrocytes, whereas this proliferative effect could be attenuated by downregulation of BLBP. Moreover, we found that astrocyte proliferation was directly regulated by BLBP independently of DHA. Taken together, low-dose DHA-induced astrocyte proliferation was disturbed by insufficient BLBP; and besides acting as a fatty acid transporter, BLBP was also involved in the proliferation of astrocytes directly. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Study of radiation dose induced by cosmic-ray origin low-energy gamma rays and electrons near sea level

    Science.gov (United States)

    Mrdja, D.; Bikit, I.; Bikit, K.; Slivka, J.; Anicin, I.

    2015-02-01

    For a long time, it has been known that low-energy continuous gamma radiation is present in open air at the Earth's surface. In previous investigations it was assumed that this radiation is produced almost exclusively by gamma photons emitted due to the natural radioactivity, which are backscattered by air above ground. We show that significant amount of this radiation (related to energy region 30-300 keV) that peaks at about 90 keV, is produced by cosmic-rays, with the photon flux of about 3000 m-2 s-1. We find that the contribution of this omnipresent low-energy gamma radiation of cosmic-ray origin, including the corresponding low-energy electron flux, to the doses of general population are non-negligible components of overall doses induced by cosmic rays near sea level.

  9. Dose-dependent effects of ethanol on lead-induced oxidative stress in rats.

    Science.gov (United States)

    Flora, S J S; Gautam, Pratibha; Dwivedi, Nidhi

    2012-01-01

    This study explored the dose-dependent effects of ethanol ingestion during co-exposure with lead in rats. Lead was administered orally, once daily at a dose of 10 mg/kg whereas ethanol was given in drinking water at 3 different doses: 1%, 2%, and 5% along with lead. The exposure continued for 3 months, after which the animals were decapitated and various biochemical assays were carried out. The results show increased oxidative stress in animals co-exposed to lead and ethanol compared with either lead or ethanol alone. A significant decrease in blood δ-aminolevulinic acid dehydratase activity, glutathione (GSH), GSH peroxidase, adenosine triphosphatase, and catalase but a significant increase in reactive oxygen species, oxidized GSH, thiobarbituric acid reactive substance, and intracellular calcium was noted in lead and ethanol co-exposed animals. The changes were found to be dose dependent in lead plus ethanol exposed animals. Decrease in glucose-6-phosphate dehydrogenase activity in blood was noted, with no significant changes in liver and kidney. Aldehyde dehdrogenase activity decreased significantly in animals exposed to either lead or ethanol but a pronounced depletion was seen in rats co-exposed to lead and ethanol (5%). The results suggest that the combined exposure to lead and ethanol leads to increased oxidative stress and possible initiation of apoptosis in rats.

  10. 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...

  11. 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

  12. 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/[...

  13. Split-dose atropine versus glycopyrrolate with neostigmine for reversal of gallamine-induced neuromuscular blockade

    DEFF Research Database (Denmark)

    Wetterslev, J; Jarnvig, I; Jørgensen, L N

    1991-01-01

    of glycopyrrolate (7 micrograms.kg-1) or two doses of atropine (8 micrograms.kg-1 each), given with an interval of 1 min. There were no differences between the two methods with respect to percentage heart rate changes, salivation or arousal time. Four patients demonstrated cardiac arhythmias in the atropine group...

  14. 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.

  15. Dose-dependent apoptotic and necrotic myocyte death induced by the beta2-adrenergic receptor agonist, clenbuterol.

    Science.gov (United States)

    Burniston, Jatin G; Chester, Neil; Clark, William A; Tan, Lip-Bun; Goldspink, David F

    2005-12-01

    We have investigated the dose- and time-dependency of myocyte apoptosis and necrosis induced by the beta2-adrenergic receptor agonist, clenbuterol, with the aim of determining whether myocyte apoptosis and necrosis are two separate processes or a continuum of events. Male Wistar rats were administered subcutaneous injections of clenbuterol, and immunohistochemistry was used to detect myocyte-specific apoptosis and necrosis. Myocyte apoptosis peaked 4 h after, and necrosis 12 h after, clenbuterol administration. In the soleus, peak apoptosis (5.8 +/- 2.0%; P clenbuterol. Twelve hours after clenbuterol administration, 73% of damaged myocytes labeled as necrotic, 27% as apoptotic and necrotic, and 0% as purely apoptotic. Administrations of clenbuterol (10 microg x kg(-1)) at 48-h intervals induced cumulative myocyte death over 8 days. These data show that the phenotype of myocyte death is dependent on the magnitude of the insult and the time at which it is investigated. Only very low doses induced apoptosis alone; in most cases apoptotic myocytes lysed and became necrotic and the magnitude of necrosis was greater than that of apoptosis. Thus, it is important to investigate both apoptotic and necrotic myocyte death, contrary to the current trend of only investigating apoptotic cell death.

  16. Dose-dependent apoptotic and necrotic myocyte death induced by the β2-adrenergic receptor agonist, clenbuterol

    Science.gov (United States)

    Burniston, Jatin G; Chester, Neil; Clark, William A; Tan, Lip-Bun; Goldspink, David F

    2007-01-01

    We have investigated the dose- and time-dependency of myocyte apoptosis and necrosis induced by the β2-adrenergic receptor agonist, clenbuterol, with the aim of determining whether myocyte apoptosis and necrosis are two separate processes or a continuum of events. Male Wistar rats were administered subcutaneous injections of clenbuterol, and immunohistochemistry was used to detect myocyte specific apoptosis and necrosis. Myocyte apoptosis peaked 4 h after, and necrosis 12 h after, clenbuterol administration. In the soleus, peak apoptosis (5.8 ± 2.0 %; Pclenbuterol kg-1. Twelve hours after clenbuterol administration, 73 % of damaged myocytes labelled as necrotic, 27 % as apoptotic and necrotic and none labelled as purely apoptotic. Bi-daily administrations of 10 μg of clenbuterol kg-1 induced cumulative myocyte death over 8 days. These data show that the phenotype of myocyte death is dependent on the magnitude of the insult and the time at which it is investigated. Only very low doses induced only apoptosis, in most cases apoptotic myocytes lysed and became necrotic and the magnitude of necrosis was greater than that of apoptosis. Thus, it is important to investigate both apoptotic and necrotic myocyte death, this being contrary to the current trend of only investigating apoptotic cell death. PMID:16007677

  17. 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.

  18. Dose-dependent inhibitory effect of melatonin on carcinogenesis induced by benzo[a]pyrene in mice.

    Science.gov (United States)

    Vesnushkin, G M; Plotnikova, N A; Semenchenko, A I; Anisimov, V N

    2006-12-01

    Three-month-old Swiss-derived SHR mice were subcutaneously injected with 2 mg of benzo[a]pyrene (BP) dissolved in 0.1 ml of olive oil. After the injections of the carcinogen two groups of mice were given melatonin with night drinking water at the doses of 2 mg/l or 20 mg/l and one group of mice was not treated with melatonin and served as a PB-control. At the 28th week after the carcinogen administration the experiment was stopped and animals were sacrificed. The results show that melatonin treatment inhibits BP-induced carcinogenesis, decreases the incidence of subcutaneous sarcomas, increases their latency and survival of mice. The malone dialdehyde (MDA) level in the serum of BP-induced tumor-bearing mice was increased by 2.6 times (p melatonina on malignancies of mesenchymal origin. Lower dose of melatonin appeared to be more effective in the inhibition of lipid peroxidation and tumorigenesis induced by chemical carcinogen than a higher one.

  19. Evidences for amelioration of reserpine-induced fibromyalgia in rat by low dose of gamma irradiation and duloxetine.

    Science.gov (United States)

    Shibrya, Eman E; Radwan, Rasha R; Abd El Fattah, Mai A; Shabaan, Esmat A; Kenawy, Sanaa A

    2017-05-01

    Fibromyalgia is a prevalent disorder characterized by chronic widespread pain and complex symptoms. This study was conducted to investigate the potential therapeutic effect of low-dose irradiation (LDI) alone or in combination with duloxetine on the reserpine-induced fibromyalgia in rats. Fibromyalgia was induced by administration of reserpine (1 mg/kg/s.c) for 3 consecutive days. Duloxetine (30 mg/kg, p.o) was administered 60 min before a forced swimming test (FST), and rats were exposed to a single dose of γ-radiation (0.5 Gy) 1 day before the FST. Reserpine significantly increased immobility time in the FST, decreased the amount of 5-hydroxytryptamine, dopamine, and norepinephrine in cerebral cortex. It also increased malondialdehyde and nitric oxide and reduced glutathione contents in brain tissue. LDI alone or combined with duloxetine completely antagonized reserpine-induced fibromyalgia as assessed by the measured parameters. One of the most significant findings in this study was that the therapeutic effect of duloxetine was more pronounced by its combination with LDI. A possible mechanism of action of LDI and duloxetine responsible for their therapeutic effect was discussed. On the basis of the presented evidences, it could be concluded that LDI alone or combined with duloxetine could be of value in the management of fibromyalgia.

  20. 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...

  1. Extended-Release Metformin Does Not Reduce the Clomiphene Citrate Dose Required to Induce Ovulation in Polycystic Ovary Syndrome

    Science.gov (United States)

    Cataldo, Nicholas A.; Barnhart, Huiman X.; Legro, Richard S.; Myers, Evan R.; Schlaff, William D.; Carr, Bruce R.; Diamond, Michael P.; Carson, Sandra A.; Steinkampf, Michael P.; Coutifaris, Christos; McGovern, Peter G.; Gosman, Gabriella; Nestler, John E.; Giudice, Linda C.

    2008-01-01

    Context: When used for ovulation induction, higher doses of clomiphene may lead to antiestrogenic side effects that reduce fecundity. It has been suggested that metformin in combination with clomiphene can restore ovulation to some clomiphene-resistant anovulators with polycystic ovary syndrome (PCOS). Objective: Our objective was to determine if cotreatment with extended-release metformin (metformin XR) can lower the threshold dose of clomiphene needed to induce ovulation in women with PCOS. Design: A secondary analysis of data from the National Institute of Child Health and Human Development Cooperative Multicenter Reproductive Medicine Network prospective, double-blind, placebo-controlled multicenter clinical trial, Pregnancy in Polycystic Ovary Syndrome, was performed. Setting: Study volunteers at multiple academic medical centers were included. Participants: Women with PCOS and elevated serum testosterone who were randomized to clomiphene alone or with metformin (n = 209 in each group) were included in the study. Interventions: Clomiphene citrate, 50 mg daily for 5 d, was increased to 100 and 150 mg in subsequent cycles if ovulation was not achieved; half also received metformin XR, 1000 mg twice daily. Treatment was for up to 30 wk or six cycles, or until first pregnancy. Main Outcome Measures: Ovulation was confirmed by a serum progesterone more than or equal to 5 ng/ml, drawn prospectively every 1–2 wk. Results: The overall prevalence of at least one ovulation after clomiphene was 75 and 83% (P = 0.04) for the clomiphene-only and clomiphene plus metformin groups, respectively. Using available data from 314 ovulators, the frequency distribution of the lowest clomiphene dose (50, 100, or 150 mg daily) resulting in ovulation was indistinguishable between the two treatment groups. Conclusion: Metformin XR does not reduce the lowest dose of clomiphene that induces ovulation in women with PCOS. PMID:18505764

  2. 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 metoclo...

  3. 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...

  4. Iron-mediated lipid peroxidation and lipid raft disruption in low-dose silica-induced macrophage cytokine production.

    Science.gov (United States)

    Premasekharan, Gayatri; Nguyen, Kennedy; Contreras, Janette; Ramon, Virginia; Leppert, Valerie Jean; Forman, Henry Jay

    2011-09-15

    Silica inhalation can induce respiratory disease. Iron is suspected of playing an important role in silica-mediated respiratory toxicity, but unambiguously determining its role has been hampered by incomplete characterization, use of high particle doses, and lack of understanding of proinflammatory mechanisms. In this study, we investigated a novel hypothesis for the mechanism of silica particle-induced increase in cytokine production. We studied the role of iron in lipid peroxidation-dependent transcription of cytokines in macrophages by ground natural silica particles at low sublethal doses. Particle size, size distribution, surface area, and structure were determined using electron microscopy, nitrogen adsorption, and X-ray diffraction. Iron impurity concentrations before and after acid treatment were determined by energy-dispersive X-ray and inductively coupled plasma mass spectroscopy. At a low noncytotoxic dose (1 μg/ml) of 2-μm silica, the presence of iron significantly increased superoxide (O(2)(•-)), lipid peroxidation, lipid raft disruption, and cytokine production in macrophages. The iron chelators deferoxamine mesylate and diethylenetriaminepentaacetic acid were found to abrogate O(2)(•-) production and inhibit lipid peroxidation, raft disruption, and cytokine induction. Tricyclodecan-9-yl xanthate, a competitive inhibitor of phosphatidylcholine-specific phospholipase C (PC-PLC), which is an upstream participant in NF-κB activation, and manganese(III) tetrakis(N-ethylpyridinium-2-yl) porphyrin, a superoxide dismutase and catalase mimic, blocked silica-stimulated cytokine production. We propose a pathway of iron-induced lipid peroxidation disrupting lipid rafts and signaling for the production of cytokines through PC-PLC in silica-exposed macrophages. Copyright © 2011 Elsevier Inc. All rights reserved.

  5. Delayed inhibition of agonist-induced granulocyte-platelet aggregation after low-dose sevoflurane inhalation in humans.

    Science.gov (United States)

    Wacker, Johannes; Lucchinetti, Eliana; Jamnicki, Marina; Aguirre, José; Härter, Luc; Keel, Marius; Zaugg, Michael

    2008-06-01

    Sevoflurane can be used as sedative-analgesic drug with endothelial protective properties. We tested whether low-dose sevoflurane inhalation provides sustained inhibition of detrimental granulocyte-platelet aggregation in humans. Ten healthy male volunteers were enrolled in this crossover study. Each subject inhaled sevoflurane for 1 h at 0.5-1 vol % end-tidal concentration in oxygen (50 vol %). Inhaling oxygen (50 vol %) alone served as control. Venous blood samples were collected at baseline before inhalation, immediately after inhalation, and 24 h thereafter, and were used for flow cytometry to determine platelet surface marker (CD41, CD42b, CD62P/P-selectin, and PAC-1) on platelets and granulocytes and for kaolin-induced clot formation, as assessed by thromboelastography. In flow cytometry experiments, platelets were stimulated with arachidonic acid (AA, 30 microM), adenosine diphosphate (ADP, 1 microM), and thrombin receptor agonist peptide-6 (TRAP-6, 6 microM). AA, ADP, and TRAP-6 markedly increased the expression of CD62P on platelets, whereas CD42b (shedding) and PAC-1 (heterotypic conjugates) expression decreased. The amount of granulocyte-platelet aggregates increased upon agonist stimulation. Low-dose sevoflurane inhalation reduced ADP-induced CD62P expression on platelets 24 h after inhalation, and inhibited the formation of granulocyte-platelet aggregates under stimulation with AA and ADP after 1 and 24 h, and with TRAP-6 after 24 h compared with control. Inhibition of granulocyte-platelet aggregates was accompanied by reduced clot firmness 24 h after sevoflurane inhalation compared with control. We demonstrated for the first time that inhaling low-dose sevoflurane (<1 vol % end-tidal) inhibits agonist-induced granulocyte-platelet interactions 24 h after administration and thus counteracts thromboinflammatory processes.

  6. Low doses of alpha particles do not induce sister chromatid exchanges in bystander Chinese hamster cells defective in homologous recombination

    Energy Technology Data Exchange (ETDEWEB)

    Nagasawa, H; Wilson, P F; Chen, D J; Thompson, L H; Bedford, J S; Little, J B

    2007-10-26

    We reported previously that the homologous recombinational repair (HRR)-deficient Chinese hamster mutant cell line irs3 (deficient in the Rad51 paralog Rad51C) showed only a 50% spontaneous frequency of sister chromatid exchange (SCE) as compared to parental wild-type V79 cells. Furthermore, when irradiated with very low doses of alpha particles, SCEs were not induced in irs3 cells, as compared to a prominent bystander effect observed in V79 cells (Nagasawa et al., Radiat. Res. 164, 141-147, 2005). In the present study, we examined additional Chinese hamster cell lines deficient in the Rad51 paralogs Rad51C, Rad51D, Xrcc2, and Xrcc3 as well as another essential HRR protein, Brca2. Spontaneous SCE frequencies in non-irradiated wild-type cell lines CHO, AA8 and V79 were 0.33 SCE/chromosome, whereas two Rad51C-deficient cell lines showed only 0.16 SCE/chromosome. Spontaneous SCE frequencies in cell lines defective in Rad51D, Xrcc2, Xrcc3, and Brca2 ranged from 0.23-0.33 SCE/chromosome, 0-30% lower than wild-type cells. SCEs were induced significantly 20-50% above spontaneous levels in wild-type cells exposed to a mean dose of 1.3 mGy of alpha particles (<1% of nuclei traversed by an alpha particle). However, induction of SCEs above spontaneous levels was minimal or absent after {alpha}-particle irradiation in all of the HRR-deficient cell lines. These data suggest that Brca2 and the Rad51 paralogs contribute to DNA damage repair processes induced in bystander cells (presumably oxidative damage repair in S-phase cells) following irradiation with very low doses of alpha particles.

  7. Effects of methiothepin on changes in brain serotonin release induced by repeated administration of high doses of anorectic serotoninergic drugs

    Science.gov (United States)

    Gardier, A. M.; Kaakkola, S.; Erfurth, A.; Wurtman, R. J.

    1992-01-01

    We previously observed, using in vivo microdialysis, that the potassium-evoked release of frontocortical serotonin (5-HT) is suppressed after rats receive high doses (30 mg/kg, i.p., daily for 3 days) of fluoxetine, a selective blocker of 5-HT reuptake. We now describe similar impairments in 5-HT release after repeated administration of two other 5-HT uptake blockers, zimelidine and sertraline (both at 20 mg/kg, i.p. for 3 days) as well as after dexfenfluramine (7.5 mg/kg, i.p. daily for 3 days), a drug which both releases 5-HT and blocks its reuptake. Doses of these indirect serotonin agonists were about 4-6 times the drug's ED50 in producing anorexia, a serotonin-related behavior. In addition, methiothepin (20 microM), a non-selective receptor antagonist, locally perfused through the dialysis probe 24 h after the last drug injection, enhanced K(+)-evoked release of 5-HT at serotoninergic nerve terminals markedly in control rats and slightly in rats treated with high doses of dexfenfluramine or fluoxetine. On the other hand, pretreatment with methiothepin (10 mg/kg, i.p.) one hour before each of the daily doses of fluoxetine or dexfenfluramine given for 3 days, totally prevented the decrease in basal and K(+)-evoked release of 5-HT. Finally, when methiothepin was injected systemically the day before the first of 3 daily injections of dexfenfluramine, it partially attenuated the long-term depletion of brain 5-HT and 5-HIAA levels induced by repeated administration of high doses of dexfenfluramine. These data suggest that drugs which bring about the prolonged blockade of 5-HT reuptake - such as dexfenfluramine and fluoxetine - can, by causing prolonged increases in intrasynaptic 5-HT levels as measured by in vivo microdialysis, produce receptor-mediated long-term changes in the processes controlling serotonin levels and dynamics.

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

    Science.gov (United States)

    Liu, Jing; Chen, Wei; Wang, Zujun; Xue, Yuanyuan; Yao, Zhibin; He, Baoping; Ma, Wuying; Jin, Junshan; Sheng, Jiangkun; Dong, Guantao

    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.

  9. 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.

  10. 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...

  11. Relapsing insulin-induced lipoatrophy, cured by prolonged low-dose oral prednisone: a case report

    Directory of Open Access Journals (Sweden)

    Chantelau Ernst A

    2011-12-01

    Full Text Available Abstract Introduction Circumscript, progressing lipoatrophy at the insulin injection sites is an unexplained, however rare condition in diabetes mellitus. Case presentation We report a case of severe localised lipoatrophy developing during insulin pump-treatment (continuous subcutaneous insulin infusion with the insulin analogue lispro (Humalog® in a woman with type-1 diabetes mellitus. After 11 months of progressing lipoatrophy at two spots on the abdomen, low-dose prednisone (5-10 mg p.o. was given at breakfast for 8 months, whereby the atrophic lesions centripetally re-filled with subcutaneous fat tissue (confirmed by MRI despite ongoing use of insulin lispro. However, 4 weeks after cessation of prednisone, lipoatrophy relapsed, but resolved after another 2 months of low-dose prednisone. No further relapse was noted during 12 months of follow-up on insulin-pump therapy with Humalog®. Conclusion Consistent with an assumed inflammatory nature of the condition, low-dose oral prednisone appeared to have cured the lipoatrophic reaction in our patient. Our observation suggests a temporary intolerance of the subcutaneous fat tissue to insulin lispro (Humalog®, triggered by an unknown endogenous mechanism.

  12. Dosing study on the effectiveness of salicylate/N-acetylcysteine for prevention of noise-induced hearing loss.

    Science.gov (United States)

    Coleman, John; Huang, Xinyan; Liu, Jianzhong; Kopke, Richard; Jackson, Ronald

    2010-01-01

    The efficacy of three different doses of sodium salicylate (SAL) in combination with one dose of N-acetylcysteine (NAC) to prevent noise-induced hearing loss was studied in chinchillas. After obtaining baseline-hearing thresholds, the chinchillas were randomly assigned to one of four treatment groups: three sets were injected intraperitoneally with 325 mg/kg NAC combined with 25, 50, or 75 mg/kg SAL, and a separate control group was injected with an equal volume of saline. Animals were injected twice daily for 2 days prior to and 1 hour before the noise exposure (6 hours to a 105-dB Standard Pressure Level octave band noise centered at 4 kHz). Immediate post-noise hearing thresholds were obtained followed by post-noise treatments at 1 hour then twice-daily for 2 days. Hearing tests continued at 1, 2, and 3 weeks post-noise, and immediately after the last hearing test, animals' cochleae were stained for hair cell counts. All the groups showed hearing improvement until week 2. However, at week 3, saline treated animals demonstrated a 17-33 dB SPL permanent threshold shift (PTS) across the test frequencies. Hearing loss was lowest in the 50 SAL/325 NAC mg/kg group (all frequencies, P noise damage to the cochlea, but SAL has a relatively narrow therapeutic dosing window.

  13. Protective effect of apigenin against N-nitrosodiethylamine (NDEA)-induced hepatotoxicity in albino rats.

    Science.gov (United States)

    Ali, Fahad; Rahul; Naz, Falaq; Jyoti, Smita; Siddique, Yasir Hasan

    2014-06-01

    A number of pharmacological properties have been attributed to apigenin. In the present study the effect of apigenin was investigated with respect to hepatotoxicity induced by N-nitrosodiethylamine (NDEA), a compound that is present in many food stuffs and has been reported to be a hepatocarcinogen. Male rats were exposed to NDEA (0.1mg/ml) dissolved in drinking-water separately, and with 10, 20, or 40mg/ml of apigenin for 21 days. The activity of glutamic-oxaloacetic transaminase (SGOT), glutamic-pyruvic transaminase (SGPT), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) was measured in blood serum. Lipid peroxidation, protein carbonyl content and micronucleus frequency were determined in hepatocytes. To assess the effect on DNA damage, the comet assay was performed on hepatocytes, blood lymphocytes and bone-marrow cells of the exposed rats. The results of the study reveal that the treatment of NDEA together with apigenin showed a significant dose-dependent decrease in the serum concentration of the enzymes SGOT, SGPT, ALP and LDH (p<0.05). Histological sections of the liver also showed a protective effect of apigenin. A significant dose-dependent reduction in lipid peroxidation and protein carbonyl content was observed in rats exposed to NDEA (0.1mg/ml) together with apigenin (p<0.05). The results obtained for the comet assay in rat hepatocytes, blood lymphocytes and bone-marrow cells showed a significant dose-dependent decrease in the mean tail length (p<0.05). The present study supports the role of apigenin as an anti-genotoxic and hepatoprotective agent. Copyright © 2014 Elsevier B.V. All rights reserved.

  14. 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

  15. The design of controlled-release formulations resistant to alcohol-induced dose dumping--a review.

    Science.gov (United States)

    Jedinger, N; Khinast, J; Roblegg, E

    2014-07-01

    The concomitant intake of alcoholic beverages together with oral controlled-release opioid formulations poses a serious safety concern since alcohol has the potential to alter the release rate controlling mechanism of the dosage form which may result in an uncontrolled and immediate drug release. This effect, known as alcohol-induced dose dumping, has drawn attention of the regulatory authorities. Thus, the Food and Drug Administration (FDA) recommends that in vitro drug release studies of controlled-release dosage forms containing drugs with narrow therapeutic range should be conducted in ethanolic media up to 40%. So far, only a limited number of robust dosage forms that withstand the impact of alcohol are available and the development of such dosage forms is still a challenge. This review deals with the physico-chemical key factors which have to be considered for the preparation of alcohol-resistant controlling dosage forms. Furthermore, appropriate matrix systems and promising technological strategies, which are suitable to prevent alcohol-induced dose dumping, are discussed. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. 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; 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 < 0.05). Mice supplemented with 50% 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. PMID:24877107

  17. Watermelon (Citrullus lanatus (Thunb. Matsum. and Nakai Juice Modulates Oxidative Damage Induced by Low Dose X-Ray in Mice

    Directory of Open Access Journals (Sweden)

    Mohd Khairul Amran Mohammad

    2014-01-01

    Full Text Available 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<0.05. Mice supplemented with 50% 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.

  18. 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.

  19. A single neurotoxic dose of methamphetamine induces a long-lasting depressive-like behaviour in mice.

    Science.gov (United States)

    Silva, Carlos D; Neves, Ana F; Dias, Ana I; Freitas, Hugo J; Mendes, Sheena M; Pita, Inês; Viana, Sofia D; de Oliveira, Paulo A; Cunha, Rodrigo A; Fontes Ribeiro, Carlos A; Prediger, Rui D; Pereira, Frederico C

    2014-04-01

    Methamphetamine (METH) triggers a disruption of the monoaminergic system and METH abuse leads to negative emotional states including depressive symptoms during drug withdrawal. However, it is currently unknown if the acute toxic dosage of METH also causes a long-lasting depressive phenotype and persistent monoaminergic deficits. Thus, we now assessed the depressive-like behaviour in mice at early and long-term periods following a single high METH dose (30 mg/kg, i.p.). METH did not alter the motor function and procedural memory of mice as assessed by swimming speed and escape latency to find the platform in a cued version of the water maze task. However, METH significantly increased the immobility time in the tail suspension test at 3 and 49 days post-administration. This depressive-like profile induced by METH was accompanied by a marked depletion of frontostriatal dopaminergic and serotonergic neurotransmission, indicated by a reduction in the levels of dopamine, DOPAC and HVA, tyrosine hydroxylase and serotonin, observed at both 3 and 49 days post-administration. In parallel, another neurochemical feature of depression--astroglial dysfunction--was unaffected in the cortex and the striatal levels of the astrocytic protein marker, glial fibrillary acidic protein, were only transiently increased at 3 days. These findings demonstrate for the first time that a single high dose of METH induces long-lasting depressive-like behaviour in mice associated with a persistent disruption of frontostriatal dopaminergic and serotonergic homoeostasis.

  20. High-dose vitamin C management in dapsone-induced methemoglobinemia.

    Science.gov (United States)

    Park, Sin-Youl; Lee, Kyung-Woo; Kang, Tae-Sin

    2014-06-01

    Methylene blue is the first-choice treatment of methemoglobinemia, but it is not readily available in most Korean emergency departments because of an import suspension. An 84-year-old woman with dapsone-induced massive methemoglobinemia visited our emergency department for unclear mentality and cyanosis. Because methylene blue was not available, we intravenously administrated vitamin C (VC) for symptomatic methemoglobinemia, although VC is not a universally accepted treatment. Vitamin C (10 g intravenously) administered 6 hourly successfully treated the dapsone-induced methemoglobinemia and did not adversely affect renal functions. Thus,we recommend that if methylene blue is unavailable, 6 hourly intravenous administrations of 10 g of VC should be considered for dapsone-induced methemoglobinemia.

  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. Prior methamphetamine self-administration attenuates serotonergic deficits induced by subsequent high-dose methamphetamine administrations.

    Science.gov (United States)

    McFadden, Lisa M; Hunt, Madison M; Vieira-Brock, Paula L; Muehle, Janice; Nielsen, Shannon M; Allen, Scott C; Hanson, Glen R; Fleckenstein, Annette E

    2012-11-01

    Pre-clinical studies indicate that high-dose, non-contingent methamphetamine (METH) administration both rapidly and persistently decreases serotonergic neuronal function. Despite research indicating the hippocampus plays an important role in METH abuse and is affected by METH use, effects of METH self-administration on hippocampal serotonergic neurons are not well understood, and were thus an important focus of the current study. Because humans often administer METH in a binge-like pattern, effects of prior METH self-administration on a subsequent "binge-like" METH treatment were also examined. Rats were treated as described above, and sacrificed 1 or 8d after self-administration or 1h or 7d after the final binge METH or saline exposure. Hippocampal serotonin (5-hydroxytryptamine; 5HT) content and transporter (SERT) function were assessed. METH self-administration per se had no persistent effect on hippocampal 5HT content or SERT function. However, this treatment attenuated the persistent, but not acute, hippocampal serotonergic deficits caused by a subsequent repeated, high-dose, non-continent METH treatment administered 1 d the last self-administration session. No attenuation in persistent deficits were seen when the high-dose administration of METH occurred 15d after the last self-administration session. The present findings demonstrate that METH self-administration alters serotonergic neurons so as to engender "tolerance" to the persistent serotonergic deficits caused by a subsequent METH exposure. However, this "tolerance" does not persist. These data provide a foundation to investigate complex questions including how the response of serotonergic neurons to METH may contribute to contingent-related disorders such as dependence and relapse. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  3. Exercise-Induced Dose-Response Alterations in Adiponectin and Leptin Levels Are Dependent on Body Fat Changes in Women at Risk for Breast Cancer.

    Science.gov (United States)

    Sturgeon, Kathleen; Digiovanni, Laura; Good, Jerene; Salvatore, Domenick; Fenderson, Desiré; Domchek, Susan; Stopfer, Jill; Galantino, Mary Lou; Bryan, Cathy; Hwang, Wei-Ting; Schmitz, Kathryn

    2016-08-01

    Dysregulation of adipokines, such as adiponectin and leptin, is associated with a variety of chronic diseases, including cancer. Physical activity protects against breast cancer and one of the mechanisms which may underlie this association is exercise-induced changes in adipokine levels. The WISER Sister Trial was a three-armed randomized controlled trial in premenopausal women (n = 137) with an elevated risk for breast cancer. A 5-menstrual-cycle-long dosed aerobic exercise intervention compared low-dose exercise (150 min/wk; n = 44) or high-dose exercise (300 min/wk; n = 48) with a control group asked to maintain usual activity levels (n = 45). Exercise intensity progressed to and was maintained at 70% to 80% of age predicted heart rate max. Body composition and adipokine levels were measured at baseline and follow-up. We observed significant linear trends for increased fitness capacity (Δ%: -2.0% control, 10.1% low dose, 13.1% high dose), decreased fat tissue-to-total tissue mass (Δ%: 0.7% control, -2.9% low dose, -3.7% high dose), increased body fat adjusted adiponectin (Δ%: -0.6% control, 0.6% low dose, 0.9% high dose), and decreased body fat adjusted leptin (Δ%: 0.7% control, -8.2% low dose, -10.2% high dose). In this randomized clinical trial of premenopausal women at risk for breast cancer, we demonstrate a dose-response effect of exercise on adiponectin and leptin and that dose response is dependent on changes in body fat. Improved adipokine levels, achieved by aerobic exercise training-induced decreases in body fat, may decrease breast cancer risk for high-risk premenopausal women. Cancer Epidemiol Biomarkers Prev; 25(8); 1195-200. ©2016 AACR. ©2016 American Association for Cancer Research.

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

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    Larissa Takser

    2016-01-01

    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.

  5. Effects of Arbutin on Radiation-Induced Micronuclei in Mice Bone Marrow Cells and Its Definite Dose Reduction Factor

    Directory of Open Access Journals (Sweden)

    Saba Nadi

    2016-05-01

    Full Text Available Background: Interactions of free radicals from ionizing radiation with DNA can induce DNA damage and lead to mutagenesis and carsinogenesis. With respect to radiation damage to human, it is important to protect humans from side effects induced by ionizing radiation. In the present study,the effects of arbutin were investigated by using the micronucleus test for anti-clastogenic activity, to calculate the ratio of polychromatic erythrocyte to polychromatic erythrocyte plus normochromatic erythrocyte (PCE/PCE+NCE in order to show cell proliferation activity. Methods: Arbutin (50, 100, and 200 mg/kg was intraperitoneally (ipadministered to NMRI mice two hours before gamma radiation at 2 and 4 gray (Gy. The frequency of micronuclei in 1000 PCEs (MnPCEs and the ratio of PCE/PCE+NCE were calculated for each sample. Data were statistically evaluated using one-way ANOVA,Tukey HSD test, and t-test. Results: The findings indicated that gamma radiation at 2 and 4 Gy extremely increased the frequencies of MnPCE (P<0.001 while reducing PCE/PCE+NCE (P<0.001 compared to the control group. All three doses of arbutin before irradiation significantly reduced the frequencies of MnPCEs and increased the ratio of PCE/PCE+NCE in mice bone marrow compared to the non-drug-treated irradiated control (P<0.001. All three doses of arbutin had no toxicity effect on bone marrow cells. The calculated dose reduction factor (DRF showed DRF=1.93 for 2Gy and DRF=2.22 for 4 Gy. Conclusion: Our results demonstrated that arbutin gives significant protection to rat bone against the clastogenic and cytotoxic effects of gamma irradiation.

  6. Oral Administration of Vitamin C, Cimetidine and Famotidine on Micronuclei Induced by Low Dose Radiation in Mouse Bone Marrow Cells

    Directory of Open Access Journals (Sweden)

    Naeeji A.

    2017-06-01

    Full Text Available Background: In many studies, chemicals and natural materials were tested to reduce the harmful effects of radiation. It is known that Famotidine and vitamin C reduce DNA damage. Objective: The aim of this study was to evaluate the radioprotective effect of vitamin C, Cimetidine and Famotidine on gamma-radiation-induced damage on mouse bone marrow. Methods: Six-to-seven week male NMRI mice (28 g ±3 were randomly divided into fourteen groups: control, 2Gy irradiation, six group drugs without irradition (Famotidine, Cimetidine, vitaminC, Fam-Cim, Fam-Vit, Cim-Vit, six groups received drugs and 2Gy radiation with a 60Co |γ|-ray source at room temperature 22 ± 2 °C. The mice were killed 48 hours after irradiation by cervical dislocation. Slides were prepared from bone marrow cells and stained in May-Granwald and Giemsa. Finally, the cells were counted with microscope, frequencies of polychromatic erythrocyte (PCE, normochoromatic erythrocyte (NCE and their micronuclated cell were recorded. PCE / PCE + NCE were calculated. Results: There were significant differences of MNPCE/1000PCE, MNNCE/1000NCE and PCE/PCE+NCE among different groups with similar radiation doses (p≤0.01. Moreover, there were significant differences of MNPCE/1000PCE and PCE/PCE+NCE among different doses of radiation (p≤0.01. While considering MNNCE/1000NCE, there were no significant differences among silimar groups with radiation dose (p˃0.05. Conclusion: Oral administration of Famotidine, vitamin C and Cimetidine demonstrate reliable and similar radioprotective effects. Additionally, the protective effect of single use of these drugs was similar to the combination form. Thus, the oral use of combination, 48 hours after irradiation cannot induce more radioprotective effect.

  7. Esophagitis induced by combined radiation and adriamycin. [Mediastinum irradiated to doses between 500 and 2500 rad

    Energy Technology Data Exchange (ETDEWEB)

    Boal, D.K.B.; Newburger, P.E.; Teele, R.L.

    1979-04-01

    With the increasing use of combined chemotherapy and radiotherapy in the treatment of certain types of malignancy, a clinically distinct type of esophagitis has been recognized as an undesirable side effect. It occurs with low doses (less than 2,000 rad) of mediastinal radiation in patients who simultaneously or sequentially receive either adriamycin or actinomycin D. Characteristic of this entity is recall: recurrent episodes of esophagitis with each course of chemotherapy. The radiographic findings are nonspecific, ranging from subtle alterations in motility to severe damage with irreversible stricture formation. The primary differential diagnostic considerations are infectious processes. The radiographic spectrum clinical aspects, and differential diagnoses in five patients are discussed.

  8. Benchmark Studies of Induced Radioactivity Produced in LHC Materials, Pt I: Remanent Dose Rates

    Energy Technology Data Exchange (ETDEWEB)

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

    2006-04-12

    Samples of materials which will be used in the LHC machine for shielding and construction components were irradiated in the stray radiation field of the CERN-EU high-energy reference field facility. After irradiation, the specific activities induced in the various samples were analyzed with a high-precision gamma spectrometer at various cooling times, allowing identification of isotopes with a wide range of half-lives. Furthermore, the irradiation experiment was simulated in detail with the FLUKA Monte Carlo code. A comparison of measured and calculated specific activities shows good agreement, supporting the use of FLUKA for estimating the level of induced activity in the LHC.

  9. Intratracheal Instillation of High Dose Adenoviral Vectors Is Sufficient to Induce Lung Injury and Fibrosis in Mice

    Science.gov (United States)

    Zhou, Qiyuan; Chen, Tianji; Bozkanat, Melike; Ibe, Joyce Christina F.; Christman, John W.; Raj, J. Usha; Zhou, Guofei

    2014-01-01

    Rationale Replication deficient adenoviruses (Ad) vectors are common tools in gene therapy. Since Ad vectors are known to activate innate and adaptive immunity, we investigated whether intratracheal administration of Ad vectors alone is sufficient to induce lung injury and pulmonary fibrosis. Methods We instilled Ad viruses ranging from 107 to 1.625×109 ifu/mouse as well as the same volume of PBS and bleomycin. 14 and 21 days after administration, we collected bronchoalveolar lavage fluid (BALF) and mouse lung tissues. We measured the protein concentration, total and differential cell counts, and TGF-β1 production, performed Trichrome staining and Sircol assay, determined gene and protein levels of profibrotic cytokines, MMPs, and Wnt signaling proteins, and conducted TUNEL staining and co-immunofluorescence for GFP and α-SMA staining. Results Instillation of high dose Ad vectors (1.625×109 ifu/mouse) into mouse lungs induced high levels of protein content, inflammatory cells, and TGF-β1 in BALF, comparable to those in bleomycin-instilled lungs. The collagen content and mRNA levels of Col1a1, Col1a2, PCNA, and α-SMA were also increased in the lungs. Instillation of both bleomycin and Ad vectors increased expression levels of TNFα and IL-1β but not IL-10. Instillation of bleomycin but not Ad increased the expression of IL-1α, IL-13 and IL-16. Treatment with bleomycin or Ad vectors increased expression levels of integrin α1, α5, and αv, MMP9, whereas treatment with bleomycin but not Ad vectors induced MMP2 expression levels. Both bleomycin and Ad vectors induced mRNA levels of Wnt2, 2b, 5b, and Lrp6. Intratracheal instillation of Ad viruses also induced DNA damages and Ad viral infection-mediated fibrosis is not limited to the infection sites. Conclusions Our results suggest that administration of Ad vectors induces an inflammatory response, lung injury, and pulmonary fibrosis in a dose dependent manner. PMID:25551570

  10. Low-dose G-CSF improves fat graft retention by mobilizing endogenous stem cells and inducing angiogenesis, whereas high-dose G-CSF inhibits adipogenesis with prolonged inflammation and severe fibrosis.

    Science.gov (United States)

    Cai, Junrong; Li, Bin; Liu, Kaiyang; Feng, Jingwei; Gao, Kai; Lu, Feng

    2017-09-23

    Hematopoietic stem cells (HSCs) promote fat graft survival by modulating its revascularization. The authors hypothesize that mobilization of HSCs by G-CSF will improve fat graft survival. Hence, we evaluated the effect of different doses of G-CSF on fat grafting. Male 8-week-old C57 mice received high-dose G-CSF (100 μg/kg), low-dose G-CSF (10 μg/kg), and PBS (control) intraperitoneally for 7 consecutive days right after autologous fat grafting. Grafted fat was harvested at 1, 4, and 12 weeks for examination. The low-dose G-CSF, high-dose G-CSF, and control groups had retention rates of 73.6% ± 3.1%, 51.6% ± 4.4%, and 44.5% ± 4.0%, respectively, at 12 weeks (low-dose G-CSF versus control and low-dose G-CSF versus high-dose G-CSF, both p fat grafts, contributing to improved angiogenesis. However, high-dose G-CSF caused a prolonged macrophage infiltration and elevated level of inflammation (IL-6 and TNF-α), which led to severe fibrosis and impaired adipogenesis (downregulated expression of PPAR-γ and CEBP-α). Low-dose G-CSF treatment successfully improved fat graft survival by mobilizing HSCs and inducing angiogenesis. However, high-dose G-CSF prolonged inflammation and caused severe fibrosis, leading to impaired adipogenesis and poor fat graft survival. Copyright © 2017. Published by Elsevier Inc.

  11. Oncologic doses of zoledronic acid induce site specific suppression of bone modelling in rice rats.

    Science.gov (United States)

    Exposto, C R; Oz, U; Callard, J S; Allen, M J; Khurana, H; Atri, A D'; Mo, X; Fernandez, S A; Tatakis, D N; Edmonds, K; Westgate, P M; Huja, S S

    2017-06-01

    To examine the effect of zoledronic acid (ZOL) on cortical bone modelling and healing of extraction sockets in the jaw bones of a rodent model. We hypothesized ZOL suppresses both the bone formation in the modelling mode in the jaw bones and alters the extraction site healing. Rice rats were administered saline solution and two dose regimens of ZOL: 0.1 mg/kg, twice a week, for 4 weeks (n=17, saline=8 & ZOL=9) and a higher dose of 0.4 mg/kg, weekly, for 9 weeks (n=30, saline=15 & ZOL=15). Two pairs of fluorochrome bone labels were administered. Extraction of maxillary teeth was performed in maxilla. Mineral apposition rate, mineralizing surface and bone formation rate (BFR) were quantified on periodontal (PDL), alveolar and basal bone surfaces, and in the trabecular bone of proximal tibia. Bone volume (BV) was evaluated at extraction sockets. Multivariate Gaussian models were used to account for repeated measurements, and analyzes were conducted in SAS V9.3. ZOL suppressed bone modelling (BFR/BS) at the PDL surfaces in the mandible (Pbone formation in the modelling mode in the jaws demonstrates the site specific effects of ZOL in rice rats. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  12. Prolonged fasting induces peripheral insulin resistance, which is not ameliorated by high-dose salicylate

    NARCIS (Netherlands)

    van der Crabben, Saskia N.; Allick, Gideon; Ackermans, Mariette T.; Endert, Erik; Romijn, Johannes A.; Sauerwein, Hans P.

    2008-01-01

    CONTEXT: Elevated plasma free fatty acids, excess reactive oxygen species, inflammation, and gluco-counterregulatory hormones induce insulin resistance (IR) through activation of Jun NH(2)-terminal kinase and nuclear factor-kappaB inhibitor kappaB kinase, which leads to hyperphosphorylation of the

  13. Low doses of UVB or UVA induce chromosomal aberrations in cultured human skin cells

    NARCIS (Netherlands)

    Emri, G.; Wenczl, E.; Erp, P. van; Jans, J.; Roza, L.; Horkay, I.; Schothorst, A.A.

    2000-01-01

    Chromosomal defects are frequently present in malignant and premalignant skin disorders; however, it is not known whether ultraviolet radiation from sunlight plays a role in their induction. To obtain information on the ability of ultraviolet A and ultraviolet B to induce chromosomal aberrations,

  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. 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.

  16. Mechanisms and biological importance of photon-induced bystander responses: do they have an impact on low-dose radiation responses.

    Science.gov (United States)

    Tomita, Masanori; Maeda, Munetoshi

    2015-03-01

    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 bystander 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. © The Author 2014. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

  17. The impact of low-dose insulin on peripheral nerve insulin receptor signaling in streptozotocin-induced diabetic rats.

    Directory of Open Access Journals (Sweden)

    Kazuhiro Sugimoto

    Full Text Available BACKGROUND: The precise mechanisms of the neuroprotective effects of insulin in streptozotocin (STZ-induced diabetic animals remain unknown, but altered peripheral nerve insulin receptor signaling due to insulin deficiency might be one cause. METHODOLOGY AND PRINCIPAL FINDINGS: Diabetes was induced in 10-week-old, male Wistar rats by injecting them with STZ (45 mg/kg. They were assigned to one group that received half of an insulin implant (∼1 U/day; I-group, n = 11 or another that remained untreated (U-group, n = 10 for 6 weeks. The controls were age- and sex-matched, non-diabetic Wistar rats (C-group, n = 12. Low-dose insulin did not change haemoglobin A1c, which increased by 136% in the U-group compared with the C-group. Thermal hypoalgesia and mechanical hyperalgesia developed in the U-group, but not in the I-group. Sensory and motor nerve conduction velocities decreased in the U-group, whereas sensory nerve conduction velocity increased by 7% (p = 0.0351 in the I-group compared with the U-group. Western blots showed unaltered total insulin receptor (IR, but a 31% decrease and 3.1- and 4.0-fold increases in phosphorylated IR, p44, and p42 MAPK protein levels, respectively, in sciatic nerves from the U-group compared with the C-group. Phosphorylated p44/42 MAPK protein decreased to control levels in the I-group (p<0.0001. CONCLUSIONS AND SIGNIFICANCE: Low-dose insulin deactivated p44/42 MAPK and ameliorated peripheral sensory nerve dysfunction in rats with STZ-induced diabetes. These findings support the notion that insulin deficiency per se introduces impaired insulin receptor signaling in type 1 diabetic neuropathy.

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

    Science.gov (United States)

    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. PMID:26184775

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

    Science.gov (United States)

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

    2015-11-01

    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. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. 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

    was prevented by a neutralizing monoclonal antibody (mAb) against IFN-gamma, but not by anti-IL-2 receptor mAb, a soluble form of TNF-receptor type 1 or recombinant human IL-6. The prevention of disease by fusidin was also partly reversed by exogenously administered recombinant mouse IFN-gamma. The data provide...... 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...... having significantly lower glycaemic values and milder (often absent) insulitis compared with sham-treated animals or controls given SZ alone. The antidiabetogenic effect was long-lasting as it was maintained up to 1 month after cessation of therapy. In contrast, fusidin prophylaxis failed to prevent...

  1. Chlorpromazine induced priapism from a single dose: an unusual complication of antipsychotic agent

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    Mohamed Ahmed Abd El Salam

    2017-08-01

    Full Text Available Priapism is considered as an unusual andrological emergency that requires urgent intervention. It is defined as prolonged penile erection (usually painful for more than 4 hours not related to sexual excitation or stimulation. Several causes have been attributed to cause such condition including the use of psychotropic drugs as chlorpromazine. Only few case reports in literature have recorded priapism as a complication of administration of chlorpromazine, however most of them were due to overdose or prolonged administration for prolonged period or as an interaction with other drugs. Here, in this case report is about a 23 years old male presented to the emergency department with neglected priapism after administration of a single dose of chlorpromazine.

  2. Nano-silver induces dose-response effects on the nematode Caenorhabditis elegans

    DEFF Research Database (Denmark)

    Ellegaard-Jensen, Lea; Alstrup Jensen, Keld; Johansen, Anders

    2012-01-01

    Toxicity of nano-formulated silver to eukaryotes was assessed by exposing nematodes (Caenorhabditis elegans) to two types of silver nanoparticles (AgNPs): with average primary particle diameters of 1 nm (AgNP1) and 28 nm (AgNP28, PVP coated), respectively. Tests were performed with and without...... adverse dose-response effects and mortality on C. elegans. LC50 for AgNP28 was lower than for AgNP1 and, hence, at the present test conditions the PVP-coated AgNP28 was more toxic than AgNP1. Including E. coil in the test medium as a food source increased AgNPs toxicity towards nematodes compared to when...

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

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    Gonze Marc-André

    2017-01-01

    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 depuration (through biological and physical mechanisms and the shielding of gamma rays emitted from the forest floor by vegetation. Our study finally suggests that airborne surveys might have not reflected dose rates at ground level in forest systems, which were predicted to slightly increase by 5 to 10% during the same period of time.

  4. Evaluation of HIFU-induced lesion region using temperature threshold and equivalent thermal dose methods

    Science.gov (United States)

    Chang, Shihui; Xue, Fanfan; Zhou, Wenzheng; Zhang, Ji; Jian, Xiqi

    2017-03-01

    Usually, numerical simulation is used to predict the acoustic filed and temperature distribution of high intensity focused ultrasound (HIFU). In this paper, the simulated lesion volumes obtained by temperature threshold (TRT) 60 °C and equivalent thermal dose (ETD) 240 min were compared with the experimental results which were obtained by animal tissue experiment in vitro. In the simulation, the calculated model was established according to the vitro tissue experiment, and the Finite Difference Time Domain (FDTD) method was used to calculate the acoustic field and temperature distribution in bovine liver by the Westervelt formula and Pennes bio-heat transfer equation, and the non-linear characteristics of the ultrasound was considered. In the experiment, the fresh bovine liver was exposed for 8s, 10s, 12s under different power conditions (150W, 170W, 190W, 210W), and the exposure was repeated 6 times under the same dose. After the exposures, the liver was sliced and photographed every 0.2mm, and the area of the lesion region in every photo was calculated. Then, every value of the areas was multiplied by 0.2mm, and summed to get the approximation volume of the lesion region. The comparison result shows that the lesion volume of the region calculated by TRT 60 °C in simulation was much closer to the lesion volume obtained in experiment, and the volume of the region above 60 °C was larger than the experimental results, but the volume deviation was not exceed 10%. The volume of the lesion region calculated by ETD 240 min was larger than that calculated by TRT 60 °C in simulation, and the volume deviations were ranged from 4.9% to 23.7%.

  5. Lead-induced anemia: Dose-response relationships and evidence for a threshold

    Energy Technology Data Exchange (ETDEWEB)

    Schwartz, J.; Landrigan, P.J.; Baker, E.L. Jr.; Orenstein, W.A.; von Lindern, I.H. (Environmental Protection Agency, Washington, DC (USA))

    1990-02-01

    We conducted a cross-sectional epidemiologic study to assess the association between blood lead level and hematocrit in 579 one to five year-old children living near a primary lead smelter in 1974. Blood lead levels ranged from 0.53 to 7.91 mumol/L (11 to 164 micrograms/dl). To predict hematocrit as a function of blood lead level and age, we derived non-linear regression models and fit percentile curves. We used logistic regression to predict the probability of hematocrit values less than 35 per cent. We found a strong non-linear, dose-response relationship between blood lead level and hematocrit. This relationship was influenced by age, but (in this age group) not by sex; the effect was strongest in youngest children. In one year-olds, the age group most severely affected, the risk of an hematocrit value below 35 percent was 2 percent above background at blood lead levels between 0.97 and 1.88 mumol/L (20 and 39 micrograms/dl), 18 percent above background at lead levels of 1.93 to 2.85 mumol/L (40 to 59 micrograms/dl), and 40 percent above background at lead levels of 2.9 mumol/L (60 micrograms/dl) and greater; background was defined as a blood lead level below 1.88 mumol/L (20 micrograms/dl). This effect appeared independent of iron deficiency. These findings suggest that blood lead levels close to the currently recommended limit value of 1.21 mumol/L (25 micrograms/dl) are associated with dose-related depression of hematocrit in young children.

  6. 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

  7. 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.

  8. Cymbopogon citratus Protects against the Renal Injury Induced by Toxic Doses of Aminoglycosides in Rabbits

    OpenAIRE

    Ullah, N.; Khan, M A; Khan, T.; Ahmad, W

    2013-01-01

    Renal injury is the most common side-effect of aminoglycosides. These antimicrobial drugs are particularly effective against Gram-negative microorganisms. The present study was conducted to investigate the renal protective activity of Cymbopogon citratus in gentamicin-induced nephrotoxicity. Male rabbits were divided into four groups (n=6) including group 1 (0.9% saline treated), group 2 (80 mg/kg/day gentamicin-treated), group 3 (200 mg/kg/day Cymbopogon citratus treated) and group 4 (80 mg/...

  9. Low-Dose Pesticide Mixture Induces Senescence in Normal Mesenchymal Stem Cells (MSC) and Promotes Tumorigenic Phenotype in Premalignant MSC.

    Science.gov (United States)

    Hochane, Mazene; Trichet, Valerie; Pecqueur, Claire; Avril, Pierre; Oliver, Lisa; Denis, Jerome; Brion, Regis; Amiaud, Jerome; Pineau, Alain; Naveilhan, Philippe; Heymann, Dominique; Vallette, François M; Olivier, Christophe

    2017-03-01

    Humans are chronically exposed to multiple environmental pollutants such as pesticides with no significant evidence about the safety of such poly-exposures. We exposed mesenchymal stem cells (MSC) to very low doses of mixture of seven pesticides frequently detected in food samples for 21 days in vitro. We observed a permanent phenotype modification with a specific induction of an oxidative stress-related senescence. Pesticide mixture also induced a shift in MSC differentiation towards adipogenesis but did not initiate a tumorigenic transformation. In modified MSC in which a premalignant phenotype was induced, the exposure to pesticide mixture promoted tumorigenic phenotype both in vitro and in vivo after cell implantation, in all nude mice. Our results suggest that a common combination of pesticides can induce a premature ageing of adult MSC, and as such could accelerate age-related diseases. Exposure to pesticide mixture may also promote the tumorigenic transformation in a predisposed stromal environment. Abstract Video Link: https://youtu.be/mfSVPTol-Gk Stem Cells 2017;35:800-811. © 2016 AlphaMed Press.

  10. Continuing Exposure to Low-Dose Nonylphenol Aggravates Adenine-Induced Chronic Renal Dysfunction and Role of Rosuvastatin Therapy

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    Yen Chia-Hung

    2012-07-01

    Full Text Available Abstract Background Nonylphenol (NP, an environmental organic compound, has been demonstrated to enhance reactive-oxygen species (ROS synthesis. Chronic exposure to low-dose adenine (AD has been reported to induce chronic kidney disease (CKD. Methods In this study, we tested the hypothesis that chronic exposure to NP will aggravate AD-induced CKD through increasing generations of inflammation, ROS, and apoptosis that could be attenuated by rosuvastatin. Fifty male Wistar rats were equally divided into group 1 (control, group 2 (AD in fodder at a concentration of 0.25%, group 3 (NP: 2 mg/kg/day, group 4 (combined AD & NP, and group 5 (AD-NP + rosuvastatin: 20 mg/kg/day. Treatment was continued for 24 weeks for all animals before being sacrificed. Results By the end of 24 weeks, serum blood urea nitrogen (BUN and creatinine levels were increased in group 4 than in groups 1–3, but significantly reduced in group 5 as compared with group 4 (all p  Conclusion NP worsened AD-induced CKD that could be reversed by rosuvastatin therapy.

  11. Ethosuximide-induced Stevens-Johnson syndrome: Beneficial effect of early intervention with high-dose corticosteroid therapy.

    Science.gov (United States)

    Tachibana, Kota; Hamada, Toshihisa; Tsuchiya, Hiroki; Shibata, Takashi; Fujii, Kazuyasu; Kobayashi, Katsuhiro; Iwatsuki, Keiji

    2018-02-11

    We report two rare cases of childhood epilepsy patients who developed ethosuximide-induced Stevens-Johnson syndrome (SJS). Unlike typical SJS, the initial eruption of both patients presented well-demarcated, infiltrating firm papules mainly on the cheeks and the extensor aspects of the arms (case 1), and multiple vesicles on the soles and oral aphthosis (case 2), which closely mimicked viral exanthema. We diagnosed both patients with ethosuximide-induced SJS, based on the dosing period and the positive results of drug-induced lymphocyte stimulation test. Systemic corticosteroids are usually selected as a standard therapy for SJS, despite controversial results regarding their effectiveness. In case 1, an i.v. pulse therapy of methylprednisolone (30 mg/kg, 3 days consecutively) was initiated on day 7 from the onset of illness, and an i.v. immunoglobulin (400 mg/kg, 5 days consecutively) was added the following day. In case 2, an i.v. prednisone treatment (1 mg/kg, for 1 week) was initiated on day 4 from the onset. Eventually, the early therapeutic interventions resulted in good outcomes in both patients. © 2018 Japanese Dermatological Association.

  12. The novel tuberculosis vaccine, AERAS-402, is safe in healthy infants previously vaccinated with BCG, and induces dose-dependent CD4 and CD8T cell responses.

    Science.gov (United States)

    Kagina, Benjamin M N; Tameris, Michele D; Geldenhuys, Hennie; Hatherill, Mark; Abel, Brian; Hussey, Gregory D; Scriba, Thomas J; Mahomed, Hassan; Sadoff, Jerald C; Hanekom, Willem A; Mansoor, Nazma; Hughes, Jane; de Kock, Marwou; Whatney, Wendy; Africa, Hadn; Krohn, Colleen; Veldsman, Ashley; Kany, Angelique Luabeya Kany; Douoguih, Macaya; Pau, Maria Grazia; Hendriks, Jenny; McClainc, Bruce; Benko, Jacqueline; Snowden, Margaret A; Hokey, David A

    2014-10-14

    Efforts to reduce risk of tuberculosis disease in children include development of effective vaccines. Our aim was to test safety and immunogenicity of the new adenovirus 35-vectored tuberculosis vaccine candidate AERAS-402 in infants, administered as a boost following a prime with the Bacille Calmette-Guerin vaccine. In a phase 1 randomised, double-blind, placebo-controlled, dose-escalation trial, BCG-vaccinated infants aged 6-9 months were sequentially assigned to four study groups, then randomized to receive an increasing dose-strength of AERAS-402, or placebo. The highest dose group received a second dose of vaccine or placebo 56 days after the first. The primary study outcome was safety. Whole blood intracellular cytokine staining assessed immunogenicity. Forty-two infants received AERAS-402 and 15 infants received placebo. During follow-up of 182 days, an acceptable safety profile was shown with no serious adverse events or discontinuations related to the vaccine. AERAS-402 induced a specific T cell response. A single dose of AERAS-402 induced CD4T cells predominantly expressing single IFN-γ whereas two doses induced CD4T cells predominantly expressing IFN-γ, TNF-α and IL-2 together. CD8T cells were induced and were more likely to be present after 2 doses of AERAS-402. AERAS-402 was safe and immunogenic in healthy infants previously vaccinated with BCG at birth. Administration of the highest dose twice may be the most optimal vaccination strategy, based on the induced immunity. Multiple differences in T cell responses when infants are compared with adults vaccinated with AERAS-402, in the same setting and using the same whole blood intracellular cytokine assay, suggest specific strategies may be important for vaccination for each population. Copyright © 2014 Elsevier Ltd. All rights reserved.

  13. Azithromycin-Induced, Biopsy-Proven Acute Interstitial Nephritis in an Adult Successfully Treated with Low-Dose Corticosteroids.

    Science.gov (United States)

    Woodruff, Ashley E; Meaney, Calvin J; Hansen, Elizabeth A; Prescott, Gina M

    2015-11-01

    Acute interstitial nephritis (AIN) is a form of acute kidney injury (AKI) characterized by a rapid deterioration of renal function, inflammatory infiltration of interstitial tissues, and renal edema. Drug-induced AIN is the most common etiology of AIN, but AIN can also have infectious, autoimmune, or idiopathic causes. β-Lactam antibacterials, nonsteroidal antiinflammatory drugs, and proton pump inhibitors are recognized as leading causes of AIN; however, many other drugs have been identified as causes. We describe the case of a 59-year-old white male who developed AIN that required hemodialysis following azithromycin treatment. He presented to the hospital with complaints of nausea, vomiting, malaise, and fever over the past 3 days, along with no urine output in the preceding 24 hours. Two weeks earlier, he had completed a 5-day course of azithromycin 500 mg on day 1 followed by 250 mg/day on days 2-5 (total dose 1.5 g) for an upper respiratory tract infection. On admission, the patient's serum creatinine (S(cr)) concentration was 7.4 mg/dl (baseline = 1.3 mg/dl). He reported a similar episode of kidney failure 2 years earlier after taking azithromycin; however, at that time it was believed the AKI was likely due to benazepril use in the setting of acute infection, and a kidney biopsy was not performed. His S(cr) concentration peaked at 11.4 mg/dl, and three sessions of hemodialysis were required. A kidney biopsy was performed that revealed AIN. Low-dose prednisone 0.3 mg/kg (30 mg)/day, tapered over the next 3 months, was administered, and his renal function improved to near baseline prior to discharge; 6 months later, his Scr concentration was 1.4 mg/dl. Despite lower than recommended dosing, this patient responded well to prednisone and did not experience long-term sequelae from renal injury. Use of the Naranjo Adverse Drug Reaction Probability Scale indicated a definite relationship (score of 10) between azithromycin exposure and the manifestation of AIN. To

  14. Low Dose Focused Ultrasound Induces Enhanced Tumor Accumulation of Natural Killer Cells.

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    Naomi S Sta Maria

    Full Text Available Natural killer (NK cells play a vital antitumor role as part of the innate immune system. Efficacy of adoptive transfer of NK cells depends on their ability to recognize and target tumors. We investigated whether low dose focused ultrasound with microbubbles (ldbFUS could facilitate the targeting and accumulation of NK cells in a mouse xenograft of human colorectal adenocarcinoma (carcinoembryonic antigen (CEA-expressing LS-174T implanted in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG mice in the presence of an anti-CEA immunocytokine (ICK, hT84.66/M5A-IL-2 (M5A-IL-2. Human NK cells were labeled with an FDA-approved ultra-small superparamagnetic iron oxide particle, ferumoxytol. Simultaneous with the intravenous injection of microbubbles, focused ultrasound was applied to the tumor. In vivo longitudinal magnetic resonance imaging (MRI identified enhanced accumulation of NK cells in the ensonified tumor, which was validated by endpoint histology. Significant accumulation of NK cells was observed up to 24 hrs at the tumor site when ensonified with 0.50 MPa peak acoustic pressure ldbFUS, whereas tumors treated with at 0.25 MPa showed no detectable NK cell accumulation. These clinically translatable results show that ldbFUS of the tumor mass can potentiate tumor homing of NK cells that can be evaluated non-invasively using MRI.

  15. Perinatal exposure to low dose glufosinate ammonium induces autism-like phenotypes in mice.

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    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.

  16. Evaluation of the Effect of Two Systemic Doses of HESA-A on Prevention of Induced Tongue Neoplasm in Rats

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    Masoumeh Mehdipour

    2013-12-01

    Full Text Available Background and aims. The aim of the present study was to compare the inhibitory effects of two systemic doses of HESA-A on prevention of 4-NQO-induced tongue neoplasms in rats. This study evaluated weight and histopathological changes. Materials and methods. Forty-eight male Sprague Dawley rats were divided into four groups of A, B, C and D of each 12 rats. The rats in groups B to D received 30 ppm of 4-Nitroquinoline-1-oxide (4-NQO in drinking water for 12 weeks. When feeding with 4-NQO was initiated, the rats in groups B and C received HESA-A at doses of 250 and 500 mg/kg, respectively, 3 times a week. Body weights were measured three times a week. At the end, the rats were euthanized and the tongue was removed. Histological evaluations for carcinogenesis were carried out under a light microscope. Results. The mean body weights of rats in groups B, C and D were significantly lower than that in group A (P < 0.05. There were no significant differences in weight changes between groups B, C and D. In the present study, after 12 weeks of treatment, Tongue specimens in groups B and C did not exhibit severe dysplastic changes; however, concurrent hyperplasia, without atypia and mild-to-moderate dysplastic changes were detected. These changes were significantly less than those in group D, with significant differences between group D and groups A, B and C (P<0.001, P<0.01 and P<0.05, respectively. Conclusion. HESA-A has dose-dependent inhibitory effects on the development of neoplasms of the tongue.

  17. 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.

  18. Dose-dependent attenuation of intravenous nalbuphine on epidural morphine-induced pruritus and analgesia after cesarean delivery

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    Mao-Kai Chen

    2014-05-01

    Full Text Available Epidural morphine in patient-controlled analgesia regimens controls postoperative pain well but easily induces pruritus and other epidural morphine-related side effects. With 90 pregnant American Society of Anesthesiologists physical status II females scheduled for elective cesarean delivery, the present study was designed to evaluate the efficacy and safety profile of patient-controlled antipruritus (PCP use of intravenous nalbuphine-based regimens for attenuation of postoperative pruritus and related side effects in combination with epidural morphine patient-controlled analgesia with regard to the quality of postoperative pain management. Patients were randomly assigned to two nalbuphine groups (5 μg/kg/hour, Group N5 or 10 μg/kg/hour, Group N10 and bolus dose of 1.6 μg/kg for PCP or the control (normal saline group. Comparable visual analog scale scores for rest pain at each measured time interval among the three groups demonstrated that adequate pain relief was offered; however, the cumulative dose of nalbuphine administered to the patients in Group N10 attenuated the analgesic effect of epidural morphine in moving pain at POh24 only. Fewer episodes and milder severity of pruritus were observed in patients in Groups N5 and N10 at all postoperative time intervals. Epidural morphine provided good postoperative pain relief but with incommodious side effects. In addition, intravenous nalbuphine not only attenuated the incidence of pruritus but also decreased total morphine consumption. In conclusion, intravenous administration of low-dose nalbuphine (5 μg/kg/hour for PCP maintained analgesia produced by epidural morphine and offered low pruritus incidence.

  19. Cymbopogon citratus Protects against the Renal Injury Induced by Toxic Doses of Aminoglycosides in Rabbits.

    Science.gov (United States)

    Ullah, N; Khan, M A; Khan, T; Ahmad, W

    2013-03-01

    Renal injury is the most common side-effect of aminoglycosides. These antimicrobial drugs are particularly effective against Gram-negative microorganisms. The present study was conducted to investigate the renal protective activity of Cymbopogon citratus in gentamicin-induced nephrotoxicity. Male rabbits were divided into four groups (n=6) including group 1 (0.9% saline treated), group 2 (80 mg/kg/day gentamicin-treated), group 3 (200 mg/kg/day Cymbopogon citratus treated) and group 4 (80 mg/kg/day gentamicin and 200 mg/kg/day Cymbopogon citratus treated). Biochemical kidney functioning parameters, urinary enzymes and histopathological examination were performed. The results of the present study showed that simultaneous administration of Cymbopogon citrates and gentamicin significantly protected alteration in body weight, blood urea nitrogen, serum creatinine, creatinine clearance, serum uric acid, serum electrolytes, urinary volume, urinary protein, urinary lactate dehydrogenase and urinary alkaline phosphatase induced by gentamicin. Histological examination of the kidney also suggested the same. It is concluded from the current study that co-administration of Cymbopogon citratus with gentamicin for 3 weeks successfully prevented renal damage associated with aminoglycosides.

  20. Continuous in vitro exposure to low dose genistein induces genomic instability in breast epithelial cells

    Science.gov (United States)

    Kim, Young Mi; Yang, Shihe; Xu, Weihong; Li, Shibo; Yang, Xiaohe

    2008-01-01

    Genistein is a major soy isoflavone with multiple properties. The impact of soy/genistein on breast cancer is controversial. One of the issues is whether soy/genistein has a genotoxic effect at physiological concentrations. To address this question using an in vitro model, we first established MCF-10A/G0 and MCF-10A/G1 cell lines, which were MCF-10A cells exposed to 0.01% DMSO (as vehicle control), i.e. MCF-10A/G0, or 1 µM of genistein for three months, MCF-10A/G1, respectively. Chromosomal changes were compared between the two cell lines by routine G-banded chromosome analyses, regular CGH and oligo array-based CGH. After three months of exposure to genistein, the cell line MCF-10A/G1 showed a loss of a normal chromosome 8, a gain of extra chromosome 20, plus a loss of a chromosomal segment on the short arm of chromosome 9, which leads to a homozygous deletion of the tumor suppressor genes, INK4/p16 and INK4/p15. Our results suggest that long-term/low concentration exposure to genistein may have the potential to induce chromosomal imbalances. These genotoxic effects may work in concert with other factors to induce genetic lesions that contribute to soy/genistein associated risk. PMID:18940470

  1. Dose-independent confusion induced by voriconazole in a patient with Asian ancestry after allogeneic hematopoietic stem cell transplant.

    Science.gov (United States)

    Hui, John

    2016-02-01

    This is the case of a 71-year-old man with Asian ancestry who had myelodysplastic syndrome admitted for allogeneic hematopoietic stem cell transplant. This case suggests that voriconazole-induced confusion is probably dose-independent and reversible with no residual symptoms after discontinuation of voriconazole. Patient can experience confusion even voriconazole is ordered according to package insert and serum voriconazole level is within therapeutic range (1-6 µg/mL). The onset of confusion can be delayed and sudden after seven days of voriconazole therapy. Genotyping of CYP2C19 can be tested for Asian populations since 15-20% of them could be poor metabolizers of voriconazole. © The Author(s) 2014.

  2. 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.

  3. High dose of aspirin moderates diabetes-induced changes of heart glycogen/glucose metabolism in rats.

    Science.gov (United States)

    Dervisevik, M; Dinevska-Kovkarovska, Suzana; Dimitrovska, M; Cipanovska, N; Miova, B

    2014-11-01

    Aspirin (ASA), as a multifunctional drug has been used as a hypoglycaemic agent in the treatment of diabetes and severe hyperglycaemia and has been established as a secondary strategy which may prevent many cardiovascular events. In this study we investigated high dose (100 mg/kg b.w./i.p) and time-dependent (2, 7 and 14 days) effects of ASA on the heart key enzymes and substrates from glycogen/glucose metabolism in control and diabetic rats. The results accomplished demonstrated that ASA significantly potentiates glycogen accumulation, as well as decreased blood glucose level and heart glycolytic potential in control rats. The treatment of diabetic rats with ASA caused moderation of the diabetic complication-significant inhibition of glycogen accumulation, lowering of blood glucose, as well as elevation of glycolytic potential. In conclusion, we propose that use of high-dose of ASA has anabolic effects in control rats and reduces heart glycogen glucose complications in diabetic rats. The moderation of diabetes-induced changes is time-dependent and involves reduction of glycogenogenesis and inhibited depression of glycolysis, with a tendency to maintenance control values.

  4. Equitoxic doses of 5-azacytidine and 5-aza-2'deoxycytidine induce diverse immediate and overlapping heritable changes in the transcriptome.

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    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.

  5. Iterative image reconstruction for sparse-view CT using normal-dose image induced total variation prior.

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    Jing Huang

    Full Text Available X-ray computed tomography (CT iterative image reconstruction from sparse-view projection data has been an important research topic for radiation reduction in clinic. In this paper, to relieve the requirement of misalignment reduction operation of the prior image constrained compressed sensing (PICCS approach introduced by Chen et al, we present an iterative image reconstruction approach for sparse-view CT using a normal-dose image induced total variation (ndiTV prior. The associative objective function of the present approach is constructed under the penalized weighed least-square (PWLS criteria, which contains two terms, i.e., the weighted least-square (WLS fidelity and the ndiTV prior, and is referred to as "PWLS-ndiTV". Specifically, the WLS fidelity term is built based on an accurate relationship between the variance and mean of projection data in the presence of electronic background noise. The ndiTV prior term is designed to reduce the influence of the misalignment between the desired- and prior- image by using a normal-dose image induced non-local means (ndiNLM filter. Subsequently, a modified steepest descent algorithm is adopted to minimize the associative objective function. Experimental results on two different digital phantoms and an anthropomorphic torso phantom show that the present PWLS-ndiTV approach for sparse-view CT image reconstruction can achieve noticeable gains over the existing similar approaches in terms of noise reduction, resolution-noise tradeoff, and low-contrast object detection.

  6. Low-dose aspartame consumption differentially affects gut microbiota-host metabolic interactions in the diet-induced obese rat.

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    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.

  7. Alterations induced by large doses of furosemide in chronic renal insufficiency.

    Science.gov (United States)

    Barrientos, A; Ruilope, L; Jarillo, D; Alcázar, J; Millet, V; Rodicio, J L

    1979-03-01

    Eleven patients with different degrees of renal failure with creatinine clearances between 7 and 32 ml/min have been studied. After a standard water overload and control periods of clearances, furosemide 1 g was given/i.v. There followed significant increase of renal plasma flow and glomerular filtration rate. In one case the increase was maintained during a follow up period of 3 hours. A significant increase was evident in phosphate, uric acid, sodium, potassium, and calcium clearances, as well as an increase in the sodium delivery to the distal nephron and a decrease in tubular reabsorption of phosphate. All this may be interpreted as the result of renal vasodilation induced by furosemide and its effect upon the proximal tubule and on Henle's loop.

  8. Single dose intratympanic mesna application inhibits propylene glycol induced cholesteatoma formation.

    Science.gov (United States)

    Ismi, O; Karabulut, Y Y; Bal, K K; Vayisoglu, Y; Unal, M

    2017-03-01

    Mesna (i.e. sodium 2-mercaptoethanesulfonate; C2H5NaO3S2) has been used in otological surgery such as cholesteatoma dissection and tympanic membrane lateralisation in atelectatic ears. However, this study aimed to investigate its effect on cholesteatoma formation. A total of 20 Wistar rats were divided into two groups of 10 animals. The right and left ears of control animals were treated with saline (saline control group; n = 10 ears) and propylene glycol plus saline (propylene glycol control group; n = 10 ears), respectively. In the mesna group, both ears were treated with propylene glycol plus mesna (n = 20 ears). On days 1, 8 and 15, the saline control group had intratympanic injections of 0.2 ml saline and the propylene glycol control and mesna groups had intratympanic injections of 0.2 ml 100 per cent propylene glycol. On day 22, the propylene glycol control group had a single intratympanic injection of 0.2 ml saline and the mesna group had a single intratympanic injection of 10 per cent mesna. Animals were killed 12 weeks after the last injection and the temporal bones were sent for histopathological evaluation. The cholesteatoma formation rate was 88 per cent in the propylene glycol control group, but was significantly lower in the mesna group (p = 0.01). There were no significant differences in granulation tissue formation (p = 0.498), cyst formation in the bulla (p = 0.381), fibrosis (p = 0.072) and epithelial hyperplasia (p = 0.081) among experimental groups. Intratympanic propylene glycol administration is an effective method of promoting experimental cholesteatoma formation. Administration of a single dose of intratympanic mesna inhibited cholesteatoma formation in an animal model.

  9. Genetic compensation of high dose radiation-induced damage in an anhydrobiotic insect

    Science.gov (United States)

    Gusev, Oleg; Nakahara, Yuichi; Sakashita, Tetsuya; Kikawada, Takahiro; Okuda, Takashi

    Anhydrobiotic larvae of African chironomid Polypedilum vanderplanki are known to show an extremely high tolerance against a range of stresses. The tolerance against various extreme environments exhibited by that insect might be due to being almost completely desiccated replacing water with trehalose, a state where little or no chemical reactions occur. From 2005 dried larvae of this insect are being used in a number of space experiments, both inside and outside of ISS as a model organism for estimation the limits of higher organisms' resistance to space environment stresses and long-term storage of the alive anhydrobiotic organisms during continues spaceflight. We have shown previously that both hydrated and dried larvae of Polypedilum vanderplanki have very higher tolerance against both highand low-linear energy transfer (LET), surviving after 7000Gy irradiation. It was suggested that the larvae would have effective DNA-reparation system in addition to artificial protection provided by glass-stage without water. In the present study we conducted analysis of stress-related gene expression in the larvae after 70-2000 Gy irradiations. Both DNA damage level and activity of DNA-reparation, anti-apoptotic and protein-damage related genes were analyzed. Direct visualization of DNA damage in the larvae fat body cells using Comet Assay showed that fragmented by radiation DNA is re-arranged within 76-98 hours after exposure. We found that massive overexpression of hsp and anti-oxidant genes occur in larvae entering anhydrobiosis , and provides refolding of proteins after rehydration. In the irradiated larvae overexpression of DNA-reparation enzymes anti-apoptotic genes was confirmed, suggesting that survival after high-dose irradiation is a result of combination of highly effective blocking of entering the apoptosis after severe DNA damage and DNA reparation.

  10. 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

  11. The effect of low-dose ketamine infusion on the remifentanil induced hemodynamic changes during general anesthesia

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    Beigmohamadi M T

    2008-05-01

    Full Text Available Background: Remifentanil is known to produce side-effects of hypotension and bradycardia. In this study, we examine the effect of low-dose ketamine infusion on the heart rate and blood pressure of patients anesthetized with remifentanil.Methods: In a randomized clinical trial, 54 patients aged 20-50 years old, with ASA physical status Ι, were studied in two groups (n=27, Ketamine- Remifentanil (K-R group and Placebo- Remifentanil (P-R group. Exclusion criteria were ASA physical status >1, gastroesophageal reflux, tachycardia, bradycardia, systemic diseases, use of antihypertensive drugs, difficult intubations, risk of aspiration and contraindications of ketamine. Remifentanil was started at a rate of 0.5 µg. kg-1. min-1 and anesthesia was induced with thiopental sodium 2 mg.kg-1. Maintenance of anesthesia included halothane and nitrous oxide/oxygen mixture. Remifentanil infusion was continued in both groups at a rate of 0.5 µg.kg-1.min-1. In the K-R group, ketamine was started with an infusion rate of 10 µg.kg-1. min-1, 10 minutes after intubation, while in the P-R group, normal saline was started with the same dose of remifentanil. Heart rate, systolic, diastolic and mean arterial blood pressure were measured and compared at 1, 3, 5, 10, 15, 20, 25 and 30 minutes.Results: No significant differences were found between basic patient characteristics of mean of age, sex, weight, systolic, diastolic and mean arterial blood pressure and heart rate (p>0.2 in the two groups. However, the rate of systolic, diastolic and mean arterial blood pressure changes in the P-R group was significantly greater than that of the K-R group (p<0.006. Heart rate changes were similar between the two groups (p=0.6. Incident of severe hypotension (a decrease of more than 25% of the basic value was less in the K-R group than that of the P-R group (11% vs. 89%; p=0.000.Conclusion: Low-dose ketamine infusion modulates the effect of remifentanil-induced hypotension and

  12. 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

  13. 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 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.

  14. 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.

  15. 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.

  16. 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.

  17. Effects of Arbutin on Radiation-Induced Micronuclei in Mice Bone Marrow Cells and Its Definite Dose Reduction Factor.

    Science.gov (United States)

    Nadi, Saba; Monfared, Ali Shabestani; Mozdarani, Hossein; Mahmodzade, Aziz; Pouramir, Mahdi

    2016-05-01

    Interactions of free radicals from ionizing radiation with DNA can induce DNA damage and lead to mutagenesis and carsinogenesis. With respect to radiation damage to human, it is important to protect humans from side effects induced by ionizing radiation. In the present study, the effects of arbutin were investigated by using the micronucleus test for anti-clastogenic activity, to calculate the ratio of polychromatic erythrocyte to polychromatic erythrocyte plus normochromatic erythrocyte (PCE/PCE+NCE) in order to show cell proliferation activity. Arbutin (50, 100, and 200 mg/kg) was intraperitoneally (ip)administered to NMRI mice two hours before gamma radiation at 2 and 4 gray (Gy). The frequency of micronuclei in 1000 PCEs (MnPCEs) and the ratio of PCE/PCE+NCE were calculated for each sample. Data were statistically evaluated using one-way ANOVA, Tukey HSD test, and t-test. The findings indicated that gamma radiation at 2 and 4 Gy extremely increased the frequencies of MnPCE (Parbutin before irradiation significantly reduced the frequencies of MnPCEs and increased the ratio of PCE/PCE+NCE in mice bone marrow compared to the non-drug-treated irradiated control (Parbutin had no toxicity effect on bone marrow cells. The calculated dose reduction factor (DRF) showed DRF=1.93 for 2Gy and DRF=2.22 for 4 Gy. Our results demonstrated that arbutin gives significant protection to rat bone against the clastogenic and cytotoxic effects of gamma irradiation.

  18. 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.

  19. Plasma-arc generated light inhibits proliferation and induces apoptosis of human gingival fibroblasts in a dose-dependent manner.

    Science.gov (United States)

    Hwang, In-Yong; Son, Young-Ok; Kim, Ji-Hae; Jeon, Young-Mi; Kim, Jong-Ghee; Lee, Choon-Bong; Park, Jong-Sun; Lee, Jeong-Chae

    2008-08-01

    This study examined the effects of blue light exposure on the proliferation and cytotoxicity of human gingival fibroblasts (HGF). Cellular mechanism by which blue light causes cytotoxic effects was also investigated. HGF were exposed to the plasma-arc generated blue light with various energy densities ranging from 2 to 48J/cm(2). After light exposure of the cells, they were processed for analyzing tritium incorporation, succinate dehydrogenase (SDH) activity, trypan blue exclusion, and DNA fragmentation. In addition, possible mechanism of the light-mediated cytotoxicity was investigated through flow cytometric and Western blot analyses. Blue light exposure significantly inhibited proliferation and SDH activity of HGF in a dose-dependent manner; exposure more than 12J/cm(2) had a toxic effect on the cells. The blue light-induced cytotoxicity of the cells resulted from apoptosis, as proven by the migration of many cells to the sub-G(1) phase of cell cycle and the appearance of DNA ladders. Additional experiments revealed that blue light induces apoptosis of HGF through mitochondrial stress and poly (ADP ribose) polymerase cleavage. This study suggests that plasma-arc generated blue light exerts some harm to cells, particularly damaging effect to DNA, and thus a long curing time more than recommended can cause biological damage on the oral tissue.

  20. High dose of antibiotic colistin induces oligomerization of molecular chaperone HSP90.

    Science.gov (United States)

    Togashi, Shuntaro; Takahashi, Kyosuke; Tamura, Arisa; Toyota, Ikumi; Hatakeyama, Shiori; Komatsuda, Atsushi; Kudo, Ikuru; Sasaki Kudoh, Erina; Okamoto, Tomoya; Haga, Asami; Miyamoto, Asuka; Grave, Ewa; Sugawara, Taku; Shimizu, Hiroaki; Itoh, Hideaki

    2017-07-01

    Colistin is an antimicrobial cationic peptide that belongs to the polymyxin family. Colistin was clinically used for the treatment of gram-negative infections but fell out of favour because of its significant side effects including neurotoxicity and nephrotoxicity. More recently, colistin has been regarded as one of the important options for nosocomial infections caused by multidrug resistant bacteria. Mechanisms of both the side effect onset of the drug and the side effect reduction are yet to be elucidated. In this study, we identified the specific binding protein of colistin using an affinity column chromatography. Colistin binds to the molecular chaperone HSP90. Although colistin slightly suppressed the chaperone activity of HSP90, there are no effects on the ATPase activity for a low concentration of colistin. Interestingly, colistin-induced aggregation of HSP90 via the N-domain. As for the cell viability of the SHSY5Y cell, the cell viability decreased to approximately 80% by the colistin 300 μM. However, the cell viability recovered to approximately 100% by adding ATP dosage. The same result was obtained by dot blot assay using anti-HSP90 antibody. Our results may help to understand the side effect mechanism of colistin. © The Authors 2017. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

  1. 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.

  2. 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.

  3. The Impact of Low-Dose Insulin on Peripheral Nerve Insulin Receptor Signaling in Streptozotocin-Induced Diabetic Rats

    Science.gov (United States)

    Sugimoto, Kazuhiro; Baba, Masayuki; Suzuki, Susumu; Yagihashi, Soroku

    2013-01-01

    Background The precise mechanisms of the neuroprotective effects of insulin in streptozotocin (STZ)-induced diabetic animals remain unknown, but altered peripheral nerve insulin receptor signaling due to insulin deficiency might be one cause. Methodology and Principal Findings Diabetes was induced in 10-week-old, male Wistar rats by injecting them with STZ (45 mg/kg). They were assigned to one group that received half of an insulin implant (∼1 U/day; I-group, n = 11) or another that remained untreated (U-group, n = 10) for 6 weeks. The controls were age- and sex-matched, non-diabetic Wistar rats (C-group, n = 12). Low-dose insulin did not change haemoglobin A1c, which increased by 136% in the U-group compared with the C-group. Thermal hypoalgesia and mechanical hyperalgesia developed in the U-group, but not in the I-group. Sensory and motor nerve conduction velocities decreased in the U-group, whereas sensory nerve conduction velocity increased by 7% (p = 0.0351) in the I-group compared with the U-group. Western blots showed unaltered total insulin receptor (IR), but a 31% decrease and 3.1- and 4.0-fold increases in phosphorylated IR, p44, and p42 MAPK protein levels, respectively, in sciatic nerves from the U-group compared with the C-group. Phosphorylated p44/42 MAPK protein decreased to control levels in the I-group (pinsulin deactivated p44/42 MAPK and ameliorated peripheral sensory nerve dysfunction in rats with STZ-induced diabetes. These findings support the notion that insulin deficiency per se introduces impaired insulin receptor signaling in type 1 diabetic neuropathy. PMID:24023699

  4. 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

  5. The Role of Target and Bystander Cells in Dose-Response Relationship of Radiation-Induced Bystander Effects in Two Cell Lines

    Science.gov (United States)

    Soleymanifard, Shokouhozaman; Bahreyni Toossi, Mohammad Taghi; Sazgarnia, Ameneh; Mohebbi, Shokoufe

    2013-01-01

    Objective(s): Radiation effect induced in nonirradiated cells which are adjacent or far from irradiated cells is termed radiation-induced bystander effect (RIBE). Published data on dose-response relationship of RIBE is controversial. In the present study the role of targeted and bystander cells in RIBE dose-response relationship of two cell lines have been investigated. Materials and Methods: Two cell lines (QU-DB and MRC5) which had previously exhibited different dose-response relationship were selected. In the previous study the two cell lines received medium from autologous irradiated cells and the results showed that the magnitude of damages induced in QU-DB cells was dependent on dose unlike MRC5 cells. In the present study, the same cells irradiated with 0.5, 2 and 4 Gy gamma rays and their conditioned media were transferred to nonautologous bystander cells; such that the bystander effects due to cross-interaction between them were studied. Micronucleus assay was performed to measure the magnitude of damages induced in bystander cells (RIBE level). Results: QU-DB cells exhibited a dose-dependent response. RIBE level in MRC5 cells which received medium from 0.5 and 2 Gy QU-DB irradiated cells was not statistically different, but surprisingly when they received medium from 4Gy irradiated QU-DB cells, RIBE was abrogated. Conclusion: Results pertaining to QU-DB and MRC5 cells indicated that both target and bystander cells determined the outcome. Triggering the bystander effect depended on the radiation dose and the target cell-type, but when RIBE was triggered, dose-response relationship was predominantly determined by the bystander cell type. PMID:24298387

  6. The role of target and bystander cells in dose-response relationship of radiation-induced bystander effects in two cell lines.

    Science.gov (United States)

    Soleymanifard, Shokouhozaman; Bahreyni Toossi, Mohammad Taghi; Sazgarnia, Ameneh; Mohebbi, Shokoufe

    2013-02-01

    Radiation effect induced in nonirradiated cells which are adjacent or far from irradiated cells is termed radiation-induced bystander effect (RIBE). Published data on dose-response relationship of RIBE is controversial. In the present study the role of targeted and bystander cells in RIBE dose-response relationship of two cell lines have been investigated. Two cell lines (QU-DB and MRC5) which had previously exhibited different dose-response relationship were selected. In the previous study the two cell lines received medium from autologous irradiated cells and the results showed that the magnitude of damages induced in QU-DB cells was dependent on dose unlike MRC5 cells. In the present study, the same cells irradiated with 0.5, 2 and 4 Gy gamma rays and their conditioned media were transferred to nonautologous bystander cells; such that the bystander effects due to cross-interaction between them were studied. Micronucleus assay was performed to measure the magnitude of damages induced in bystander cells (RIBE level). QU-DB cells exhibited a dose-dependent response. RIBE level in MRC5 cells which received medium from 0.5 and 2 Gy QU-DB irradiated cells was not statistically different, but surprisingly when they received medium from 4Gy irradiated QU-DB cells, RIBE was abrogated. RESULTS pertaining to QU-DB and MRC5 cells indicated that both target and bystander cells determined the outcome. Triggering the bystander effect depended on the radiation dose and the target cell-type, but when RIBE was triggered, dose-response relationship was predominantly determined by the bystander cell type.

  7. Involvement of p27CIP/KIP in HSP25 or inducible HSP70 mediated adaptive response by low dose radiation

    Energy Technology Data Exchange (ETDEWEB)

    Seo, Hang Rhan; Lee, Yoon Jin; Bae, Sangwoo; Lee, Yun Sil; Lee, Su Jae [Korea Institute of Radiological and Medical Science, Seoul (Korea, Republic of); Chung, Hee Yong [Hanyang University, Seoul (Korea, Republic of); Baek, Min [Ministry of Science and Technology, Gwacheon (Korea, Republic of)

    2006-04-15

    ThermoResistant (TR) clones of Radiation-Induced Fibrosarcoma (RIF) cells have been reported to show an adaptive response to 1cGy of low dose radiation, and HSP25 and inducible HSP70 are involved in this process. In this study, to further elucidate the mechanism by which HSP25 and inducible HSP70 regulate the adaptive response, HSP25 or inducible HSP70 overexpressed RIF cells were irradiated with 1cGy and the cell cycle was analyzed. HSP25 or inducible HSP70 overexpressed cells together with TR cells showed increased G1 phase after 1cGy irradiation, while RIF cells did not. [{sup 3}H]-Thymidine and BrdU incorporation also indicated that both HSP25 and inducible HSP70 are involved in G1 arrest after 1cGy irradiation. Molecular analysis revealed upregulation of p27Cip/Kip protein in HSP25 and inducible HSP70 overexpressed cells, and cotransfection of p27Cip/Kip antisense abolished the induction of the adaptive response and 1cGy-mediated G1 arrest. The above results indicate that induction of an adaptive response by HSP25 and inducible HSP70 is mediated by upregulation of p27Cip/Kip protein, resulting in low dose radiation-induced G1 arrest.

  8. 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.

  9. Rapid assessment of high-dose radiation exposures through scoring of cell-fusion-induced premature chromosome condensation and ring chromosomes.

    Science.gov (United States)

    Lamadrid Boada, A I; Romero Aguilera, I; Terzoudi, G I; González Mesa, J E; Pantelias, G; García, O

    2013-09-18

    Analysis of premature chromosome condensation (PCC) mediated by fusion of G0-lymphocytes with mitotic CHO cells in combination with rapid visualization and quantification of rings (PCC-Rf) is proposed as an alternative technique for dose assessment of radiation-exposed individuals. Isolated lymphocytes or whole blood from six individuals were γ-irradiated with 5, 10, 15 and 20Gy at a dose rate of 0.5Gy/min. Following either 8- or 24-h post-exposure incubation of irradiated samples at 37°C, chromosome spreads were prepared by standard PCC cytogenetic procedures. The protocol for PCC fusion proved to be effective at doses as high as 20Gy, enabling the analysis of ring chromosomes and excess PCC fragments. The ring frequencies remained constant during the 8-24-h repair time; the pooled dose relationship between ring frequency (Y) and dose (D) was linear: Y=(0.088±0.005)×D. During the repair time, excess fragments decreased from 0.91 to 0.59 chromatid pieces per Gy, revealing the importance of information about the exact time of exposure for dose assessment on the basis of fragments. Compared with other cytogenetic assays to estimate radiation dose, the PCC-Rf method has the following benefits: a 48-h culture time is not required, allowing a much faster assessment of dose in comparison with conventional scoring of dicentrics and rings in assays for chemically-induced premature chromosome condensation (PCC-Rch), and it allows the analysis of heavily irradiated lymphocytes that are delayed or never reach mitosis, thus avoiding the problem of saturation at high doses. In conclusion, the use of the PCC fusion assay in conjunction with scoring of rings in G0-lymphocytes offers a suitable alternative for fast dose estimation following accidental exposure to high radiation doses. Copyright © 2013 Elsevier B.V. All rights reserved.

  10. Quality of the transgene-specific CD8+ T cell response induced by adenoviral vector immunization is critically influenced by virus dose and route of vaccination

    DEFF Research Database (Denmark)

    Holst, Peter Johannes; Ørskov, Cathrine; Thomsen, Allan Randrup

    2010-01-01

    Adenoviral vectors have been widely used for experimental gene therapy and vaccination, yet there is a surprising lack of knowledge connecting the route and dose of adenovirus administration to the induced transgene-specific immune response. We have recently demonstrated polyfunctional CD8(+) T...... effector functions, accumulated in the spleen. These findings indicate that the localization of the adenoviral inoculum and not the total Ag load determines the quality of the CD8(+) T cell response induced with adenoviral vaccines....

  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...... blockade in patients induced and maintained under propofol anesthesia. However, sevoflurane anesthesia, unlike propofol, can prolong the effect of neuromuscular blocking drugs (NMBDs) such as rocuronium and vecuronium....

  12. Hyperalgesia induced by low-dose opioid treatment before orthopaedic surgery: An observational case-control study.

    Science.gov (United States)

    Hina, Nabil; Fletcher, Dominique; Poindessous-Jazat, Frédérique; Martinez, Valéria

    2015-04-01

    Chronic pain and opioid consumption may trigger diffuse hyperalgesia, but their relative contributions to pain vulnerability remain unclear. To assess preoperative opioid-induced hyperalgesia and its postoperative clinical consequences in patients with chronic pain scheduled for orthopaedic surgery. A prospective observational study. Raymond Poincare teaching hospital. Adults with or without long-term opioid treatment, scheduled for orthopaedic surgery. Preoperative hyperalgesia was assessed with eight quantitative sensory tests, in a pain-free zone. Postoperative morphine consumption and pain intensity were evaluated using a numerical rating scale (NRS) in the recovery room and during the first 72 h. We analysed results from 68 patients (28 opioid-treated patients and 40 controls). Mean daily opioid consumption was 42 ± 25 mg of morphine equivalent. The opioid-treated group displayed significantly higher levels of preoperative hyperalgesia in three tests: heat tolerance threshold (47.1°C vs. 48.4°C; P = 0.045), duration of tolerance to a 47°C stimulus (40.2 vs. 51.1 s; P = 0.03) and mechanical temporal summation [1.79 vs. 1.02 (ΔNRS10-1); P = 0.036]. Patients in the opioid-treated group consumed more morphine (19.1 vs. 9.38 mg; P = 0.001), had a higher pain intensity (7.6 vs. 5.5; P = 0.001) in the recovery room and a higher cumulative morphine dose at 72 h (39.8 vs. 25.6 mg; P = 0.02). Chronic pain patients treated with low doses of opioid had hyperalgesia before surgery. These results highlight the need to personalise the management of patients treated with opioids before surgery. ID-RCB 2011-A00304-37.

  13. Radiotherapy for benign disease; assessing the risk of radiation-induced cancer following exposure to intermediate dose radiation

    Science.gov (United States)

    Hatfield, Paul; Prestwich, Robin JD; Shaffer, Richard E; Taylor, Roger E

    2015-01-01

    Most radiotherapy (RT) involves the use of high doses (>50 Gy) to treat malignant disease. However, low to intermediate doses (approximately 3–50 Gy) can provide effective control of a number of benign conditions, ranging from inflammatory/proliferative disorders (e.g. Dupuytren's disease, heterotopic ossification, keloid scarring, pigmented villonodular synovitis) to benign tumours (e.g. glomus tumours or juvenile nasopharyngeal angiofibromas). Current use in UK RT departments is very variable. This review identifies those benign diseases for which RT provides good control of symptoms with, for the most part, minimal side effects. However, exposure to radiation has the potential to cause a radiation-induced cancer (RIC) many years after treatment. The evidence for the magnitude of this risk comes from many disparate sources and is constrained by the small number of long-term studies in relevant clinical cohorts. This review considers the types of evidence available, i.e. theoretical models, phantom studies, epidemiological studies, long-term follow-up of cancer patients and those treated for benign disease, although many of the latter data pertain to treatments that are no longer used. Informative studies are summarized and considered in relation to the potential for development of a RIC in a range of key tissues (skin, brain etc.). Overall, the evidence suggests that the risks of cancer following RT for benign disease for currently advised protocols are small, especially in older patients. However, the balance of risk vs benefit needs to be considered in younger adults and especially if RT is being considered in adolescents or children. PMID:26462717

  14. Irradiation of Mesenchymal Stromal Cells With Low and High Doses of Alpha Particles Induces Senescence and/or Apoptosis.

    Science.gov (United States)

    Alessio, Nicola; Esposito, Giuseppe; Galano, Giovanni; De Rosa, Roberto; Anello, Pasquale; Peluso, Gianfranco; Tabocchini, Maria Antonella; Galderisi, Umberto

    2017-09-01

    The use of high-linear energy transfer charged particles is gaining attention as a medical tool because of the emission of radiations with an efficient cell-killing ability. Considerable interest has developed in the use of targeted alpha-particle therapy for the treatment of micrometastases. Moreover, the use of helium beams is gaining momentum, especially for treating pediatric tumors. We analyzed the effects of alpha particles on bone marrow mesenchymal stromal cells (MSCs), which have a subpopulation of stem cells capable of generating adipocytes, chondrocytes, and osteocytes. Further, these cells contribute toward maintenance of homeostasis in the body. MSCs were irradiated with low and high doses of alpha particles or X-rays and a comparative biological analysis was performed. At a low dose (40 mGy), alpha particles exhibited a limited negative effect on the biology of MSCs compared with X-rays. No significant perturbation of cell cycle was observed, and a minimal increase in apoptosis or senescence was detected. Self-renewal was preserved as revealed by the CFU assay. On the contrary, with 2000 mGy alpha particles, we observed adverse effects on the vitality, functionality, and stemness of MSCs. These results are the consequence of different proportion of cells targeted by alpha particles or X-rays and the quality of induced DNA damage. The present study suggests that radiotherapy with alpha particles may spare healthy stem cells more efficaciously than X-ray treatments, an observation that should be taken into consideration by physicians while planning irradiation of tumor areas close to stem cell niches, such as bone marrow. J. Cell. Biochem. 118: 2993-3002, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  15. 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

  16. Dosing study on the effectiveness of salicylate/N-acetylcysteine for prevention of noise-induced hearing loss

    Directory of Open Access Journals (Sweden)

    John Coleman

    2010-01-01

    Full Text Available The efficacy of three different doses of sodium salicylate (SAL in combination with one dose of N-acetylcysteine (NAC to prevent noise-induced hearing loss was studied in chinchillas. After obtaining baseline-hearing thresholds, the chinchillas were randomly assigned to one of four treatment groups: three sets were injected intraperitoneally with 325 mg/kg NAC combined with 25, 50, or 75 mg/kg SAL, and a separate control group was injected with an equal volume of saline. Animals were injected twice daily for 2 days prior to and 1 hour before the noise exposure (6 hours to a 105-dB Standard Pressure Level octave band noise centered at 4 kHz. Immediate post-noise hearing thresholds were obtained followed by post-noise treatments at 1 hour then twice-daily for 2 days. Hearing tests continued at 1, 2, and 3 weeks post-noise, and immediately after the last hearing test, animals′ cochleae were stained for hair cell counts. All the groups showed hearing improvement until week 2. However, at week 3, saline treated animals demonstrated a 17-33 dB SPL permanent threshold shift (PTS across the test frequencies. Hearing loss was lowest in the 50 SAL/325 NAC mg/kg group (all frequencies, P < 0.001, and although PTS was reduced in the 25 and 75 mg/kg SAL dosage groups compared to the saline group, only the 75 mg/kg SAL group was significantly different at all but 2 kHz frequency. Coupled with the hearing loss, outer hair cell (OHC loss was maximal in the 4-8 kHz cochlear region of saline treated animals. However, there was a substantial reduction in the mean OHC loss of the NAC plus 50 or 75 mg/kg (but not the 25 mg/kg SAL groups. These findings suggest that SAL in combination with NAC is effective in reducing noise damage to the cochlea, but SAL has a relatively narrow therapeutic dosing window.

  17. Local High-Dose Radiotherapy Induces Systemic Immunomodulating Effects of Potential Therapeutic Relevance in Oligometastatic Breast Cancer

    Directory of Open Access Journals (Sweden)

    Elena Muraro

    2017-11-01

    Full Text Available Local irradiation of cancer through radiotherapy can induce spontaneous regression of non-directly irradiated lesions, suggesting the involvement of systemic antitumor immune responses. In oligometastatic breast cancer (BC patients, the use of stereotactic body radiotherapy (SBRT favors the local control of treated lesions and may contribute to break local tolerance and release tumor-associated antigens (TAAs, improving host antitumor immunity. We performed a detailed immunomonitoring of BC patients undergoing SBRT to verify its ability to “switch on” the anti-tumor immunity both systemically, in peripheral blood, and locally, employing in vitro BC models. Twenty-one BC patients with ≤6 metastases were treated with 3 daily doses of 10 Gy with SBRT. Blood samples for immune profiling were collected before and after treatment. One month after treatment a third of patients displayed the boosting or even the de novo appearance of polyfunctional CD4+ and CD8+ T cell responses against known BC TAAs (survivin, mammaglobin-A, HER2, through intracellular staining in flow cytometry. Half of patients showed increased numbers of activated natural killer (NK cells, measured with multispectral flow cytometry, immediately after the first dose of SBRT. Interestingly, high levels of activated NK cells at diagnosis correlated with a longer progression-free survival. BC in vitro models, treated with the same SBRT modality, showed enhanced expression of MHC class-I and class-II, major histocompatibility complex class I-related chain A/B, and Fas molecules, and increased release of pro-inflammatory cytokines, such as IL-1β and TNF-α. Consistently, we noticed enhanced production of perforin by CD4+ T cells when patients’ lymphocytes were cultured in the presence of irradiated BC cell line, compared to untreated targets. Besides immunogenic effects, SBRT also enhanced the percentages of circulating regulatory T cells, and increased indoleamine 2

  18. 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.

  19. 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...

  20. Inhibition of allergen-induced airway inflammation by low-dose oral immunotherapy with transgenic rice seeds independently of immunoglobulin e synthesis.

    Science.gov (United States)

    Saeki, Mayumi; Nishimura, Tomoe; Kaminuma, Osamu; Suzuki, Kazuya; Takai, Toshiro; Mori, Akio; Takada, Kazuko; Takaiwa, Fumio; Hiroi, Takachika

    2012-01-01

    Oral immunotherapy is potentially useful for the treatment of allergic diseases. We previously demonstrated that allergen-induced airway inflammation and immunoglobulin E (IgE) production in mice were suppressed by oral administration of high-dose transgenic (Tg) rice seeds (approximately 50 g/kg/day) expressing a T cell epitope of Dermatophagoides pteronyssinus group 1 allergen (Der p 1). However, this amount of Tg rice seeds was not realistic in our daily life. In this study, allergen-induced airway inflammation and IgE production following oral immunotherapy with a realistic (lowest) dose of Tg rice seeds were investigated. Mice orally administered with Tg or non-Tg rice seeds at approximately 5 g/kg/day for 1 week were immunized with recombinant Der p 1, and then challenged with the corresponding allergen. The infiltration of inflammatory cells into the airways and the levels of allergen-specific serum IgE were examined. Low-dose oral administration of Tg rice seeds significantly inhibited the allergen-induced infiltration of eosinophils and lymphocytes into the airways, but allergen-specific IgE synthesis was not changed. Low-dose oral immunotherapy with Tg rice seeds could suppress allergen-induced airway inflammation through mechanisms other than the downregulation of IgE synthesis. Copyright © 2012 S. Karger AG, Basel.

  1. ATRAZINE DOES NOT INDUCE GASTROINTESTINAL DISCOMFORT (PICA) IN RATS AT DOSES THAT INCREASE HPA-AXIS ACTIVATION AND CAUSE CONDITIONED TASTE AVERSION.

    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) and serum corticosterone (CORT), with a NOEL equal to 5mg/kg. The mechanism for these effects ...

  2. ATRAZINE DOES NOT INDUCE GASTROINTESTINAL DISCOMFORT (PICA) IN RATS AT DOSES THAT INCREASE ACTH ANDCORTICOSTERONE RELEASE AND CAUSE CONDITIONED TASTE AVERSION.

    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) and serum corticosterone (CORT), with a LOEL of 12.5mg/kg. The mechanism for these effects is unk...

  3. Effects of Home-Based Constraint-Induced Therapy versus Dose-Matched Control Intervention on Functional Outcomes and Caregiver Well-Being in Children with Cerebral Palsy

    Science.gov (United States)

    Lin, Keh-chung; Wang, Tien-ni; Wu, Ching-yi; Chen, Chia-ling; Chang, Kai-chieh; Lin, Yu-chan; Chen, Yi-ju

    2011-01-01

    This study compared home-based constraint-induced therapy (CIT) with a dose-matched home-based control intervention for children with cerebral palsy (CP). The differences in unilateral and bilateral motor performance, daily functions, and quality of parental well-being (i.e., the stress level of their parents) were evaluated. The study included 21…

  4. Addition of Hyperoxic Component to Adaptation to Hypoxia Prevents Impairments Induced by Low Doses of Toxicants (Free Radical Oxidation and Proteins of HSP Family).

    Science.gov (United States)

    Sazontova, T G; Stryapko, N V; Arkhipenko, Yu V

    2016-01-01

    We studied the possibility of preventing disturbances caused by administration of low doses of toxicants by adaptation to interval hypoxia and hyperoxia. The preventive protective effect of adaptation to hypoxia-hyperoxia manifested in suppression of free radical oxidation, decrease in the levels of HIF-1α and inducible HOx-1, and improvement of tolerance to physical exercises.

  5. Low-Dose Bone Morphogenetic Protein-2/Stromal Cell-Derived Factor-1β Cotherapy Induces Bone Regeneration in Critical-Size Rat Calvarial Defects

    Science.gov (United States)

    Herberg, Samuel; Susin, Cristiano; Pelaez, Manuel; Howie, R. Nicole; Moreno de Freitas, Rubens; Lee, Jaebum; Cray, James J.; Johnson, Maribeth H.; Elsalanty, Mohammed E.; Hamrick, Mark W.; Isales, Carlos M.; Wikesjö, Ulf M.E.

    2014-01-01

    Increasing evidence suggests that stromal cell-derived factor-1 (SDF-1/CXCL12) is involved in bone formation, though underlying molecular mechanisms remain to be fully elucidated. Also, contributions of SDF-1β, the second most abundant splice variant, as an osteogenic mediator remain obscure. We have shown that SDF-1β enhances osteogenesis by regulating bone morphogenetic protein-2 (BMP-2) signaling in vitro. Here we investigate the dose-dependent contribution of SDF-1β to suboptimal BMP-2-induced local bone formation; that is, a dose that alone would be too low to significantly induce bone formation. We utilized a critical-size rat calvarial defect model and tested the hypotheses that SDF-1β potentiates BMP-2 osteoinduction and that blocking SDF-1 signaling reduces the osteogenic potential of BMP-2 in vivo. In preliminary studies, radiographic analysis at 4 weeks postsurgery revealed a dose-dependent relationship in BMP-2-induced new bone formation. We then found that codelivery of SDF-1β potentiates suboptimal BMP-2 (0.5 μg) osteoinduction in a dose-dependent order, reaching comparable levels to the optimal BMP-2 dose (5.0 μg) without apparent adverse effects. Blocking the CXC chemokine receptor 4 (CXCR4)/SDF-1 signaling axis using AMD3100 attenuated the osteoinductive potential of the optimal BMP-2 dose, confirmed by qualitative histologic analysis. In conclusion, SDF-1β provides potent synergistic effects that support BMP-induced local bone formation and thus appears a suitable candidate for optimization of bone augmentation using significantly lower amounts of BMP-2 in spine, orthopedic, and craniofacial settings. PMID:24341891

  6. Specific hemosiderin deposition in spleen induced by a low dose of cisplatin: altered iron metabolism and its implication as an acute hemosiderin formation model.

    Science.gov (United States)

    Wang, Yingze; Juan, L V; Ma, Xiaowei; Wang, Dongliang; Ma, Huili; Chang, Yanzhong; Nie, Guangjun; Jia, Lee; Duan, Xianglin; Liang, Xing-Jie

    2010-07-01

    Cisplatin is one of the commonly-used chemotherapeutic drugs to efficiently treat malignant tumors in clinic, however, the adverse effects of cisplatin such as nephrotoxicity, neurotoxicity, and hemolytic uremic syndrome are often observed at its clinical doses (approximately 60 mg/m(2)), which limit its broader application. In earlier studies, little attention was paid to the subtle changes in the architecture of lymphatic organs after low doses of cisplatin treatment. This paper reviews current understanding of cisplatin-induced erythrocyte injury, and presents our latest finding that a low dose of cisplatin (3.6 mg/m(2)/day, 14 days) could induce specific hemosiderin deposition in spleen of both normal and hepatoma-22 (H22) inoculated Balb/C mice. This dose of cisplatin significantly inhibited H22-induced acute ascites development. No significant toxicity was induced by this dose of cisplatin to tissues except for hemosiderin accumulation in the spleen of both normal and H22 tumor-bearing mice. Increased splenic iron content and erythrocyte injury were observed after treatment with the low dose of cisplatin. The mRNA levels of ferroportin (FPN1) and ferritin were upregulated by 25 and 5-fold in spleen, respectively. Overexpression of FPN1 and ferritin protein were also been observed at protein levels by Western blotting analysis. In addition, the mRNA expression of hepcidin was also increased, suggesting blockage of iron recycling through FPN1 in spleen with cisplatin treatment. In conclusion, cisplatin treatment damages the erythrocytes which accumulate in the red pulp of spleen with defective recycling of FPN1 and ferritin protein. Hepcidin inhibits the function of FPN1 as iron-exporter leading to iron overloaded inside ferritins of splenic cells, which are stained with abnormal hemosiderin accumulation. These results demonstrate that cisplatin-caused hemosiderin deposition in spleen provides a valuable clue for understanding the molecular basis of toxicity of

  7. 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.

  8. Treatment of Lipoxin A(4) and its analogue on low-dose endotoxin induced preeclampsia in rat and possible mechanisms.

    Science.gov (United States)

    Lin, Feng; Zeng, Pan; Xu, Zhangye; Ye, Duyun; Yu, Xiaofang; Wang, Ni; Tang, Jie; Zhou, Ye; Huang, Yinping

    2012-12-01

    Preeclampsia (PE) is known to represent an exaggerated maternal inflammatory response to pregnancy. Lipoxin A(4) (LXA(4)), considered as an endogenous stop signal in inflammation, has been extensively studied pre clinically for its inflammatory pro-resolving effects. Thus, in the current study, we tested the effect of BML-111 (synthetic analogue of LXA(4)) on experimental PE rats induced by low-dose endotoxin (LPS) and of LXA(4) on human extravillous trophoblast cell line (TEV-1). In vivo experiment results showed that systolic blood pressure, 24 h-urinary albumin excretion, serum TNF-α and IL-8 levels and morphologic damage of placenta and kidney caused by LPS were all effectively alleviated by BML-111. LXA(4) also inhibited LPS-triggered apoptosis, activation of NF-κB, TNF-α and IL-8 mRNA and protein expression in TEV-1 cells. At the same time, BML-111 protected the cells from LPS-reduced proliferation. The current study demonstrated for the first time that LXA(4) could alleviate the symptoms of PE in endotoxin exposed rats. Copyright © 2012 Elsevier Inc. All rights reserved.

  9. 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.

  10. Low dose aspirin prevents duodenoesophageal reflux induced mucosal changes in wistar rat esophagus by MAP kinase mediated pathways.

    Science.gov (United States)

    Selvan, Ben; Ramachandran, Anup; Korula, Anu; Amirtharaj, G Jayakumar; Kettimuthu, Kavithapriya; Nair, Sheila; Nair, Aravindan; Samuel, Prasanna; Mathew, George

    2012-01-01

    aspirin group (p aspirin reduced the incidence of duodenoesophageal reflux induced histological changes in the esophagus by preventing activation of proliferative & anti-apoptotic MAP kinases such as p38 & ER as well as protease activity. Though Barretts' changes and adenocarcinoma have not developed, it could explain the role of duodenoesophageal reflux in the development of different histological but potential premalignant lesions and molecular level changes which are prevented by low dose aspirin. Copyright © 2011 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.

  11. 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.

  12. 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.

  13. Selenium and high dose vitamin E administration protects cisplatin-induced oxidative damage to renal, liver and lens tissues in rats.

    Science.gov (United States)

    Naziroglu, Mustafa; Karaoğlu, Aziz; Aksoy, Asude Orhan

    2004-02-15

    Cisplatin is one of the most active cytotoxic agents in the treatment of cancer but its clinical use is associated with nephrotoxicity. Several studies suggest that supplementation with antioxidant can influence cisplatin induced nephrotoxicity. In the present study, we investigated the effect of selenium with high dose vitamin E administration on lipid peroxidation (MDA) and scavenging enzyme activity in kidneys, liver and lens of cisplatin-induced toxicity in rats. Forty female Wistar rats were used. They were randomly divided into five groups. The first and second groups were used as control and cisplatin (6 mg/kg BW) intraperitoneally administrated groups. Groups III, IV and V received intraperitoneally five doses of selenium (1.5 mg/kg BW) and a high dose of vitamin E (1000 mg/kg BW) combination before, simultaneously and after with cisplatin, respectively. Glutathione peroxidase (GSH-Px), vitamin E and beta-carotene levels in the kidney, lens and liver, vitamin A and reduced glutathione (GSH) levels in the kidney were significantly (Pselenium and a high dose vitamin E injection. In conclusion, this data demonstrates that there is an increase in lipid peroxidation in the kidney, liver and lens of animals administered with cisplatin whereas there is a decrease in antioxidant vitamins and enzymes. However, intraperitoneally injected selenium combined with a high dose of vitamin E seem to produce a significant improvement on antioxidants concentrations in rats treated before, simultaneously and after with cisplatin. The selenium with high dose vitamin E injection may play a role in preventing cisplatin-induced nephropathy and cataract formation in cancer patient.

  14. 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

  15. 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

  16. Dose reduction assessment in dynamic CT myocardial perfusion imaging in a porcine balloon-induced-ischemia model

    Science.gov (United States)

    Fahmi, Rachid; Eck, Brendan L.; Vembar, Mani; Bezerra, Hiram G.; Wilson, David L.

    2014-03-01

    We investigated the use of an advanced hybrid iterative reconstruction (IR) technique (iDose4, Philips Health- care) for low dose dynamic myocardial CT perfusion (CTP) imaging. A porcine model was created to mimic coronary stenosis through partial occlusion of the left anterior descending (LAD) artery with a balloon catheter. The severity of LAD occlusion was adjusted with FFR measurements. Dynamic CT images were acquired at end-systole (45% R-R) using a multi-detector CT (MDCT) scanner. Various corrections were applied to the acquired scans to reduce motion and imaging artifacts. Absolute myocardial blood flow (MBF) was computed with a deconvolution-based approach using singular value decomposition (SVD). We compared a high and a low dose radiation protocol corresponding to two different tube-voltage/tube-current combinations (80kV p/100mAs and 120kV p/150mAs). The corresponding radiation doses for these protocols are 7.8mSv and 34.3mSV , respectively. The images were reconstructed using conventional FBP and three noise-reduction strengths of the IR method, iDose. Flow contrast-to-noise ratio, CNRf, as obtained from MBF maps, was used to quantitatively evaluate the effect of reconstruction on contrast between normal and ischemic myocardial tissue. Preliminary results showed that the use of iDose to reconstruct low dose images provide better or comparable CNRf to that of high dose images reconstructed with FBP, suggesting significant dose savings. CNRf was improved with the three used levels of iDose compared to FBP for both protocols. When using the entire 4D dynamic sequence for MBF computation, a 77% dose reduction was achieved, while considering only half the scans (i.e., every other heart cycle) allowed even further dose reduction while maintaining relatively higher CNRf.

  17. Mechanisms involved in the possible nephroprotective effect of rutin and low dose γ irradiation against cisplatin-induced nephropathy in rats.

    Science.gov (United States)

    Radwan, Rasha R; Abdel Fattah, Salma M

    2017-04-01

    Cisplatin has demonstrated high antitumor efficacy. However, nephrotoxicity is a dose-limiting factor in its clinical use. The present study was designed to investigate the protective effect of rutin and low dose of irradiation (LDR) on cisplatin-induced nephrotoxicity in rats. Rats received rutin (200mg/kg/day, p.o) for 10 consecutive days and subjected to LDR (0.5Gy) 1day prior to cisplatin. Intraperitoneal administration of single dose of cisplatin (7.5mg/kg) was used to induce nephrotoxicity. Data showed that cisplatin caused elevation in serum creatinine and urea, disturbance in blood count, elevation in gene expression of tumor necrosis factor alpha, nuclear factor kappa B, interleukin-1β, caspase-3, mitochondrial cytochrome C and apoptosis-inducing factor in renal tissue. Moreover, it caused elevation in renal malondialdehyde accompanied by reduction in glutathione content. These effects were confirmed by histopathological examination. It was observed that LDR and rutin ameliorated the studied parameters. In conclusion, LDR could be considered as a novel approach for prophylaxis of cisplatin induced renal damage, also it augmented the nephroprotective effect of rutin via modulating the expression of inflammatory, oxidative stress and apoptotic mediators as well as histological changes in rats kidneys and hence might be valuable in improving the therapeutic index of cisplatin. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Dose-dependent misrejoining of radiation-induced DNA double-strand breaks in human fibroblasts: Experimental and theoretical study for high and low LET radiation

    Energy Technology Data Exchange (ETDEWEB)

    Rydberg, Bjorn; Cooper, Brian; Cooper, Priscilla K.; Holley, William; Chatterjee, Aloke

    2004-11-18

    Misrejoining of DNA double-strand breaks (DSBs) was measured in human primary fibroblasts after exposure to X-rays and high LET particles (He, N and Fe) in the dose range 10-80 Gy. To measure joining of wrong DNA ends, the integrity of a 3.2 Mbp restriction fragment was analyzed directly after exposure and after 16 hr of repair incubation. It was found that the misrejoining frequency for X-rays was non-linearly related to dose, with less probability of misrejoining at low doses than at high doses. The dose dependence for the high LET particles, on the other hand, was closer to being linear, with misrejoining frequencies higher than for X-rays particularly at the lower doses. These experimental results were simulated with a Monte-Carlo approach that includes a cell nucleus model with all 46 chromosomes present, combined with realistic track structure simulations to calculate the geometrical positions of all DSBs induced for each dose. The model assumes that the main determinant for misrejoining probability is the distance between two simultaneously present DSBs. With a Gaussian interaction probability function with distance, it was found that both the low and high LET data could be fitted with an interaction distance (sigma of the Gaussian curve) of 0.25 {micro}m. This is half the distance previously found to best fit chromosomal aberration data in human lymphocytes using the same methods (Holley et al. Radiat. Res . 158, 568-580 (2002)). The discrepancy may indicate inadequacies in the chromosome model, for example insufficient chromosomal overlap, but may also partly be due to differences between fibroblasts and lymphocytes. Although the experimental data was obtained at high doses, the Monte Carlo calculations could be extended to lower doses. It was found that a linear component of misrejoining versus dose dominated for doses below 1 Gy for all radiations, including X-rays. The calculated relative biological efficiency (RBE) for misrejoining at this low dose

  19. High-dose methylprednisolone treatment of laser-induced retinal injury exacerbates acute inflammation and long-term scarring

    Science.gov (United States)

    Schuschereba, Steven T.; Cross, Michael E.; Scales, David K.; Pizarro, Jose M.; Edsall, Peter R.; Stuck, Bruce E.; Marshall, John

    1999-06-01

    Purpose. To evaluate therapeutics for attenuating retinal laser injury. Methods. New Zealand Red rabbits (n=76) were pretreated (IV) with either a single dose of hydroxyethyl starch conjugated deferoxamine (HES-DFO, n=29) (6.1 ml/kg, 16.4 mg/ml) or methylprednisolone sodium succinate (MP, n=22) (30 mg/kg, followed by taper of 30, 20, 20, and 10 mg/kg/day for a total of 5d). Controls were untreated (n=25). Fifteen min later, animals were irradiated with a multiline cw argon laser (285 mW, 10 msec pulse durations, 16 lesions/eye). Funduscopy, fluorescein angiography, histology, and morphometry were performed at 10 min, 1h, 3h, 24h, 1 mo, and 6 mo after irradiation. Leukocytes were counted at lesion centers for retinal and choroidal compartments at 1, 3, and 24h. Results. At 3h, percent area incrase for the lesions was highest for MP (44%) and lowest for HES-DFO (16%)(p<0.05). In hemorrhagic lesions, MP treatment resulted in the highest increase of retinal neotrophils by 24h (p<0.05), and by 1 and 6 mo extensive chorio-retinal scarring occurred in nonhemorrhagic and hemorrhagic lesions. Also, no benefit was demonstrated on sparing of photoreceptors with MP treatment. Conclusions. Treatment of laser-induced retinal injury with methylprednisolone (MP) exacerbates acute inflammation and long-term chorio-retinal scarring; however, hydroxyethyl starch conjugated deferoxamine therapy ameliorates these aspects of injury. Data suggest caution in the use of MP therapy for laser injuries.

  20. Chromosomal damage to human lymphocytes induced by hyperthermia pre and post extremely low dose neutron or gamma radiation

    Directory of Open Access Journals (Sweden)

    Daryoush Fatehi

    2010-04-01

    Full Text Available BackgroundOne of the most important problems in radiotherapy(RT with χ and γ-rays is hypoxic cells, in the centre ofsolids tumours. Due to insufficient blood perfusion,these cells are more resistant to RT. The purpose ofthe study is to assess the effect of heating cells onchromosomal damages induced by an extremely lowdose of neutron or γ irradiation, in humanlymphocytes.MethodHuman blood samples were exposed to hyperthermia(HT, 6 cGy neutron (or γ-rays, HT+neutron/γ, andneutron/γ+HT. HT was applied at 41.5°C for 30 and60min as well as 43°C for 15 and 30min. The timeinterval between the two treatments was 1hr. Aftercell culture, harvesting, fixation, and staining, thechromosomal damages were scored in metaphasestage and statistical analyses were performed.ResultsIn comparison to the control groups, HT alone at41.5°C (neither for 30 nor 60min did not inducesignificantly higher chromosomal damages (p=0.8;however, the number of damages was significantlyhigher at 43°C for 30min (p<0.05. Furthermore,compared to the control groups the chromosomaldamages was significantly different when cellsirradiated with neutron/γ-rays (p<0.05. Comparisonbetween applying HT 1hr before and after irradiation,HT after neutron/γ irradiation significantly inducedhigher chromosome damages (p<0.05. Comparingneutron and γ irradiation, the number of chromosomaldamages was remarkably higher when cells irradiatedwith neutron (p<0.01.ConclusionSince applying an extremely low dose of neutron plusHT caused more chromosomal damages, incomparison to neutron/γ alone, or HT plus neutron/γ;and because cell death is directly related to thechromosomal damage; thus, this combined regimemight be considered as a treatment modality in cancertreatment.

  1. Anti-diabetic effect of camel milk in alloxan-induced diabetic dogs: a dose-response experiment.

    Science.gov (United States)

    Sboui, A; Khorchani, T; Djegham, M; Agrebi, A; Elhatmi, H; Belhadj, O

    2010-08-01

    This study was conducted to evaluate the effect of camel milk in alloxan-induced diabetic dogs and to follow this effect at three doses of milk. Firstly, three groups of dogs were used: two groups composed each of four diabetic dogs and receiving raw camel milk (treatment 1) or cow milk (treatment 2), and four healthy dogs getting raw camel milk (treatment 3) were used as control. Each animal was treated with 500 ml of milk daily. Secondly, we compared the effects of three amounts of camel milk: 100 ml, 250 ml and 500 ml to treat the diabetic dogs. After week 3, the dogs treated with camel milk showed a statistically significant decrease in blood glucose (from 10.88 +/- 0.55 to 6.22 +/- 0.5 mmol/l) and total protein concentrations (from 78.16 +/- 2.61 g/l to 63.63 +/- 4.43 g/l). For cholesterol levels, there was a decrease from week 2 (from 6.17 +/- 0.5 mmol/l to 4.79 +/- 0.5 mmol/l). There were no significant difference in blood glucose, cholesterol or total protein concentrations in dogs drinking 250 and 500 ml of camel milk. The dogs treated with 100 ml of camel milk did not show any significant decrease in blood glucose levels, and cholesterol and total protein concentrations. The investigation was not limited to the improvement in glycemic balance, lipids and proteins control in diabetic dogs getting camel milk, but we also noted a stability of this state after the dogs stopped to drink milk. This effect depended on the quantity of camel milk used to treat diabetic dogs.

  2. The effects of methamphetamine self-administration on cortical monoaminergic deficits induced by subsequent high-dose methamphetamine administrations.

    Science.gov (United States)

    McFadden, Lisa M; Hanson, Glen R; Fleckenstein, Annette E

    2013-12-01

    Preclinical models suggest that repeated high-dose methamphetamine (METH) exposures, administered in a "binge-like" pattern, acutely decrease norepinephrine (NE), and acutely and persistently decrease serotonin (5-hydroxytryptamine; 5HT) content in the frontal cortex. However, the impact of METH self-administration on this region is unknown. Because of the importance of the monoaminergic neurons in the frontal cortex to a variety of cognitive and addictive processes, effects of METH self-administration on cortical NE and 5HT content were assessed. Results revealed several novel findings. First, METH self-administration decreased cortical NE content as assessed 24 h after last exposure. Consistent with previous preclinical reports after a binge METH regimen, this decrease was reversed 8 days after the final METH exposure. Second, and in contrast to our previous reports involving the hippocampus or striatum, METH self-administration caused persistent decreases in 5HT content as assessed 8 days after the final METH exposure. Of note, the magnitude of this decrease (≈ 20%) was less than that observed typically after a binge METH treatment. Third, prior METH self-administration attenuated METH-induced serotonergic deficits as assessed 7 days, but not 1 h, following a neurotoxic METH regimen. No protection was observed when the binge exposure occurred 15 days after the last self-administration session. Taken together, these data demonstrate important and selective alterations in cortical serotonergic neuronal function subsequent to METH self-administration. These data provide a foundation to investigate complex questions involving "resistance" to the persistent deficits caused by neurotoxic METH exposure and frontal cortical function. Copyright © 2013 Wiley Periodicals, Inc.

  3. 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

    2016-11-01

    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.

  4. Corticosterone protects against memory impairments and reduced hippocampal BDNF levels induced by a chronic low dose of ethanol in C57BL/6J mice.

    Science.gov (United States)

    Ebada, Mohamed Elsaed; Latif, Liaque M; Kendall, David A; Pardon, Marie Christine

    2014-01-01

    Acute low doses of ethanol can produce reversible memory deficits, but it is unknown whether they persist upon chronic use. We investigated whether the chronic intake of a low dose of ethanol induces memory impairments in the ethanol-preferring C57BL/6J mouse strain. Because stress precipitates alcohol abuse and the stress hormone corticosterone contributes to memory processes, ethanol consumption and toxic effects, we also determined the impact of co-treatment with corticosterone on these effects. BDNF contributes to memory function and toxic effects of ethanol, therefore its levels were quantified in the hippocampus and frontal cortex. Ethanol (1% in drinking water) and corticosterone (250 μg/mL) were administered using the two-bottle choice test to monitor their appetitive properties. Spatial and non-spatial memory performance was assessed using the spontaneous alternation, object recognition and object location tests. The chronic exposure to a low dose of ethanol caused spatial and non-spatial memory deficits after withdrawal associated with a reduction in hippocampal BDNF levels, which were prevented by co-treatment with corticosterone (~21 mg/kg/day). The protective effect of corticosterone on memory was no longer observed at higher doses (~41 mg/kg/day), but persisted for hippocampal BDNF levels. C57BL/6J mice did not develop an appetence for 1% ethanol, but the addition of corticosterone increased voluntary consumption of and preference for the ethanol+corticosterone solutions. Although acute low doses of corticosterone (1 mg/kg) were found to rescue established memory impairments, this is the first report of a protective effect of chronic doses of corticosterone in the range of 20-32 mg/kg, and particularly against memory deficits induced by alcohol.

  5. In growing pigs, chlortetracycline induces a reversible green bone discoloration and a persistent increase of bone mineral density dependent of dosing regimen.

    Science.gov (United States)

    Guillot, Martin; Alexander, Kate; Pomar, Candido; Del Castillo, Jérôme R E

    2011-06-01

    We studied in growing pigs the effects of exposure to dietary chlortetracycline on bone mineral density (BMD) and bone color. Pigs were randomly allocated to a drug-free diet (n=48) or a diet fortified with 800 ppm of chlortetracycline, starting either at 28- or 84-d of age, and for either a 28- or 56-d duration (n=16 pigs/group). The lumbar vertebral discoloration and BMD of randomly chosen pigs were evaluated at 28-d intervals up to 168-d of age. The odds of bone discoloration increased with dosing duration and age at treatment onset, and decreased with the withdrawal time and age at treatment onset interaction (p induced bone discoloration is reversible, and may be prevented with proper dosing regimen design. Moreover, TC induces a persistent increase on BMD that could be detected with quantitative computed tomography. Copyright © 2010. Published by Elsevier India Pvt Ltd.

  6. Dietary exposure to continuous small doses of α-cypermethrin in the presence or absence of dietary curcumin does not induce oxidative stress in male Wistar rats

    Directory of Open Access Journals (Sweden)

    Surat Hongsibsong

    2014-01-01

    Full Text Available α-Cypermethrin is a widely used insecticide and, at high doses, induces oxidative stress in mammals. Curcumin is an antioxidant phytochemical commonly used for food coloring and flavoring. We aimed to investigate the effects of continuous dietary exposure to low doses of α-cypermethrin, as is the case in exposed humans, on oxidative stress and its potential prevention by dietary curcumin. Four groups of ten male Wistar rats were ad libitum-fed a control diet or identical diets fortified with α-cypermethrin (350 mg/kg diet, curcumin (1000 mg/kg diet, or α-cypermethrin and curcumin (350 and 1000 mg/kg diet, respectively for 7 weeks. α-Cypermethrin accumulated in adipose tissues and was detectable in kidney, liver, and brains. Dietary α-cypermethrin did not alter concentrations of malondialdehyde, ascorbic and uric acid, retinol, liver damage markers, or the activities of CAT and SOD, but reduced vitamin E in blood. α-Cypermethrin did not affect malondialdehyde or reduced glutathione concentrations in any of the tissues, but significantly increased glutathione disulfide in kidney and subcutaneous adipose tissue. In conclusion, dietary exposure to small doses of α-cypermethrin did not induce oxidative stress in rats and may be less toxic than exposure to comparable quantities administered as single high doses by gastric intubation.

  7. Oral low-dose testosterone administration induces whole-body protein anabolism in postmenopausal women: a novel liver-targeted therapy.

    Science.gov (United States)

    Birzniece, Vita; Umpleby, Margot A; Poljak, Anne; Handelsman, David J; Ho, Ken K Y

    2013-09-01

    In hypopituitary men, oral delivery of unesterified testosterone in doses that result in a solely hepatic androgen effect enhances protein anabolism during GH treatment. In this study, we aimed to determine whether liver-targeted androgen supplementation induces protein anabolism in GH-replete normal women. Eight healthy postmenopausal women received 2-week treatment with oral testosterone at a dose of 40 mg/day (crystalline testosterone USP). This dose increases portal concentrations of testosterone, exerting androgenic effects on the liver without a spillover into the systemic circulation. The outcome measures were whole-body leucine turnover, from which leucine rate of appearance (LRa, an index of protein breakdown) and leucine oxidation (Lox, a measure of irreversible protein loss) were estimated, energy expenditure and substrate utilization. We measured the concentration of liver transaminases as well as of testosterone, SHBG and IGF1. Testosterone treatment significantly reduced LRa by 7.1 ± 2.5% and Lox by 14.6 ± 4.5% (Panabolism by reducing protein breakdown and oxidation without inducing systemic androgen excess in women. We conclude that a small oral dose of unesterified testosterone holds promise as a simple novel treatment of protein catabolism and muscle wasting.

  8. 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

  9. Membrane Signaling Induced by High Doses of Ionizing Radiation in the Endothelial Compartment. Relevance in Radiation Toxicity

    Directory of Open Access Journals (Sweden)

    Isabelle Corre

    2013-11-01

    Full Text Available Tumor areas can now be very precisely delimited thanks to technical progress in imaging and ballistics. This has also led to the development of novel radiotherapy protocols, delivering higher doses of ionizing radiation directly to cancer cells. Despite this, radiation toxicity in healthy tissue remains a major issue, particularly with dose-escalation in these new protocols. Acute and late tissue damage following irradiation have both been linked to the endothelium irrigating normal tissues. The molecular mechanisms involved in the endothelial response to high doses of radiation are associated with signaling from the plasma membrane, mainly via the acid sphingomyelinase/ceramide pathway. This review describes this signaling pathway and discusses the relevance of targeting endothelial signaling to protect healthy tissues from the deleterious effects of high doses of radiation.

  10. Low-dose perinatal exposure to di(2-ethylhexyl) phthalate induces anti-androgenic effects in male rats

    DEFF Research Database (Denmark)

    Christiansen, Sofie; Boberg, Julie; Petersen, Marta Axelstad

    2010-01-01

    A and B from a study, in which time-mated Wistar rats were gavaged from gestation day 7 to postnatal day 16 with 0, 10, 30, 100, 300, 600 and 900 mg/kg bw/day and 0, 3, 10, 30 and 100 mg/kg/day, respectively. The dose levels were selected with the aim of covering the whole dose-response curve...

  11. 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.

  12. Subclinical Doses of ATP-Sensitive Potassium Channel Modulators Prevent Alterations in Memory and Synaptic Plasticity Induced by Amyloid-β.

    Science.gov (United States)

    Salgado-Puga, Karla; Rodríguez-Colorado, Javier; Prado-Alcalá, Roberto A; Peña-Ortega, Fernando

    2017-01-01

    In addition to coupling cell metabolism and excitability, ATP-sensitive potassium channels (KATP) are involved in neural function and plasticity. Moreover, alterations in KATP activity and expression have been observed in Alzheimer's disease (AD) and during amyloid-β (Aβ)-induced pathology. Thus, we tested whether KATP modulators can influence Aβ-induced deleterious effects on memory, hippocampal network function, and plasticity. We found that treating animals with subclinical doses (those that did not change glycemia) of a KATP blocker (Tolbutamide) or a KATP opener (Diazoxide) differentially restrained Aβ-induced memory deficit, hippocampal network activity inhibition, and long-term synaptic plasticity unbalance (i.e., inhibition of LTP and promotion of LTD). We found that the protective effect of Tolbutamide against Aβ-induced memory deficit was strong and correlated with the reestablishment of synaptic plasticity balance, whereas Diazoxide treatment produced a mild protection against Aβ-induced memory deficit, which was not related to a complete reestablishment of synaptic plasticity balance. Interestingly, treatment with both KATP modulators renders the hippocampus resistant to Aβ-induced inhibition of hippocampal network activity. These findings indicate that KATP are involved in Aβ-induced pathology and they heighten the potential role of KATP modulation as a plausible therapeutic strategy against AD.

  13. [Comparative activity of antihistamines on area under dose-response curve from histamine-induced wheal and flare responses in human skin].

    Science.gov (United States)

    Wang, Rui-Qi; Zhang, Hong-Yu

    2004-12-01

    To compare the activity of antihistamines by the index of area under dose-response curve (AUDRC) obtained from histamine-induced wheal and flare reactions. Mizolastine 10 mg, loratadine 10 mg, and placebo were given to 90 healthy volunteers and 60 allergic patients in a double-blind and randomized manner. Histamine titration tests (histamine concentrations 54.3, 20.0, 7.3, and 2.7 mmol/L) were performed for each one before dosing and 2, 4, and 24 hours after dosing. The reactivity was evaluated by histamine-induced wheal and flare areas. The AUDRC values of the wheal and flare areas as a function of the natural logarithm transformed histamine concentration were calculated for each subject, and compared. There was no significant difference of the wheal and flare areas between health volunteers and allergic patients. The AUDRC(27-54.3 mmol/l.) for wheal and flare of mizolastine was 115.7, 23.4, 7.7, 49.8 and 902.1, 40.9, 2.6, 46.9 ln (mmol/L) x mm2 at each time (before dosing and 2, 4, 24 hours after dosing) respectively. Compared with loratadine [116.2, 80.2, 49.7, 71.9 and 957.6, 495.3, 153.5, 205.9 ln (mmol/L) x mm2], mizolastine decreased AUDRC(2.7 - 54.3 mmol/L significantly (P wheal and flare inhibition test is a reliable pharmacodynamic model for antihistamines, and AUDRC may be an useful index to predict antihistamines pharmacodynamic activity.

  14. 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.

  15. 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.

  16. Modulatory effect of Pleurotus ostreatus on oxidant/antioxidant status in 7, 12-dimethylbenz (a) anthracene induced mammary carcinoma in experimental rats--A dose-response study.

    Science.gov (United States)

    Krishnamoorthy, Deepalakshmi; Sankaran, Mirunalini

    2016-01-01

    Worldwide, breast cancer is the second most prevalent cancer among women and its incidence is increasing alarmingly. To determine a dose-response effect of Pleurotus ostreatus on oxidant/antioxidant status in 7,12-dimethylbenz. (a) antheracene induced. (DMBA) mammary carcinoma in experimental rats. Cancer bearing female Sprague Dawley rats were orally treated with Pleurotus ostreatus ethanolic extract (POEet) (150, 300 and 600 mg/kg body weight) for 16 weeks. By means of high performance liquid chromatography (HPLC) analysis, ergosterol (48.82%) were identified and quantified in POEet. Body weight of experimental rats in each groups and the biochemical parameters of plasma, liver and mammary tissues were carried out. Histopathological analyses were also determined. Results were analyzed using SPSS software package, version 16.0. The values were analyzed by one way analysis of variance (ANOVA) followed by Duncan's multiple range test (DMRT). The result showed that depleted activities of enzymatic and non-enzymatic antioxidant level and significant elevated TBARS level were observed in DMBA group of plasma, mammary and liver tissues of experimental rats. The effects were dose.dependent and the above noted parameters were renovated to near normal after supplementation with different dose of POEet (150 mg, 300 mg and 600 mg/kg bwt). The data obtained from the study indicate that POEet at a dose of 600 mg/kg bwt possesses optimum anticancer effects against DMBA induced mammary carcinogenesis. Based on the scientific appraisal, we conclude that the POEet is having a potent antioxidant capacity; thereby it offers maximum protection against DMBA-induced mammary carcinogenesis.

  17. Parathyroid hormone linked to a collagen binding domain promotes hair growth in a mouse model of chemotherapy-induced alopecia in a dose-dependent manner.

    Science.gov (United States)

    Katikaneni, Ranjitha; Ponnapakkam, Tulasi; Seymour, Andrew; Sakon, Joshua; Gensure, Robert

    2014-08-01

    Chemotherapy-induced alopecia is a major source of psychological stress in patients undergoing cancer chemotherapy, and it can influence treatment decisions. Although there is currently no therapy for alopecia, a fusion protein of parathyroid hormone and collagen binding domain (PTH-CBD) has shown promise in animal models. The aim of this study was to determine whether there are dose-dependent effects of PTH-CBD on chemotherapy-induced alopecia in a mouse model. C57BL/6J mice were waxed to synchronize hair follicles; treated on day 7 with vehicle or PTH-CBD (100, 320, and 1000 mcg/kg subcutaneous injection); and treated on day 9 with vehicle or cyclophosphamide (150 mg/kg intraperitoneally). Mice were photographed every 3-4 days and killed on day 63 for histological analysis. Photographs were quantified by gray scale analysis to assess hair content. Mice not receiving chemotherapy showed regrowth of hair 2 weeks after waxing and normal histology after 2 months. Mice receiving chemotherapy alone showed marked hair loss after chemotherapy, which was sustained for 10 days and was followed by rapid regrowth of a normal coat. Histological analysis revealed rapid cycling dystrophic anagen/catagen follicles. Animals receiving chemotherapy and PTH-CBD showed decreased hair loss and more rapid regrowth of hair than that seen with chemotherapy alone (increased hair growth by gray scale analysis, Phair follicles in animals receiving the highest dose of PTH-CBD were in a quiescent phase, similar to that in mice that did not receive chemotherapy. Single-dose subcutaneous administration of PTH-CBD showed dose-dependent effects in minimizing hair loss and speeding up recovery from chemotherapy-induced alopecia.

  18. Dose-responsiveness and persistence of microRNA expression alterations induced by cigarette smoke in mouse lung

    Energy Technology Data Exchange (ETDEWEB)

    Izzotti, Alberto; Larghero, Patrizia; Longobardi, Mariagrazia; Cartiglia, Cristina; Camoirano, Anna [Department of Health Sciences, University of Genoa, Genoa (Italy); Steele, Vernon E. [National Cancer Institute (NCI), Rockville, MD (United States); De Flora, Silvio, E-mail: sdf@unige.it [Department of Health Sciences, University of Genoa, Genoa (Italy)

    2011-12-01

    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{sup 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 Prime -deoxyguanosine (8-oxodGuo) were measured by {sup 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.

  19. TH-E-BRF-03: A Multivariate Interaction Model for Assessment of Hippocampal Vascular Dose-Response and Early Prediction of Radiation-Induced Neurocognitive Dysfunction

    Energy Technology Data Exchange (ETDEWEB)

    Farjam, R; Pramanik, P; Srinivasan, A; Chapman, C; Tsien, C; Lawrence, T; Cao, Y [University of Michigan, Ann Arbor, MI (United States)

    2014-06-15

    Purpose: Vascular injury could be a cause of hippocampal dysfunction leading to late neurocognitive decline in patients receiving brain radiotherapy (RT). Hence, our aim was to develop a multivariate interaction model for characterization of hippocampal vascular dose-response and early prediction of radiation-induced late neurocognitive impairments. Methods: 27 patients (17 males and 10 females, age 31–80 years) were enrolled in an IRB-approved prospective longitudinal study. All patients were diagnosed with a low-grade glioma or benign tumor and treated by 3-D conformal or intensity-modulated RT with a median dose of 54 Gy (50.4–59.4 Gy in 1.8− Gy fractions). Six DCE-MRI scans were performed from pre-RT to 18 months post-RT. DCE data were fitted to the modified Toft model to obtain the transfer constant of gadolinium influx from the intravascular space into the extravascular extracellular space, Ktrans, and the fraction of blood plasma volume, Vp. The hippocampus vascular property alterations after starting RT were characterized by changes in the hippocampal mean values of, μh(Ktrans)τ and μh(Vp)τ. The dose-response, Δμh(Ktrans/Vp)pre->τ, was modeled using a multivariate linear regression considering integrations of doses with age, sex, hippocampal laterality and presence of tumor/edema near a hippocampus. Finally, the early vascular dose-response in hippocampus was correlated with neurocognitive decline 6 and 18 months post-RT. Results: The μh(Ktrans) increased significantly from pre-RT to 1 month post-RT (p<0.0004). The multivariate model showed that the dose effect on Δμh(Ktrans)pre->1M post-RT was interacted with sex (p<0.0007) and age (p<0.00004), with the dose-response more pronounced in older females. Also, the vascular dose-response in the left hippocampus of females was significantly correlated with memory function decline at 6 (r = − 0.95, p<0.0006) and 18 (r = −0.88, p<0.02) months post-RT. Conclusion: The hippocampal vascular

  20. Comparative study of dose-response curve for chromosome aberrations induced in human lymphocytes by {sup 60}Co and X-Rays

    Energy Technology Data Exchange (ETDEWEB)

    Mendes, Mariana E.; Mendonça, Julyanne C.G.; Andrade, Aida M.G.; Silva, Laís M.; Hwang, Suy; Melo, Ana M.M.A.; Santos, Neide; Lima, Fabiana F., E-mail: mendes_sb@hotmail.com [Centro Regional de Ciencias Nucleares (CRCN-NE/CNEN-PE), Recife, PE (Brazil); Universidade Federal de Pernambuco (UFPE), Recife, PE (Brazil)

    2017-11-01

    Biodosimetry represents a biological marker to the estimation of health risks after accidental overexposure to ionizing radiation. Chromosomal dicentric in peripheral blood lymphocytes have been the most reliable biomarker of exposure to IR during the last several decades. This technique could be used to support physical dosimetry or when it is impossible to achieve it. A reliable measurement of the absorbed dose is critical for medical decision, including the assessment of long-term health consequences. The aim of this research is to compare dose-response curves for dicentric aberration induced in human lymphocytes by {sup 60}Co and X-Rays. For both quality of radiation, the samples were exposed to at least eight different absorbed doses. The X-rays with dose rate of 0,275 Gy/min at Laboratory of Metrology (CRCN/NE - PE - Brazil) and the second one was exposed to cobalt source with dose rate of 0.055 Gy/min ({sup 60}Co Gammacell 220) located at Department of Nuclear Energy (UFPE-DEN-BRASIL). Mitotic metaphase cells were obtained by lymphocyte culture for chromosomal analysis and slides were stained with Giemsa 5%. The frequencies of dicentrics were counted in more than 18.000 metaphases for this comparison. After that, all frequencies and distributions of dicentrics were tested to analyze their conformity with Poisson distribution and then each quality of radiation were used for build the calibration curves using Dose Estimate program. These results showed that both curves followed the Poisson distribution and coefficients of each one are: YX-rays = 0,0013 (± 0,0006) + 0,0271 (± 0,0086)⁎D + 0,0556(±0,0050))⁎D{sup 2} and Y{sub Co-60} = 0,0014 (± 0,0010) + 0,0081 (± 0,0073))⁎D + 0,0451 (± 0,0046))⁎D{sup 2} (Y = frequency of dicentrics and D = absorbed dose). It was expected that there was no significant difference between this two types of radiation because both were low LET. We believed that dose rate have been a principal factor to produce this

  1. Carcinogenesis induced by UVA (365-nm) radiation: the dose-time dependence of tumor formation in hairless mice.

    Science.gov (United States)

    de Laat, A; van der Leun, J C; de Gruijl, F R

    1997-05-01

    Although ultraviolet B (UVB wavelengths 280-315 nm) dominates the carcinogenic effect of sunlight, ultraviolet A (UVA 315-400 nm) is estimated to contribute 10-20% to the carcinogenic dose; a substantial background that is not affected by a depletion of the ozone layer. Furthermore, certain high-power modern tanning lamps emit mainly long wave UVA (UVA1; 340-400 nm). For a proper risk estimate of UVA exposure its carcinogenicity relative to that of UVB exposure needs to be determined more accurately. To this end we determined the dose-time relationship for skin tumor induction in hairless mice that were irradiated daily with custom-made Philips 365-nm sources. Irradiation of the group exposed to the highest of the four daily doses (430, 240, 140 and 75 kJ/m2) had to be discontinued because severe scratching set in after 3 months (no tumors). In the lower dose-groups the prevalence curves for skin carcinomas (percentage of tumor-bearing mice versus logarithm of time) ran virtually parallel, and were similar to those found with daily UVB exposure. However, the relationship between the daily dose (D) and the median tumor induction time (t50) appeared to differ: with UVB we found that t50 D(r) = constant, with r = 0.6, whereas with UVA1 we found r approximately 0.4. This would imply that 365-nm carcinogenesis shows less of a dose-dependency than UVB carcinogenesis, and that 365-nm radiation becomes more carcinogenic, relative to UVB, as the daily doses are lowered. This relative shift at low doses complicates extrapolation of UVB to UVA risks in humans. Based on the t50 from the lowest dose-group we found that the carcinogenicity at 365 nm (per J/m2) is 0.9 x 10(-4) times that at 293 nm, the wavelength of maximum carcinogenicity in hairless mice. This result for 365-nm carcinogenicity falls well within the margins of error of the wavelength dependency that was estimated earlier from experiments with broadband UV sources.

  2. Evaluation of 2 nomogram-based strategies for dosing argatroban in patients with known or suspected heparin-induced thrombocytopenia.

    Science.gov (United States)

    Arpino, Paul A; Goeller, Adrienne J; Fatalo, Anthony; Van Cott, Elizabeth M

    2015-04-01

    No study has compared 2 different dosing strategies for argatroban titration nor has any published nomogram demonstrated improvement in outcomes. This study was conducted to evaluate the effectiveness of 2 argatroban nomograms on reaching therapeutic anticoagulation. Patients treated with argatroban were separated into 2 sliding scale groups, percentage adjustments (PAs) and predefined dose increments (PDIs). The primary outcome was the time to reach a therapeutic activated partial thromboplastin time (aPTT). The average initial dose and dose to achieve a therapeutic aPTT were similar between the groups. There was also no difference in the number of dose changes. The time to reach a therapeutic aPTT was 2 hours shorter in the PDI compared to the PA group, 8 ± 4 hours versus 10 ± 4 hours, P = .015. This study demonstrates a significant time advantage associated with a PDI nomogram compared to a PA nomogram but no difference with respect to the number of rate changes. © The Author(s) 2013.

  3. Dose dependent activation of retinoic acid-inducible gene-I promotes both proliferation and apoptosis signals in human head and neck squamous cell carcinoma.

    Directory of Open Access Journals (Sweden)

    Jingzhou Hu

    Full Text Available The retinoic-acid-inducible gene (RIG-like receptor (RLR family proteins are major pathogen reorganization receptors (PRR responsible for detection of viral RNA, which initiates antiviral response. Here, we evaluated the functional role of one RLR family member, RIG-I, in human head and neck squamous cell carcinoma (HNSCC. RIG-I is abundantly expressed both in poorly-differentiated primary cancer and lymph node metastasis, but not in normal adjacent tissues. Activation of RIG-I by transfection with low dose of 5'-triphosphate RNA (3p-RNA induces low levels of interferon and proinflammatory cytokines and promotes NF-κB- and Akt-dependent cell proliferation, migration and invasion. In contrast, activation of RIG-I by a high dose of 3p-RNA induces robust mitochondria-derived apoptosis accompanied by decreased activation of Akt, which is independent of the interferon and TNFα receptor, but can be rescued by over-expression of constitutively active Akt. Furthermore, co-immunoprecipitation experiments indicate that the CARD domain of RIG-I is essential for inducing apoptosis by interacting with caspase-9. Together, our results reveal a dual role of RIG-I in HNSCC through regulating activation of Akt, in which RIG-I activation by low-dose viral dsRNA increases host cell survival, whereas higher level of RIG-I activation leads to apoptosis. These findings highlight the therapeutic potential of dsRNA mediated RIG-I activation in the treatment of HNSCC.

  4. A single-dose cytomegalovirus-based vaccine encoding tetanus toxin fragment C induces sustained levels of protective tetanus toxin antibodies in mice.

    Science.gov (United States)

    Tierney, Rob; Nakai, Toru; Parkins, Christopher J; Caposio, Patrizia; Fairweather, Neil F; Sesardic, Dorothea; Jarvis, Michael A

    2012-04-26

    The current commercially available vaccine used to prevent tetanus disease following infection with the anaerobic bacterium Clostridium tetani is safe and effective. However, tetanus remains a major source of mortality in developing countries. In 2008, neonatal tetanus was estimated to have caused >59,000 deaths, accounting for 1% of worldwide infant mortality, primarily in poorer nations. The cost of multiple vaccine doses administered by injection necessary to achieve protective levels of anti-tetanus toxoid antibodies is the primary reason for low vaccine coverage. Herein, we show that a novel vaccine strategy using a cytomegalovirus (CMV)-based vaccine platform induces protective levels of anti-tetanus antibodies that are durable (lasting >13 months) in mice following only a single dose. This study demonstrates the ability of a 'single-dose' CMV-based vaccine strategy to induce durable protection, and supports the potential for a tetanus vaccine based on CMV to impact the incidence of tetanus in developing countries. Copyright © 2012 Elsevier Ltd. All rights reserved.

  5. The potential benefits of nicaraven to protect against radiation-induced injury in hematopoietic stem/progenitor cells with relative low dose exposures.

    Science.gov (United States)

    Ali, Haytham; Galal, Omima; Urata, Yoshishige; Goto, Shinji; Guo, Chang-Ying; Luo, Lan; Abdelrahim, Eman; Ono, Yusuke; Mostafa, Emtethal; Li, Tao-Sheng

    2014-09-26

    Nicaraven, a hydroxyl radical-specific scavenger has been demonstrated to attenuate radiation injury in hematopoietic stem cells with 5Gy γ-ray exposures. We explored the effect and related mechanisms of nicaraven for protecting radiation injury induced by sequential exposures to a relatively lower dose γ-ray. C57BL/6 mice were given nicaraven or placebo within 30min before exposure to 50mGy γ-ray daily for 30days in sequences (cumulative dose of 1.5Gy). Mice were victimized 24h after the last radiation exposure, and the number, function and oxidative stress of hematopoietic stem cells were quantitatively estimated. We also compared the gene expression in these purified stem cells from mice received nicaraven and placebo treatment. Nicaraven increased the number of c-kit(+) stem/progenitor cells in bone marrow and peripheral blood, with a recovery rate around 60-90% of age-matched non-irradiated healthy mice. The potency of colony forming from hematopoietic stem/progenitor cells as indicator of function was completely protected with nicaraven treatment. Furthermore, nicaraven treatment changed the expression of many genes associated to DNA repair, inflammatory response, and immunomodulation in c-kit(+) stem/progenitor cells. Nicaraven effectively protected against damages of hematopoietic stem/progenitor cells induced by sequential exposures to a relatively low dose radiation, via complex mechanisms. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Low doses of gamma-irradiation induce an early bystander effect in zebrafish cells which is sufficient to radioprotect cells.

    Science.gov (United States)

    Pereira, Sandrine; Malard, Véronique; Ravanat, Jean-Luc; Davin, Anne-Hélène; Armengaud, Jean; Foray, Nicolas; Adam-Guillermin, Christelle

    2014-01-01

    The term "bystander effect" is used to describe an effect in which cells that have not been exposed to radiation are affected by irradiated cells though various intracellular signaling mechanisms. In this study we analyzed the kinetics and mechanisms of bystander effect and radioadaptation in embryonic zebrafish cells (ZF4) exposed to chronic low dose of gamma rays. ZF4 cells were irradiated for 4 hours with total doses of gamma irradiation ranging from 0.01-0.1 Gy. In two experimental conditions, the transfer of irradiated cells or culture medium from irradiated cells results in the occurrence of DNA double strand breaks in non-irradiated cells (assessed by the number of γ-H2AX foci) that are repaired at 24 hours post-irradiation whatever the dose. At low total irradiation doses the bystander effect observed does not affect DNA repair mechanisms in targeted and bystander cells. An increase in global methylation of ZF4 cells was observed in irradiated cells and bystander cells compared to control cells. We observed that pre-irradiated cells which are then irradiated for a second time with the same doses contained significantly less γ-H2AX foci than in 24 h gamma-irradiated control cells. We also showed that bystander cells that have been in contact with the pre-irradiated cells and then irradiated alone present less γ-H2AX foci compared to the control cells. This radioadaptation effect is significantly more pronounced at the highest doses. To determine the factors involved in the early events of the bystander effect, we performed an extensive comparative proteomic study of the ZF4 secretomes upon irradiation. In the experimental conditions assayed here, we showed that the early events of bystander effect are probably not due to the secretion of specific proteins neither the oxidation of these secreted proteins. These results suggest that early bystander effect may be due probably to a combination of multiple factors.

  7. Radiation-Induced Liver Injury in Three-Dimensional Conformal Radiation Therapy (3D-CRT) for Postoperative or Locoregional Recurrent Gastric Cancer: Risk Factors and Dose Limitations.

    Science.gov (United States)

    Li, Guichao; Wang, Jiazhou; Hu, Weigang; Zhang, Zhen

    2015-01-01

    This study examined the status of radiation-induced liver injury in adjuvant or palliative gastric cancer radiation therapy (RT), identified risk factors of radiation-induced liver injury in gastric cancer RT, analysed the dose-volume effects of liver injury, and developed a liver dose limitation reference for gastric cancer RT. Data for 56 post-operative gastric cancer patients and 6 locoregional recurrent gastric cancer patients treated with three-dimensional conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) from Sep 2007 to Sep 2009 were analysed. Forty patients (65%) were administered concurrent chemotherapy. Pre- and post-radiation chemotherapy were given to 61 patients and 43 patients, respectively. The radiation dose was 45-50.4 Gy in 25-28 fractions. Clinical parameters, including gender, age, hepatic B virus status, concurrent chemotherapy, and the total number of chemotherapy cycles, were included in the analysis. Univariate analyses with a non-parametric rank test (Mann-Whitney test) and logistic regression test and a multivariate analysis using a logistic regression test were completed. We also analysed the correlation between RT and the changes in serum chemistry parameters [including total bilirubin, (TB), direct bilirubin (D-TB), alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and serum albumin (ALB)] after RT. The Child-Pugh grade progressed from grade A to grade B after radiotherapy in 10 patients. A total of 16 cases of classic radiation-induced liver disease (RILD) were observed, and 2 patients had both Child-Pugh grade progression and classic RILD. No cases of non-classic radiation liver injury occurred in the study population. Among the tested clinical parameters, the total number of chemotherapy cycles correlated with liver function injury. V35 and ALP levels were significant predictive factors for radiation liver injury. In 3D-CRT for gastric cancer patients

  8. Negligible risk of inducing resistance in Mycobacterium tuberculosis with single-dose rifampicin as post-exposure prophylaxis for leprosy

    NARCIS (Netherlands)

    Mieras, L. (Liesbeth); R. Anthony (Richard); W.H. van Brakel (Wim); Bratschi, M.W. (Martin W.); van den Broek, J. (Jacques); Cambau, E. (Emmanuelle); Cavaliero, A. (Arielle); Kasang, C. (Christa); Perera, G. (Geethal); Reichman, L. (Lee); J.H. Richardus (Jan Hendrik); P. Saunderson (Paul); Steinmann, P. (Peter); Yew, W.W. (Wing Wai)

    2016-01-01

    textabstractPost-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

  9. Substance P-induced skin inflammation is not modulated by a single dose of sitagliptin in human volunteers.

    Science.gov (United States)

    Grouzmann, Eric; Bigliardi, Paul; Appenzeller, Monique; Pannatier, André; Buclin, Thierry

    2011-03-01

    Substance P (SP), an undecapeptide belonging to the tachykinin family, is released during the activation of sensory nerves, and causes vasodilation, edema and pain through activation of tissular Neurokinin 1 receptors. SP proinflammatory effects are terminated by angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP), while the aminopeptidase dipeptidylpeptidase IV (DPPIV) can also play a role. The aim of this randomized, crossover, double-blind study was to assess the cutaneous vasoreactivity (flare and wheal reaction, burning pain sensation) to intradermal injection of ascending doses of SP in six volunteers receiving a single therapeutic dose of the DPPIV inhibitor sitagliptin or a matching placebo. Cutaneous SP challenges produced the expected, dose-dependent flare and wheal response, while eliciting mild to moderate local pain sensation with little dose dependency. However, no differences were shown in the responses observed under sitagliptin compared with placebo, while the study would have been sufficiently powered to detect a clinically relevant increase in sensitivity to SP. The results of this pilot study are in line with proteolytic cleavage of SP by ACE and NEP compensating the blockade of DPPIV to prevent an augmentation of its proinflammatory action.

  10. Mechanisms underlying the adaptive response against spontaneous neoplastic transformation induced by low doses of low LET radiation - Final Technical Report

    Energy Technology Data Exchange (ETDEWEB)

    John Leslie Redpath

    2007-01-17

    The objective of the research was to examine mechanisms underlying the suppressive effects of low doses (<10 cGy) of low-LET radiation on the endpoint of neoplastic transformation in vitro. The findings indicated a role for upregulation of DNA repair but not of antioxidants.

  11. Optimum dose range for the amelioration of tong term radiation-induced hyposalivation using prophylactic pilocarpine treatment

    NARCIS (Netherlands)

    Burlage, Fred Ronald; Roesink, Judith M.; Faber, Hette; Vissink, Arjan; Langendijk, Johannes A.; Kampinga, Harm H.; Coppes, Rob P.

    Background: To determine dose and time dependency of pilocarpine pre-treatment protection from late damage after unilateral irradiation of the rat parotid gland. Methods and materials: The right parotid gland of saline (1 mg/ml) or pilocarpine (4 mg/kg) pre-treated rats was irradiated with 10, 15

  12. Spontaneous and Dosing Route-related Lung Lesions in Beagle Dogs from Oral Gavage and Inhalation Toxicity Studies: Differentiation from Compound-induced Lesions.

    Science.gov (United States)

    Mukaratirwa, Sydney; Garcia, Begonya; Isobe, Kaori; Petterino, Claudio; Bradley, Alys

    2016-10-01

    This study was conducted to characterize lung microscopic lesions in control beagle dogs from inhalation and oral gavage toxicity studies, to determine differences associated with the route of administration, and to discuss distinguishing features from compound-induced lung lesions. Samples from 138 control dogs from oral gavage studies and 124 control dogs from inhalation (vehicle control) studies were evaluated microscopically. There was no significant sex-related difference in the incidence of all lesions. Perivascular mononuclear cell infiltration, centriacinar mixed cell infiltration, bronchopneumonia, subpleural septal fibrosis, and alveolar macrophage accumulation were the most common lesions. Aspiration pneumonia was more common in dogs from gavage studies, suggesting reflux after gavage dosing or accidental administration of test formulation as possible causes. Centriacinar mixed cell infiltration was more common in dogs from inhalation studies, suggesting mild irritation by the vehicles used. Vascular lesions, which included pulmonary arteriopathy and smooth muscle mineralization, were observed in a few animals. Some of the spontaneous lesions are similar to lesions induced by test compounds. Compared to spontaneous lesions, compound-induced lesions tend to be multifocal or diffuse, follow a pattern of distribution (e.g., centriacinar, perivascular, and interstitial), show a dose response in the incidence and severity, and may show cell-specific toxicity. © The Author(s) 2016.

  13. Preventative effects of the flowers of Inula britannica on autoimmune diabetes in C57BL/KsJ mice induced by multiple low doses of streptozotocin.

    Science.gov (United States)

    Kobayashi, Takao; Song, Qing-Hua; Hong, Tie; Kitamura, Hajime; Cyong, Jong-Chol

    2002-06-01

    We have reported that an aqueous extract from the flowers of Inula britannica L. subsp. japonica Kitam. (IB) prevented immunologically induced experimental hepatitis in mice and suggested that the antihepatitic effect of IB is due to inhibition of IFN-gamma production. We then investigated the effects of IB on diabetes in mice induced by multiple low doses of streptozotocin (MLDSTZ), which is a mouse model for IFN-gamma-dependent autoimmune diabetes. C57BL/KsJ mice (male, 7 weeks) were provided with IB extract (500 mg/ kg/ day) in drinking water ad libitum, starting 7 days before the first STZ injection. Autoimmune diabetes was induced by MLDSTZ (40 mg/kg/day for 5 daily doses, i.p.). The IB treatment significantly suppressed the increase of blood glucose levels. Histological analysis of the pancreas showed that the degree of insulitis and destruction of beta-cells were reduced by IB treatment. The IFN-gamma production from stimulated splenic T lymphocytes was inhibited by the IB treatment. Moreover, the proportion of IFN-gamma-producing cells in the CD4(+) population, which was increased by MLDSTZ, was significantly decreased by the IB treatment. These results suggest that IB has a preventative effect on autoimmune diabetes by regulating cytokine production. Copyright 2002 John Wiley & Sons, Ltd.

  14. Manganese superoxide dismutase interacts with a large scale of cellular and mitochondrial proteins in low dose radiation-induced adaptive radioprotection

    Science.gov (United States)

    Eldridge, Angela; Fan, Ming; Woloschak, Gayle; Grdina, David J.; Chromy, Brett A.; Li, Jian Jian

    2012-01-01

    Cellular adaptive response to certain low level genotoxic stresses including the exposure to low dose ionizing radiation (LDIR) shows promise as a tool to enhance radioprotection in normal cells but not in tumor cells. Manganese superoxide dismutase (MnSOD), a fundamental mitochondrial antioxidant in mammalian cells plays a key role in LDIR-induced adaptive response. In this study, we aim to elucidate the signaling network associated with the MnSOD-induced radiation protection. A MnSOD-interacting protein profile was established in LDIR-treated human skin cells. Human skin keratinocytes (HK18) were irradiated with a single dose LDIR (10 cGy x-ray) and the cell lysates were immunoprecipitated using α-MnSOD and applied to two different gel-based proteomics followed by mass spectrometry for protein identification. Analysis of the profiles of MnSOD interacting partners before and after LDIR detected different patterns of MnSOD protein-protein interactions in response to LDIR. Interestingly, many of the MnSOD interacting proteins are known to have functions related to mitochondrial regulations on cell metabolism, apoptosis and DNA repair. These results provide the evidence indicating that in addition to the enzymatic action detoxifying superoxide, the antioxidant MnSOD may function as a signaling regulator in stress induced adaptive protection through cell survival pathways. PMID:23000060

  15. DETECTION OF LOW DOSE RADIATION-AND CHEMICALLY-INDUCED DNA DAMAGE USING TEMPERATURE DIFFERENTIAL FLUORESCENCE ASSAYS

    Science.gov (United States)

    Rapid, sensitive and simple assays for radiation- and chemically-induced DNA damage can be of significant benefit to a number of fields including radiation biology, clinical research, and environmental monitoring. Although temperature-induced DNA strand separation has been use...

  16. Suppression by developing ovarian follicles of the low-dose endotoxin-induced glomerular inflammatory reaction in the pregnant rat

    NARCIS (Netherlands)

    Schuiling, GA; Valkhof, N; Faas, MM

    OBJECTIVE: In the current study the role of developing ovarian follicles in the control of the endotoxin-induced pregnancy-specific inflammatory reaction was evaluated. STUDY DESIGN: Follicular development was induced in pregnant rats (n = 20) by means of daily intraperitoneal injections of

  17. Mechanisms underlying the adaptive response against spontaneous neoplastic transformation induced by low doses of low LET radiation, Final Technical Report

    Energy Technology Data Exchange (ETDEWEB)

    J. Leslie Redpath, Ph.D.

    2006-01-23

    The goal of this project was to investigate mechanisms underlying the adaptive response seen following exposure of HeLa x skin fibroblast human hybrid cells to low doses of low LET radiation. It was proposed to investigate the contributions of three possible mechanisms. These were: 1. Upregulation of cellular antioxidant status. 2. Upregulation of DNA repair. 3. Upregulation of gap junction intracellular communication. We have completed the study of the role of upregulation of reduced glutathione (GSH) as a possible mechanism underlying our observed suppression of transformation frequency at low radiation doses. We have also completed our study of the possible role of upregulation of DNA repair in the observed adaptive response against neoplastic transformation. We concluded that upregulation of DNA repair may be more important in modulating transformation at the higher dose. A manuscript describing the above studies has been submitted published in Carcinogenesis 24:1961-1965, 2003. Finally, we have completed two studies of the possible role of upregulation of gap junction intercellular communication (GJIC) in modulating transformation frequency at low doses of low LET radiation. This research was published in Radiation Research 162:646-654, 2004. In order to optimize the opportunity for GJIC, we then carried out a study where confluent cultures were irradiated. The results indicated, that while the degree of low dose suppression was somewhat reduced compared to that seen for subconfluent cultures, it was not completely absent. This research has been submitted for publication. Our research program was of sufficient interest to generate two invited reviews, and five invited presentations.

  18. The potential benefits of nicaraven to protect against radiation-induced injury in hematopoietic stem/progenitor cells with relative low dose exposures

    Energy Technology Data Exchange (ETDEWEB)

    Ali, Haytham [Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Department of Medical Physiology and Cell Biology, Qena Faculty of Medicine, South Valley University (Egypt); Galal, Omima [Department of Medical Physiology and Cell Biology, Qena Faculty of Medicine, South Valley University (Egypt); Urata, Yoshishige; Goto, Shinji; Guo, Chang-Ying; Luo, Lan [Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Abdelrahim, Eman [Department of Medical Histology, Qena Faculty of Medicine, South Valley University (Egypt); Ono, Yusuke [Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Mostafa, Emtethal [Department of Medical Physiology and Cell Biology, Qena Faculty of Medicine, South Valley University (Egypt); Li, Tao-Sheng, E-mail: litaoshe@nagasaki-u.ac.jp [Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan)

    2014-09-26

    Highlights: • Nicaraven mitigated the radiation-induced reduction of c-kit{sup +} stem cells. • Nicaraven enhanced the function of hematopoietic stem/progenitor cells. • Complex mechanisms involved in the protection of nicaraven to radiation injury. - Abstract: Nicaraven, a hydroxyl radical-specific scavenger has been demonstrated to attenuate radiation injury in hematopoietic stem cells with 5 Gy γ-ray exposures. We explored the effect and related mechanisms of nicaraven for protecting radiation injury induced by sequential exposures to a relatively lower dose γ-ray. C57BL/6 mice were given nicaraven or placebo within 30 min before exposure to 50 mGy γ-ray daily for 30 days in sequences (cumulative dose of 1.5 Gy). Mice were victimized 24 h after the last radiation exposure, and the number, function and oxidative stress of hematopoietic stem cells were quantitatively estimated. We also compared the gene expression in these purified stem cells from mice received nicaraven and placebo treatment. Nicaraven increased the number of c-kit{sup +} stem/progenitor cells in bone marrow and peripheral blood, with a recovery rate around 60–90% of age-matched non-irradiated healthy mice. The potency of colony forming from hematopoietic stem/progenitor cells as indicator of function was completely protected with nicaraven treatment. Furthermore, nicaraven treatment changed the expression of many genes associated to DNA repair, inflammatory response, and immunomodulation in c-kit{sup +} stem/progenitor cells. Nicaraven effectively protected against damages of hematopoietic stem/progenitor cells induced by sequential exposures to a relatively low dose radiation, via complex mechanisms.

  19. Diet induced mild hypercholesterolemia in pigs: local and systemic inflammation, effects on vascular injury - rescue by high-dose statin treatment.

    Directory of Open Access Journals (Sweden)

    Marco Busnelli

    Full Text Available OBJECTIVE: The aim of the present study was to comprehensively evaluate systemic and local inflammation as well as progression of vascular inflammation in normal and mechanically injured vessels in a large animal model of mild hypercholesterolemia. Our aim was also to test the effect of high-dose statin treatment on these processes. METHODS: Pigs were kept for 120 days on a standard diet (SD, n=7, high-cholesterol diet (HCD, n=7 or high-cholesterol diet with Atorvastatin starting after 50 days (STATIN, n=7. Left carotid artery balloon injury was conducted in all groups after 60 days of diet treatment. Biochemical analysis together with evaluation of blood and tissue markers of vascular injury and inflammation were performed in all groups at the end of experiment. RESULTS: HCD compared to SD induced systemic inflammation demonstrated by increased number of circulating monocytes and lymphocytes. HCD compared to SD induced also local inflammation demonstrated by adipocyte hypertrophy and infiltration of T-lymphocytes in abdominal white adipose tissue, activation of hepatic stellate cells with infiltration of T- and B-lymphocytes and macrophages in the liver and increased macrophage content in lung parenchyma. These changes were accompanied by increased Intima/Media thickness, stenosis, matrix deposition and activated T-cell infiltrates in injured but not in uninjured contralateral carotid artery as we previously reported. The treatment with high-dose statin attenuated all aspects of systemic and local inflammation as well as pathological changes in injured carotid artery. CONCLUSIONS: Diet related mild hypercholesterolemia induce systemic and local inflammation in the liver, lung and adipose tissue that coincide with enhanced inflammation of injured vessel but is without deleterious effect on uninjured vessels. High dose statin attenuated systemic and local inflammation and protected injured vessels. However, finding exact role of reduced systemic

  20. Type V collagen-induced oral tolerance plus low-dose cyclosporine prevents rejection of MHC class I and II incompatible lung allografts.

    Science.gov (United States)

    Yamada, Yoshito; Sekine, Yasuo; Yoshida, Shigetoshi; Yasufuku, Kazuhiro; Petrache, Irina; Benson, Heather L; Brand, David D; Yoshino, Ichiro; Wilkes, David S

    2009-07-01

    Autoimmunity to type V collagen (col(V)) is a major risk factor for lung allograft rejection. Although col(V)-induced oral tolerance abrogates rejection of minor histoincompatible lung transplants, its ability to prevent rejection of fully MHC incompatible lung allografts is unknown. Rat lung allografts fully incompatible at MHC class I and II loci (Brown Norway (RT1(n))) were transplanted into untreated Wistar Kyoto rat recipients (WKY, RT1(l)), or WKY rats were fed col(V) pretransplantation. To determine whether col(V) enhanced cyclosporine (CsA)-mediated immune suppression, WKY rats were treated with low-dose CsA (5 mg/kg), posttransplant, or oral col(V) plus CsA. The data showed that in contrast to col(V) or CsA, col(V) plus low-dose CsA significantly prevented rejection pathology, down-regulated alloantigen-induced production of IFN-gamma and IL-17A, and suppressed chemotaxis for lung macrophages in allograft bronchoalveolar lavage fluid that was associated with lower local levels of MCP-1 (CCL2). Col(V) plus CsA was associated with alloantigen-induced expression of IL-10 in mediastinal lymph node or splenic T cells, intragraft expression of IL-10 and Foxp3 in perivascular and peribronchiolar mononuclear cells, and constitutive production of IL-10 from allograft alveolar macrophages. These data demonstrate that col(V) enhances low-dose CsA-mediated immune suppression, and suggest a role for oral col(V) in immune modulation in lung transplantation.

  1. Low-dose D-methionine and N-acetyl-L-cysteine for protection from permanent noise-induced hearing loss in chinchillas.

    Science.gov (United States)

    Clifford, Royce E; Coleman, John K M; Balough, Ben J; Liu, Jianzhong; Kopke, Richard D; Jackson, Ronald L

    2011-12-01

    Despite efforts at public health awareness and stringent industrial standards for hearing protection, noise-induced hearing loss (NIHL) remains a formidable public health concern. Although many antioxidants have proven to be beneficial in the laboratory for prevention of permanent NIHL, low-dose combinations of compounds with different biochemical mechanisms of action may allow long-term administration with fewer side effects and equal efficacy. The mixture of D-methionine and N-acetyl-L-cysteine administered at levels less than 10% of standard dosing has not been previously reported. Twenty-six female adult Chinchilla laniger were placed in 4 study groups, consisting of (1) a group receiving combination 12.5 mg/kg each D-methionine and N-acetyl-L-cysteine (DMET/NAC group), (2) a group receiving 12.5 mg/kg D-methionine (DMET-only group), (3) a group receiving 12.5 mg/kg N-acetyl-L-cysteine (NAC-only group), and (4) saline controls. Laboratory. All groups received twice-daily intraperitoneal injections 2 days prior to noise exposure, 1 hour before and after exposure on day 3, and for 2 days subsequently, totaling 10 doses of 125 mg/kg for each antioxidant over 5 days. Although NAC-only animals paralleled saline control recovery during 3 weeks, the DMET-only group revealed gradual improvement with statistically significant recovery in the middle frequencies. The DMET/NAC group showed significant improvement at most frequencies compared with controls (P noise exposure with either DMET only or a combination of low-dose DMET/NAC, demonstrating a considerably lower dose of antioxidants required than previously reported for hearing recovery following acoustic trauma.

  2. Vitamin E can improve behavioral tests impairment, cell loss, and dendrite changes in rats' medial prefrontal cortex induced by acceptable daily dose of aspartame.

    Science.gov (United States)

    Rafati, Ali; Noorafshan, Ali; Jahangir, Mahboubeh; Hosseini, Leila; Karbalay-Doust, Saied

    2018-01-01

    Aspartame is an artificial sweetener used in about 6000 sugar-free products. Aspartame consumption could be associated with various neurological disorders. This study aimed to evaluate the effect of aspartame onmedial Prefrontal Cortex (mPFC) as well as neuroprotective effects of vitamin E. The rats were divided into seven groups, including distilled water, corn oil, vitamin E (100mg/kg/day), and low (acceptable daily dose) and high doses of aspartame (40 and 200mg/kg/day) respectively, with or without vitamin E consumption, for 8 weeks. Behavioral tests were recorded and the brain was prepared for stereological assessments. Novel objects test and eight-arm radial maze showed impairmentoflong- and short-termmemoriesin aspartame groups. Besides, mPFC volume, infralimbic volume, neurons number, glial cells number, dendrites length per neuron,and number of spines per dendrite length were decreased by 7-61% in the rats treated with aspartame. However, neurons' number, glial cells number, and rats' performance in eight-arm radial mazes were improved by concomitant consumption of vitamin E and aspartame. Yet, the mPFC volume and infralimbic cortex were protected only in the rats receiving the low dose of aspartame+vitamin E. On the other hand, dendrites length, spines number,and novel object recognition were not protected by treatment with vitamin E+aspartame. The acceptable daily dose or higher doses of aspartame could induce memory impairments and cortical cells loss in mPFC. However, vitamin E could ameliorate some of these changes. Copyright © 2017 Elsevier GmbH. All rights reserved.

  3. Code intercomparison and benchmark for muon fluence and absorbed dose induced by an 18-GeV electron beam after massive iron shielding

    CERN Document Server

    Fassò, Alberto; Ferrari, Anna; Mokhov, Nikolai V.; Müller, Stefan E.; Nelson, Walter Ralph; Roesler, Stefan; Sanami, Toshiya; Striganov, Sergei I.; Versaci, Roberto

    2015-01-01

    In 1974, Nelson, Kase, and Svenson published an experimental investigation on muon shielding using the SLAC high energy LINAC. They measured muon fluence and absorbed dose induced by a 18 GeV electron beam hitting a copper/water beam dump and attenuated in a thick steel shielding. In their paper, they compared the results with the theoretical mode ls available at the time. In order to compare their experimental results with present model calculations, we use the modern transport Monte Carlo codes MARS15, FLUKA2011 and GEANT4 to model the experimental setup and run simulations. The results will then be compared between the codes, and with the SLAC data.

  4. Update on the Code Intercomparison and Benchmark for Muon Fluence and Absorbed Dose Induced by an 18 GeV Electron Beam After Massive Iron Shielding

    Energy Technology Data Exchange (ETDEWEB)

    Fasso, A. [SLAC; Ferrari, A. [CERN; Ferrari, A. [HZDR, Dresden; Mokhov, N. V. [Fermilab; Mueller, S. E. [HZDR, Dresden; Nelson, W. R. [SLAC; Roesler, S. [CERN; Sanami, t.; Striganov, S. I. [Fermilab; Versaci, R. [Unlisted, CZ

    2016-12-01

    In 1974, Nelson, Kase and Svensson published an experimental investigation on muon shielding around SLAC high-energy electron accelerators [1]. They measured muon fluence and absorbed dose induced by 14 and 18 GeV electron beams hitting a copper/water beamdump and attenuated in a thick steel shielding. In their paper, they compared the results with the theoretical models available at that time. In order to compare their experimental results with present model calculations, we use the modern transport Monte Carlo codes MARS15, FLUKA2011 and GEANT4 to model the experimental setup and run simulations. The results are then compared between the codes, and with the SLAC data.

  5. 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

    be overcome by ligands, which bind to GH or PRL receptors. Conclusion: Knockdown of SOCS2 makes mice less sensitive to MLDSTZ. These results are consistent with the proposal that elimination of SOCS2 in pancreatic islets creates a state of β-cell hypersensitivity to GH/PRL that mimics events in pregnancy...... 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...

  6. Polysubstance-induced relapse of schizoaffective disorder refractory to high-dose antipsychotic medications: a case report.

    Science.gov (United States)

    Tucker, Murray G; Kekulawala, Sebastian; Kent, Michelle; Mostafa, Sam; Harvey, Richard

    2016-09-06

    The high prevalence of comorbid illicit drug use in persons with chronic psychotic illness represents a strong determinant of psychotic relapse and rehospitalization. Epidemiological studies indicate changing patterns of illicit drug use in Australia, which are concerning because of increased use of crystal methamphetamine, also known as "ice." An important complication of habitual use of crystal methamphetamine is the development of a dose-dependent acute psychotic reaction. We report a case of an acute psychotic relapse in response to polydrug use most notable for multiple recent binges of crystal methamphetamine. Unlike previously described case reports, our patient's acute psychosis was refractory to ultra-high doses of multiple antipsychotic medications. This presented safety challenges due to the risk of serious side effects with high-dose antipsychotic medications. A 30-year-old white man with a past history of schizoaffective disorder was brought to our emergency department by the police in a state of extreme agitation, combativeness, and paranoia after use of cannabis and crystal methamphetamine. Despite existing compliance with zuclopenthixol decanoate depot medication, he required multiple emergency injections of zuclopenthixol acetate, and regular high-dose droperidol, chlorpromazine, and lorazepam. However, he remained severely agitated and psychotic with continuous threats of harm to others. A test of antipsychotic drug metabolism by cytochrome P450 enzymes did not reveal a pharmacogenetic cause for the poor therapeutic efficacy of antipsychotic medications. His psychosis did not appear to be modified by psychoactive medications but was instead self-limited to the presence of endogenous methamphetamine within his system. He fully recovered 96 to 120 hours post-presentation and was discharged home with out-patient clinic follow-up. The current case highlights the challenging nature of a severe psychotic relapse precipitated by illicit substances that

  7. In Vivo Imaging Reveals Significant Tumor Vascular Dysfunction and Increased Tumor Hypoxia-Inducible Factor-1α Expression Induced by High Single-Dose Irradiation in a Pancreatic Tumor Model

    Energy Technology Data Exchange (ETDEWEB)

    Maeda, Azusa [Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario (Canada); Department of Medical Biophysics, University of Toronto, Toronto, Ontario (Canada); Chen, Yonghong; Bu, Jiachuan; Mujcic, Hilda [Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario (Canada); Wouters, Bradly G. [Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario (Canada); Department of Medical Biophysics, University of Toronto, Toronto, Ontario (Canada); Department of Radiation Oncology, University of Toronto, Toronto, Ontario (Canada); DaCosta, Ralph S., E-mail: rdacosta@uhnres.utoronto.ca [Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario (Canada); Department of Medical Biophysics, University of Toronto, Toronto, Ontario (Canada); Techna Institute, University Health Network, Toronto, Ontario (Canada)

    2017-01-01

    Purpose: To investigate the effect of high-dose irradiation on pancreatic tumor vasculature and microenvironment using in vivo imaging techniques. Methods and Materials: A BxPC3 pancreatic tumor xenograft was established in a dorsal skinfold window chamber model and a subcutaneous hind leg model. Tumors were irradiated with a single dose of 4, 12, or 24 Gy. The dorsal skinfold window chamber model was used to assess tumor response, vascular function and permeability, platelet and leukocyte adhesion to the vascular endothelium, and tumor hypoxia for up to 14 days after 24-Gy irradiation. The hind leg model was used to monitor tumor size, hypoxia, and vascularity for up to 65 days after 24-Gy irradiation. Tumors were assessed histologically to validate in vivo observations. Results: In vivo fluorescence imaging revealed temporary vascular dysfunction in tumors irradiated with a single dose of 4 to 24 Gy, but most significantly with a single dose of 24 Gy. Vascular functional recovery was observed by 14 days after irradiation in a dose-dependent manner. Furthermore, irradiation with 24 Gy caused platelet and leukocyte adhesion to the vascular endothelium within hours to days after irradiation. Vascular permeability was significantly higher in irradiated tumors compared with nonirradiated controls 14 days after irradiation. This observation corresponded with increased expression of hypoxia-inducible factor-1α in irradiated tumors. In the hind leg model, irradiation with a single dose of 24 Gy led to tumor growth delay, followed by tumor regrowth. Conclusions: Irradiation of the BxPC3 tumors with a single dose of 24 Gy caused transient vascular dysfunction and increased expression of hypoxia-inducible factor-1α. Such biological changes may impact tumor response to high single-dose and hypofractionated irradiation, and further investigations are needed to better understand the clinical outcomes of stereotactic body radiation therapy.

  8. Evaluation of the Comet Assay for Assessing the Dose-Response Relationship of DNA Damage Induced by Ionizing Radiation

    Science.gov (United States)

    Wang, Yan; Xu, Chang; Du, Li Qing; Cao, Jia; Liu, Jian Xiang; Su, Xu; Zhao, Hui; Fan, Fei-Yue; Wang, Bing; Katsube, Takanori; Fan, Sai Jun; Liu, Qiang

    2013-01-01

    Dose- and time-response curves were combined to assess the potential of the comet assay in radiation biodosimetry. The neutral comet assay was used to detect DNA double-strand breaks in lymphocytes caused by γ-ray irradiation. A clear dose-response relationship with DNA double-strand breaks using the comet assay was found at different times after irradiation (p < 0.001). A time-response relationship was also found within 72 h after irradiation (p < 0.001). The curves for DNA double-strand breaks and DNA repair in vitro of human lymphocytes presented a nice model, and a smooth, three-dimensional plane model was obtained when the two curves were combined. PMID:24240807

  9. Experimental liver fibrosis induced in rats receiving high doses of alcohol and alternating between regular and vitamin-depleted diets.

    Science.gov (United States)

    Hirano, H; Hirano, T; Hirata, K; Tamura, M; Yamaura, T; Hamada, T

    1996-07-15

    Liver fibrosis was induced in rats by simulating human alcoholic eating and drinking patterns. Alcohol addiction was established by gradually increasing the ethanol concentration in the drinking water; salts were added at the terminal stage. The hepatocytes of rats receiving alcohol concentrations exceeding 50% (v/v) (similar to vodka) exhibited alcoholic hyaline (Mallory bodies). Alcoholic liver fibrosis was induced by alternating between regular and autoclaved (vitamin-depleted) diets, simulating the irregular eating habits of human alcoholics. In the livers of rats receiving 70% (v/v) ethanol (comparable to absinthe) with 25% saline and fed the alternating diets, pericellular fibrosis was induced. No significant difference in calorie intake between control and alcohol rats was detected except when rats underwent drinking bouts (heavy drinking phase). This indicates that neither a high-fat diet nor a choline-depleted diet is necessary to induce the alcoholic fibrosis seen in human alcoholics.

  10. Potential pre-cataractous markers induced by low-dose radiation effects in cultured human lens cells

    Science.gov (United States)

    Blakely, E.; McNamara, M.; Bjornstad, K.; Chang, P.

    The human lens is one of the most radiosensitive organs of the body. Cataract, the opacification of the lens, is a late-appearing response to radiation damage. Recent evidence indicates that exposure to relatively low doses of space radiation are associated with an increased incidence and early appearance of human cataracts (Cucinotta et al., Radiat. Res. 156:460-466, 2001). Basic research in this area is needed to integrate the early responses of various late-responding tissues into our understanding and estimation of radiation risk for space travel. In addition, these studies may contribute to the development of countermeasures for the early lenticular changes, in order to prevent the late sequelae. Radiation damage to the lens is not life threatening but, if severe, can affect vision unless surgically corrected with synthetic lens replacement. The lens, however, may be a sensitive detector of radiation effects for other cells of ectodermal origin in the body for which there are not currently clear endpoints of low-dose radiation effects. We have investigated the dose-dependent expression of several radiation-responsive endpoints using our in vitro model of differentiating human lens epithelial cells (Blakely et al., Investigative Ophthalmology &Visual Sciences, 41(12):3898-3907, 2000). We have investigated radiation effects on several gene families that include, or relate to, DNA damage, cytokines, cell-cycle regulators, cell adhesion molecules, cell cytoskeletal function and apoptotic cell death. In this paper we will summarize some of our dose-dependent data from several radiation types, and describe the model of molecular and cellular events that we believe may be associated with precataractous events in the human lens after radiation exposure. This work was supported by NASA Grant #T-965W.

  11. The Effects of Methamphetamine Self-Administration on Cortical Monoaminergic Deficits Induced by Subsequent High-Dose Methamphetamine Administrations

    OpenAIRE

    McFadden, Lisa M.; Hanson, Glen R.; Fleckenstein, Annette E.

    2013-01-01

    Preclinical models suggest that repeated high-dose methamphetamine (METH) exposures, administered in a “binge-like” pattern, acutely decrease norepinephrine (NE), and acutely and persistently decrease serotonin (5-hydroxytryptamine; 5HT) content in the frontal cortex. However, the impact of METH self-administration on this region is unknown. Because of the importance of the monoaminergic neurons in the frontal cortex to a variety of cognitive and addictive processes, effects of METH self-admi...

  12. HIGH ETHANOL DOSE DURING EARLY ADOLESCENCE INDUCES LOCOMOTOR ACTIVATION AND INCREASES SUBSEQUENT ETHANOL INTAKE DURING LATE ADOLESCENCE

    OpenAIRE

    Acevedo, María Belén; Molina, Juan Carlos; Nizhnikov, Michael E.; Spear, Norman E.; Pautassi, Ricardo Marcos

    2010-01-01

    Adolescent initiation of ethanol consumption is associated with subsequent heightened probability of ethanol-use disorders. The present study examined the relationship between motivational sensitivity to ethanol initiation in adolescent rats and later ethanol intake. Experiment 1 determined that ethanol induces locomotor activation shortly after administration but not if tested at a later post-administration interval. In Experiment 2, adolescents were assessed for ethanol-induced locomotor ac...

  13. A Single High Dose of Methamphetamine Induces Apoptotic and Necrotic Striatal Cell Loss Lasting Up to Three Months in Mice

    OpenAIRE

    Tulloch, Ingrid; Afanador, Lauriaselle; Mexhitaj, Ina; Ghazaryan, Nane; GarzaGongora, Arturo G.; Angulo, Jesus A.

    2011-01-01

    Methamphetamine (METH) is an addictive agent that poses a public health problem due to its toxic effects on neural tissue. We have shown that METH induces striatal lesions (cell loss) within 24 hours of administration. Because cell proliferation has been found to follow excitotoxic and other types of lesions in adult brain, we tested the hypothesis that cell proliferation would follow METH-induced striatal cell death. To that end, METH (30 mg/kg ip) was injected into adult male mice followed ...

  14. Lamotrigine blocks repeated high-dose methamphetamine-induced behavioral sensitization to dizocilpine (MK-801), but not methamphetamine in rats.

    OpenAIRE

    Nakato, Yasuya; Abekawa, Tomohiro; Inoue, Takeshi; Ito,Koki; Koyama, Tsukasa

    2011-01-01

    We recently proposed a new psychostimulant animal model of the progressive pathophysiological changes of schizophrenia. Studies using that model produced a treatment strategy for preventing progression. Lamotrigine (LTG) blocks repeated high-dosage methamphetamine (METH)-induced initiation and expression of prepulse inhibition deficit and development of apoptosis in the medial prefrontal cortex (mPFC). Moreover, it inhibits METH-induced increases in extracellular glutamate levels in the mPFC ...

  15. DNA damage and oxidative stress induced at low doses by the fungicide hexachlorobenzene in human intestinal Caco-2 cells.

    Science.gov (United States)

    Chalouati, Hela; Boutet, Elisa; Metais, Benjamin; Fouche, Edwin; Ben Sâad, Mohamed Moncef; Gamet-Payrastre, Laurence

    2015-01-01

    Hexachlorobenzene (HCB), a persistent chlorinated organic chemical, could be detected in human tissues in several countries of the world. Human exposure to Persistent Organic Pollutants (POPs) occurring primarily through diet, HCB and its metabolites are therefore supposed to interact directly with intestinal mucosa. The aim of this study was to investigate the possible effects of low doses of HCB on DNA integrity, cellular viability, differentiation and oxidative status in vitro in human colonic carcinoma cell line Caco-2. Cells were exposed to increasing doses of HCB for 14 days to assess the cytotoxic, genotoxic and oxidative properties of this compound. The involvement of oxidative stress in the observed effects was evaluated by co exposure of Caco-2 cells with HCB and α-tocopherol. Exposure of Caco-2 cells to HCB resulted in a dose-dependent cytotoxicity, DNA damages and alterations of the cell layer integrity and the barrier function. Moreover, exposure of Caco-2 cells to HCB led to an enhancement of H(2)O(2) production and to an increased activity of antioxidant enzymes. In addition, Co exposure of Caco-2 cells to HCB and α-tocopherol reversed the effects observed in cells exposed to HCB alone. These results suggested that HCB effects on Caco-2 cells could be linked, at least in part, to its pro-oxidative potential.

  16. Basal renal function reserve and mean kidney dose predict future radiation-induced kidney injury in stomach cancer patients.

    Science.gov (United States)

    Yavas, Guler; Elsurer, Rengin; Yavas, Cagdas; Ata, Ozlem

    2014-02-01

    Adjuvant chemoradiotherapy (CRT) improves the survival in patients with locally advanced stomach cancer. The kidneys are the major dose-limiting organs for radiotherapy (RT) in upper abdominal cancers. We aimed to evaluate the impact of adjuvant CRT on renal function of patients with stomach cancer. Fifty-nine stomach cancer patients who underwent postoperative CRT were included. Demographic parameters (age, gender), and basal and 12th-month biochemical parameters were recorded. Mean kidney dose (MKD) administered was determined. Estimated glomerular filtration rate (eGFR) was calculated by modification of diet in renal disease formula. Fifty-nine patients were recruited (age 60.8 ± 11.9 years; female/male 25/34; follow-up duration 15.6 ± 9.8 months). Twenty-one patients (35.6 %) had basal eGFR cancer be evaluated for their basal renal reserve prior to RT, and it may be more convenient to further minimize the dose to the kidneys with more sophisticated RT techniques in patients with stomach cancer, more specifically in patients with decreased renal reserve.

  17. Lamotrigine blocks apoptosis induced by repeated administration of high-dose methamphetamine in the medial prefrontal cortex of rats.

    Science.gov (United States)

    Nakato, Yasuya; Abekawa, Tomohiro; Ito, Koki; Inoue, Takeshi; Koyama, Tsukasa

    2011-03-03

    Lamotrigine (LTG) is sometimes co-administered with antipsychotic drugs for the treatment of schizophrenia. Nevertheless, the pharmacological basis of LTG use for schizophrenia has not been reported. Our group recently proposed a new psychostimulant animal model that might reflect the progressive pathophysiology of schizophrenia. Results obtained using that model show that LTG blocks the initiation and expression of repeated high-dosage methamphetamine-induced prepulse inhibition deficit in rats (Nakato et al., 2010, Neurosci. Lett. [25]). Using the model, the effect of LTG (30 mg/kg) on methamphetamine (METH, 2.5 mg/kg)-induced increases in extracellular glutamate levels in the medial prefrontal cortex (mPFC) was examined in this study. Then the effect of repeated co-administration of LTG (30 mg/kg) on repeated METH (2.5 mg/kg)-induced apoptosis in this region of rats was investigated. Results show that LTG (30 mg/kg) blocked the METH (2.5 mg/kg)-induced glutamate increase in the mPFC. Repeated co-administration of LTG (30 mg/kg) blocked the development of apoptosis induced by repeated administration of METH (2.5 mg/kg) in the mPFC. The LTG blocks histological abnormalities induced by repeated administration of METH, which suggests a mechanism of LTG that protects against progressive pathophysiology in schizophrenia. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  18. 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...... 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.......9(6.4-9.3) and 8.7(7.8-9.5) vs 3.6(3.4-3.9) mmol/l, p insulin levels. Area under plasma glucose curve, peak plasma glucose, time to peak and duration of plasma glucose above baseline...

  19. Review of oral fixed-dose combination netupitant and palonosetron (NEPA) for the treatment of chemotherapy-induced nausea and vomiting.

    Science.gov (United States)

    Lorusso, Vito; Karthaus, Meinolf; Aapro, Matti

    2015-01-01

    Current guidelines recommend the combination of a neurokinin-1 (NK1) receptor antagonist (RA) and a 5-hydroxytryptamine-3 (5-HT3) RA, together with corticosteroids, in order to prevent chemotherapy-induced nausea and vomiting with anthracycline-cyclophosphamide and highly emetogenic chemotherapy, and it is to be considered with moderately emetogenic chemotherapy. Netupitant and palonosetron (NEPA) is a fixed-dose combination of netupitant, a novel, highly selective NK1 RA, and palonosetron, a new-generation 5-HT3 RA, targeting two major emetic pathways in a single oral capsule. In clinical trials, NEPA administered on day 1 together with dexamethasone was highly effective and well tolerated in the prevention of chemotherapy-induced nausea and vomiting in patients with solid tumors undergoing moderately emetogenic chemotherapy or highly emetogenic chemotherapy. NEPA offers maximal convenience, and as a simple guideline-based regimen, has the potential to improve adherence to guidelines.

  20. Complete remission and long-term survival of a patient with melanoma metastases treated with high-dose fever-inducing Viscum album extract

    Science.gov (United States)

    Werthmann, Paul G.; Hintze, Alexander; Kienle, Gunver S.

    2017-01-01

    Abstract Introduction: Metastatic malignant cutaneous melanoma (MCM)—a highly immunogenic cancer—typically has a poor prognosis. Viscum album extracts (VAEs) have strong immune-stimulating, apoptogenic, and cytotoxic effects. Case presentation: A 66-year-old MCM patient with newly diagnosed lymph node metastases opted for sole VAE treatment. VAEs were initially applied subcutaneously, and then later in exceptionally high, fever-inducing doses, both intravenously and intralesionally. The metastases shrunk over the following months, and after 2 years, all lesions had completely remitted (regional and hilar lymph nodes). The patient has been tumor free for 3.5 years at the time of publication (and for 5 years since initiation of intensified VAE treatment). Besides fever and flu-like symptoms, no side effects occurred. Discussion: We presume that VAE triggered an increased release of tumor-associated antigens, enhanced immunologic recognition, and increased immune response against the tumor tissue and induced tumor remission. PMID:29145317

  1. Complete remission and long-term survival of a patient with melanoma metastases treated with high-dose fever-inducing Viscum album extract: A case report.

    Science.gov (United States)

    Werthmann, Paul G; Hintze, Alexander; Kienle, Gunver S

    2017-11-01

    Metastatic malignant cutaneous melanoma (MCM)-a highly immunogenic cancer-typically has a poor prognosis. Viscum album extracts (VAEs) have strong immune-stimulating, apoptogenic, and cytotoxic effects. A 66-year-old MCM patient with newly diagnosed lymph node metastases opted for sole VAE treatment. VAEs were initially applied subcutaneously, and then later in exceptionally high, fever-inducing doses, both intravenously and intralesionally. The metastases shrunk over the following months, and after 2 years, all lesions had completely remitted (regional and hilar lymph nodes). The patient has been tumor free for 3.5 years at the time of publication (and for 5 years since initiation of intensified VAE treatment). Besides fever and flu-like symptoms, no side effects occurred. We presume that VAE triggered an increased release of tumor-associated antigens, enhanced immunologic recognition, and increased immune response against the tumor tissue and induced tumor remission.

  2. The effectiveness of low-dose desmopressin in improving hypothermia-induced impairment of primary haemostasis under influence of aspirin - a randomized controlled trial.

    Science.gov (United States)

    Tsui, Pui Yee; Cheung, Chi Wai; Lee, Yvonne; Leung, Susan Wai Sum; Ng, Kwok Fu Jacobus

    2015-05-28

    Mild hypothermia (34-35 °C) increases perioperative blood loss. Our previous studies showed that desmopressin could have in vitro beneficial effects on hypothermia-induced primary haemostasis impairment. In this study, we investigate the in vitro effects of desmopressin on hypothermia-induced primary haemostasis impairment under the influence of aspirin in healthy volunteers. Sixty healthy volunteers were randomly allocated to taking aspirin 100 mg or placebo for three days. On the sixth day blood samples were taken before and after the injection of desmopressin (1.5 microgram or 5 microgram) or normal saline subcutaneously. Measurements including Platelet Function Analyzer (PFA-100®) closure times, plasma von Willebrand Factor antigen, haemoglobin and platelet levels were made at 32 °C and 37 °C respectively. Collagen/epinephrine closure time (EPICT) was significantly prolonged by 21.13 % (95 %CI 2.34-39.74 %, p = 0.021) in aspirin group at 37 °C. While hypothermia alone prolonged both collagen/adenosine diphosphate (ADPCT) and EPICT by 17.63 % (95 %CI 13.5-20.85 %, p desmopressin 1.5 microgram and 5 microgram significantly reduced ADPCT to below baseline levels at 37 °C (p = 0.025 and desmopressin 5 microgram (p =0.008). The effect was less pronounced at 32 °C, with a significant reduction in EPICT obtained with a dosage of 5 microgram only (p = 0.011). It was shown that aspirin could further potentiate the hypothermia-induced closure time prolongations. Low dose desmopressin (1.5 microgram) reduced PFA-100® closure times towards baseline. A higher dosage (5 microgram) further reduced the closure times below baseline. Therefore low dose desmopressin (1.5 microgram) might have the potential to correct hypothermia-induced primary haemostasis impairment under the influence of aspirin during the perioperative period. ClinicalTrials.gov: NCT01382134.

  3. High-Dose {sup 111}In Induces G1 Cell Cycle Arrest and Cell Death in Rat Bone Marrow Mesenchymal Stem Cells

    Energy Technology Data Exchange (ETDEWEB)

    Park, Bok Nam; Shim, Woo Young; Ahn, Young Hwan; Lee, Jae Ho; Yoon, Joon Kee [Ajou Univ. School of Medicine, Suwon (Korea, Republic of)

    2012-06-15

    This study was performed to evaluate the effect of {sup 111}In-labeling on the cell growth, cycle and viability of bone marrow mesenchymal stem cells (BMSCs). Rat BMSCs were labeled with various doses of {sup 111}In (0.4-11.1 Bq/cell). The growth curve of {sup 111}In-BMSCs was obtained up to 14th day of labeling. The cell cycle was evaluated by 5-bromo-2-deoxyuridine (BrdU) labeling or prospidium iodide (PI) staining. Senescent cells were counted under a light microscope after staining with 5-bromo-4-chloro-3-indolyl-{sup D-}galactopyranoside. Flow cytometry was performed to measure apoptotic and necrotic fractions after staining with annexin V-FITC and PI. The growth of BMSCs labeled with higher doses of {sup 111}In (4.4 or 11.1 Bq/cell) was significantly inhibited from the 3rd day of labeling. Flow cytometry revealed less BrdU-positive BMSCs at 11.1 Bq {sup 111}In/cell (9.07%/3.18%) on the 14th day (control=1.60%/0.39%). However, no cellular senescence was visualized up to the 14th day. A high dose of {sup 111}In-labeling induced cell cycle arrest and death in BMSCs; therefore, it should be used with a careful dosimetry in case of applying it to humans.

  4. Site-Specific Phosphorylation of Ikaros Induced by Low-Dose Ionizing Radiation Regulates Cell Cycle Progression of B Lymphoblast Through CK2 and AKT Activation

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Seong-Jun; Kang, Hana [KHNP Radiation Health Institute, Korea Hydro & Nuclear Power Co, Seoul (Korea, Republic of); Kim, Min Young [Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan (Korea, Republic of); Lee, Jung Eun; Kim, Sung Jin; Nam, Seon Young; Kim, Ji Young; Kim, Hee Sun [KHNP Radiation Health Institute, Korea Hydro & Nuclear Power Co, Seoul (Korea, Republic of); Pyo, Suhkneung [College of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do (Korea, Republic of); Yang, Kwang Hee, E-mail: kwangheey@khnp.co.kr [KHNP Radiation Health Institute, Korea Hydro & Nuclear Power Co, Seoul (Korea, Republic of)

    2016-04-01

    Purpose: To determine how low-dose ionizing radiation (LDIR) regulates B lympho-proliferation and its molecular mechanism related with Ikaros, transcription factor. Methods and Materials: Splenocytes and IM-9 cells were uniformly irradiated with various doses of a {sup 137}Cs γ-source, and cell proliferation was analyzed. To determine the LDIR-specific phosphorylation of Ikaros, immunoprecipitation and Western blot analysis were performed. To investigate the physiologic function of LDIR-mediatied Ikaros phosphorylation, Ikaros mutants at phosphorylation sites were generated, and cell cycle analysis was performed. Results: First, we found that LDIR enhances B lymphoblast proliferation in an Ikaros-dependent manner. Moreover, we found that LDIR elevates the phosphorylation level of Ikaros protein. Interestingly, we showed that CK2 and AKT are involved in LDIR-induced Ikaros phosphorylation and capable of regulating DNA binding activity of Ikaros via specific phosphorylation. Finally, we identified LDIR-specific Ikaros phosphorylation sites at S391/S393 and showed that the Ikaros phosphorylations at these sites control Ikaros's ability to regulate G1/S cell cycle progression. Conclusion: Low-dose ionizing radiation specifically phosphorylates Ikaros protein at Ser 391/393 residues to regulate cell cycle progression in B lymphoblast.

  5. Safety, efficacy, and patient acceptability of single-dose fosaprepitant regimen for the prevention of chemotherapy-induced nausea and vomiting

    Directory of Open Access Journals (Sweden)

    Celio L

    2013-05-01

    Full Text Available Luigi Celio, Francesca Ricchini, Filippo De BraudMedical Oncology Unit 1, Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, ItalyAbstract: Control of chemotherapy-induced nausea and vomiting (CINV is a crucial factor in ensuring that patients undergoing cancer chemotherapy can get the full benefit of therapy. Current antiemetic guidelines recommend that the neurokinin-1 receptor (NK-1R antagonist aprepitant should be used as part of a combination regimen with dexamethasone and a serotonin receptor antagonist for the prevention of CINV in patients receiving highly emetogenic chemotherapy (HEC. Fosaprepitant is a water-soluble N-phosphoryl derivative of aprepitant that, when infused, is rapidly metabolized back to an active aprepitant. The existing literature in PubMed about fosaprepitant was screened and selected in order to address the emerging data from two randomized clinical trials evaluating the efficacy and safety of a single-dose fosaprepitant regimen. These phase III trials demonstrated that fosaprepitant given as a single intravenous dose of 150 mg was either noninferior to the conventional 3-day aprepitant or significantly superior to placebo for the prevention of acute and delayed CINV in patients receiving high-dose cisplatin. In both trials, fosaprepitant was well tolerated although more frequent infusion-site adverse events were observed with fosaprepitant. The new dosage regimen of fosaprepitant, therefore, would be an option for CINV control in patients receiving cisplatin-based chemotherapy. The clinical efficacy is consistent with the findings from a time-on-target, positron-emission tomography study evaluating the NK-1R occupancy in the central nervous system (CNS over 5 days after a single-dose infusion of 150 mg fosaprepitant in healthy participants. The single-dose regimen is capable of blocking more than 90% of the NK-1Rs in the CNS for at least 48 hours after infusion, which is sufficient

  6. Augmentation of aluminum-induced oxidative stress in rat cerebrum by presence of pro-oxidant (graded doses of ethanol) exposure.

    Science.gov (United States)

    Nayak, Prasunpriya; Sharma, Shiv Bhushan; Chowdary, Nadella Vijaya Subbaraya

    2010-11-01

    Both aluminum and ethanol are pro-oxidants and neurotoxic. Considering the possibilities of co-exposure and sharing mechanisms of producing neurotoxicity, the present study was planned to identify the level of aluminum-induced oxidative stress in altered pro-oxidant (ethanol exposure) status of cerebrum. Male rats were coexposed to aluminum and ethanol for 4 weeks. After the exposure period, cerebral levels of protein, reduced glutathione (GSH), lipid peroxidation (TBARS) were measured. Activities of catalase, superoxide dismutase (SOD), glutathione reductase (GR) and glutathione perioxidase (GPx) of cerebrum were estimated. In most of the cases significant correlations were observed between the alterations and graded ethanol doses, suggesting a dose-dependency in pushing the oxidant equilibrium toward pro-oxidants. Aluminum is found to influence significantly all the studied parameters of oxidative stress. Likewise, ethanol also influenced these parameters significantly, except GR, while the interaction between ethanol and aluminum could significantly influence only the GSH content and GR activity of cerebrum. Present study demonstrate that coexposure of aluminum with pro-oxidant might favor development of aluminum-induced oxidative stress in cerebrum. This observation might be helpful in understanding of mechanism of neurodegenerative disorders and ameliorate them.

  7. Protective effects of low-dose rosuvastatin on isoproterenol-induced chronic heart failure in rats by regulation of DDAH-ADMA-NO pathway.

    Science.gov (United States)

    Zhou, Ru; Ma, Ping; Xiong, Aiqin; Xu, Yehua; Wang, Yang; Xu, Qingbin

    2017-04-01

    Cardiovascular disease is the leading cause of death with high morbidity and mortality, and chronic heart failure is the terminal phase of it. This study aimed to investigate the protective effects of the low-dose rosuvastatin on isoproterenol-induced chronic heart failure and to explore the possible related mechanisms. Male Sprague Dawley rats were given isoproterenol 5 mg/kg once a day for 7 days to establish heart failure model by subcutaneous injection. Simultaneously, low-dose rosuvastatin (5 mg/kg) was orally administrated from day 1 to day 14. Protective effects were evaluated by hemodynamic parameter, histopathological variables, serum asymmetric dimethylarginine (ADMA), cardiac troponin I (cTnI), brain natriuretic peptide (BNP) and myocardial nitric oxide (NO), and the levels of dimethylarginine dimethylaminohydrolase 2 (DDAH2), arginine methyltransferases 1 (PRMT1) and endothelial nitric oxide synthase (eNOS) expression were analyzed. Therapeutic rosuvastatin (5 mg/kg) significantly attenuated isoproterenol-induced hypertrophy, remodeling and dysfunction of ventricle, reduced the increased serum content of ADMA, cTnI, and BNP, and elevated myocardial NO in rats (Pheart failure in rats by modulating DDAH-ADMA-NO pathway, and it may present the new therapeutic value in ameliorating chronic heart failure. © 2016 John Wiley & Sons Ltd.

  8. Caffeine protects against memory loss induced by high and non-anxiolytic dose of cannabidiol in adult zebrafish (Danio rerio).

    Science.gov (United States)

    Nazario, Luiza Reali; Antonioli, Régis; Capiotti, Katiucia Marques; Hallak, Jaime Eduardo Cecílio; Zuardi, Antonio Waldo; Crippa, José Alexandre S; Bonan, Carla Denise; da Silva, Rosane Souza

    2015-08-01

    Cannabidiol (CBD) has been investigated in a wide spectrum of clinical approaches due to its psychopharmacological properties. CBD has low affinity for cannabinoid neuroreceptors and agonistic properties to 5-HT receptors. An interaction between cannabinoid and purinergic receptor systems has been proposed. The purpose of this study is to evaluate CBD properties on memory behavioral and locomotor parameters and the effects of pre-treatment of adenosine receptor blockers on CBD impacts on memory using adult zebrafish. CBD (0.1, 0.5, 5, and 10mg/kg) was tested in the avoidance inhibitory paradigm and anxiety task. We analyzed the effect of a long-term caffeine pre-treatment (~20mg/L - four months). Also, acute block of adenosine receptors was performed in co-administration with CBD exposure in the memory assessment. CBD promoted an inverted U-shaped dose-response curve in the anxiety task; in the memory assessment, CBD in the dose of 5mg/Kg promoted the strongest effects without interfering with social and aggressive behavior. Caffeine treatment was able to prevent CBD (5mg/kg) effects on memory when CBD was given after the training session. CBD effects on memory were partially prevented by co-treatment with a specific A2A adenosine receptor antagonist when given prior to or after the training session, while CBD effects after the training session were fully prevented by adenosine A1 receptor antagonist. These results indicated that zebrafish have responses to CBD anxiolytic properties that are comparable to other animal models, and high doses changed memory retention in a way dependent on adenosine. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Oxygen free-radical scavengers and immune destruction of murine islets in allograft rejection and multiple low-dose streptozocin-induced insulitis.

    Science.gov (United States)

    Mendola, J; Wright, J R; Lacy, P E

    1989-03-01

    We examined the effects of desferrioxamine (DFX), a potent inhibitor of the formation of oxygen-derived hydroxyl radicals, and nicotinamide (NIC), a poly(ADP-ribose) synthetase inhibitor and a weak free-radical scavenger, on two models of immune destruction of murine islets [i.e., allograft rejection and multiple low-dose streptozocin (STZ)-induced insulitis]. Freshly isolated or low-temperature-cultured BALB/cJ islets were transplanted beneath the kidney capsules of C57BL/6J recipients. The recipients were treated with NIC alone (500 mg.kg-1.day-1), DFX alone (4.2 mg/day x 14 days), or NIC + DFX. Only recipients treated with NIC + DFX, receiving cultured islets, showed a mean graft survival time significantly longer than control mice receiving freshly isolated or cultured islets. Control CD-1 mice treated with multiple low doses of STZ developed insulitis and diabetes. Treatment with NIC alone, DFX alone, or NIC + DFX decreased the severity of hyperglycemia relative to the controls. Treatment with DFX alone was more effective than NIC alone or NIC + DFX. Only the group treated with DFX alone had a lower incidence of diabetes (mean plasma glucose level greater than 200 mg/dl) than the controls after 4 wk. Histologically, islets from control mice showed severe insulitis, islet destruction, and absence of stainable insulin, whereas islets from DFX-treated mice showed only mild peri-insulitis and a relative preservation of beta-cell granulation. Our study showed that NIC and DFX partially protect islets from immune destruction in allograft rejection and in low-dose STZ-induced insulitis. Apparently, hydroxyl radicals play important roles in both of these models.

  10. Low-Dose Methylmercury-Induced Genes Regulate Mitochondrial Biogenesis via miR-25 in Immortalized Human Embryonic Neural Progenitor Cells

    Directory of Open Access Journals (Sweden)

    Xinjin Wang

    2016-12-01

    Full Text Available Mitochondria are essential organelles and important targets for environmental pollutants. The detection of mitochondrial biogenesis and generation of reactive oxygen species (ROS and p53 levels following low-dose methylmercury (MeHg exposure could expand our understanding of underlying mechanisms. Here, the sensitivity of immortalized human neural progenitor cells (ihNPCs upon exposure to MeHg was investigated. We found that MeHg altered cell viability and the number of 5-ethynyl-2′-deoxyuridine (EdU-positive cells. We also observed that low-dose MeHg exposure increased the mRNA expression of cell cycle regulators. We observed that MeHg induced ROS production in a dose-dependent manner. In addition, mRNA levels of peroxisome-proliferator-activated receptor gammacoactivator-1α (PGC-1α, mitochondrial transcription factor A (TFAM and p53-controlled ribonucleotide reductase (p53R2 were significantly elevated, which were correlated with the increase of mitochondrial DNA (mtDNA copy number at a concentration as low as 10 nM. Moreover, we examined the expression of microRNAs (miRNAs known as regulatory miRNAs of p53 (i.e., miR-30d, miR-1285, miR-25. We found that the expression of these miRNAs was significantly downregulated upon MeHg treatment. Furthermore, the overexpression of miR-25 resulted in significantly reducted p53 protein levels and decreased mRNA expression of genes involved in mitochondrial biogenesis regulation. Taken together, these results demonstrated that MeHg could induce developmental neurotoxicity in ihNPCs through altering mitochondrial functions and the expression of miRNA.

  11. Sphingosine-1-Phosphate Induces Dose-Dependent Chemotaxis or Fugetaxis of T-ALL Blasts through S1P1 Activation.

    Directory of Open Access Journals (Sweden)

    Carolina V Messias

    Full Text Available Sphingosine-1-phosphate (S1P is a bioactive sphingolipid involved in several physiological processes including cell migration and differentiation. S1P signaling is mediated through five G protein-coupled receptors (S1P1-S1P5. S1P1 is crucial to the exit of T-lymphocytes from the thymus and peripheral lymphoid organs through a gradient of S1P. We have previously observed that T-ALL and T-LBL blasts express S1P1. Herein we analyzed the role of S1P receptors in the migratory pattern of human T-cell neoplastic blasts. S1P-triggered cell migration was directly related to S1P1 expression. T-ALL blasts expressing low levels of S1P1 mRNA (HPB-ALL did not migrate toward S1P, whereas those expressing higher levels of S1P1 (MOLT-4, JURKAT and CEM did migrate. The S1P ligand induced T-ALL cells chemotaxis in concentrations up to 500 nM and induced fugetaxis in higher concentrations (1000-10000 nM through interactions with S1P1. When S1P1 was specifically blocked by the W146 compound, S1P-induced migration at lower concentrations was reduced, whereas higher concentrations induced cell migration. Furthermore, we observed that S1P/S1P1 interactions induced ERK and AKT phosphorylation, and modulation of Rac1 activity. Responding T-ALL blasts also expressed S1P3 mRNA but blockage of this receptor did not modify migratory responses. Our results indicate that S1P is involved in the migration of T-ALL/LBL blasts, which is dependent on S1P1 expression. Moreover, S1P concentrations in the given microenvironment might induce dose-dependent chemotaxis or fugetaxis of T-ALL blasts.

  12. Antibody induced by one-dose varicella vaccine soon became weak in children: evidence from a cross-sectional seroepidemiological survey in Beijing, PRC.

    Science.gov (United States)

    Suo, Luodan; Lu, Li; Chen, Meng; Pang, Xinghuo

    2015-11-10

    Numerous post-licensure studies, mostly from field epidemiological evidences such as outbreak surveys, have demonstrated the effectivenesss and insufficiency of one-dose varicella vaccine in outbreak control. Serological evidence of immunization failure is, however, relatively less reported in contrast. A cross-sectional seroepidemiological survey of Beijing residents was performed in 2012 in the People's Republic of China, after the one-dose varicella vaccine had been widely used for several years. Multistage stratified random sampling method was designed to recruit 2 144 subjects. The ELISA method was used to test the present blood samples collected and the reserve samples collected in 2008 to assess the trends of anti-VZV seroprevalence in the past 5 years and to determine the risk factors for varicella infection. The age- and sex- adjusted overall anti-VZV seropositivity of Beijing residents in 2012 was 84.5%. Two groups' adjusted overall anti-VZV seroprevalence in 2012 showed obvious growth compared with 2008 (groups, respectively. Of subjects who had received the one-dose vaccine, 36% (216/603) showed negative anti-VZV concentrations (anti-VZV concentrations were in the lowest positive concentration group (110-299 mIU/mL). Seropositivity in permanent residents of 1-9 yr old with verified vaccination was merely 61.8%. Various age groups (1-3 yr, 4-6 yr, and 7-9 yr) all showed seropositivity that gradually decreased with increasing of the interval between vaccination and blood sampling. Mass varicella vaccination significantly improved the immunity of younger Beijing residents. However, vaccine-induced anti-VZV antibody soon became weak in children with high coverage (approximately 80%) after vaccination for several years which is significantly higher than reported in pre-licensure studies. A government-funded 2-dose immunization program with mandatory vaccination schedule for Beijing residents may need consideration in the near future.

  13. 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)

    Kuttappan, V A; Vicuña, E A; Faulkner, O B; Huff, G R; Freeman, K A; Latorre, J D; Menconi, A; Tellez, G I; Hargis, B M; Bielke, L R

    2016-11-01

    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, 2 doses of DSS (0.45 g/dose) administered as oral gavage resulted in increased mucosal permeability. The main objective of the present study was to compare serum turbidity in control and DSS treated birds plus with feed restriction ( FR: ), and evaluate the associated serum chemistry. Three independent experiments were conducted with different combinations of treatment groups. In Experiment 1, control full-fed ( CON: ) and DSS full-fed ( FFD: ) with n = 15 birds/group were evaluated, Experiment 2 had groups (n = 15/group) CON, FFD, feed restriction ( FRS: for 34 h), and DSS with feed restriction ( FRD: ), and Experiment 3 (n = 15/group) had CON, FFD, and FRS (29 h FRS). All DSS treated birds received one or 2 doses of DSS by oral gavage (0.45 g/dose/bird). Results showed that, compared to CON group, there was an increase (P  0.05). Administration of DSS did not result in increase of serum enzymes such as alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase ( LDH: ), nonetheless, the FFD showed lower (P < 0.05) LDH level compared to CON in Experiment 2. Among the various serum chemistry parameters evaluated triglycerides had the highest positive correlation (r2 = 0.85; P < 0.05) with serum turbidity. DSS administration resulted in decreased serum protein levels, especially albumin. These results suggest that oral gavage with DSS in broiler chicks could result in changes to serum chemistry parameters which could be developed as potential marker/s for gut leakage. © 2016 Poultry Science Association Inc.

  14. Mitigating effects of L-selenomethionine on low-dose iron ion radiation-induced changes in gene expression associated with cellular stress.

    Science.gov (United States)

    Nuth, Manunya; Kennedy, Ann R

    2013-07-01

    Ionizing radiation associated with highly energetic and charged heavy (HZE) particles poses a danger to astronauts during space travel. The aim of the present study was to evaluate the patterns of gene expression associated with cellular exposure to low-dose iron ion irradiation, in the presence and absence of L-selenomethionine (SeM). Human thyroid epithelial cells (HTori-3) were exposed to low-dose iron ion (1 GeV/n) irradiation at 10 or 20 cGy with or without SeM pretreatment. The cells were harvested 6 and 16 h post-irradiation and analyzed by the Affymetrix U133Av2 gene chip arrays. Genes exhibiting a 1.5-fold expression cut-off and 5% false discovery rate (FDR) were considered statistically significant and subsequently analyzed using the Database for Annotation, Visualization and Integrated Discovery (DAVID) for pathway analysis. Representative genes were further validated by real-time RT-PCR. Even at low doses of radiation from iron ions, global genome profiling of the irradiated cells revealed the upregulation of genes associated with the activation of stress-related signaling pathways (ubiquitin-mediated proteolysis, p53 signaling, cell cycle and apoptosis), which occurred in a dose-dependent manner. A 24-h pretreatment with SeM was shown to reduce the radiation effects by mitigating stress-related signaling pathways and downregulating certain genes associated with cell adhesion. The mechanism by which SeM prevents radiation-induced transformation in vitro may involve the suppression of the expression of genes associated with stress-related signaling and certain cell adhesion events.

  15. Efficacy and tolerability of rupatadine at four times the recommended dose against histamine- and platelet-activating factor-induced flare responses and ex vivo platelet aggregation in healthy males.

    Science.gov (United States)

    Church, M K

    2010-12-01

    European guidelines recommend increasing H1-antihistamine doses up to fourfold in poorly responding patients with urticaria. To assess the efficacy and tolerability of high-dose rupatadine (40 mg) against platelet-activating factor (PAF)- and histamine-induced flare responses in human skin and to verify its anti-PAF activity by assessing its inhibition of PAF-induced platelet aggregation in the blood of subjects receiving rupatadine 40 mg. In the flare study, six male volunteers received a single dose of rupatadine 40 mg. Flares were induced before dosing and up to 96 h afterwards by intradermal PAF and histamine. In the ex vivo study, four male volunteers received an oral dose of rupatadine 40 mg and blood samples were taken 4 h afterwards. Platelet aggregation was assessed in platelet-rich plasma by incubation for 5 min with PAF. Rupatadine 40 mg reached maximal plasma levels of 15·1 ± 4·4 ng mL⁻¹)1 at 1 h and its metabolite, desloratadine, 5·2 ± 0·9 ng mL⁻¹)1 at 2 h. Neither was detectable at 12 h. Inhibition of histamine- and PAF-induced flares was significant within 2 h, maximal at 6 h (87·8 ± 3·1% and 87·1 ± 2·5% inhibition, respectively, P Rupatadine 40 mg inhibited PAF-induced platelet aggregation ex vivo by 82 ± 9% (P = 0·023). A single oral dose of rupatadine 40 mg was well tolerated with mild transient somnolence being reported. A single dose of rupatadine at four times the recommended dose is well tolerated, highly effective for up to 72 h against PAF- and histamine-induced dermal flares and has demonstrable PAF-receptor antagonism ex vivo.

  16. R-CHOP with dose-attenuated radiation therapy could induce good prognosis in gastric diffuse large B cell lymphoma

    Directory of Open Access Journals (Sweden)

    Mishima Yuko

    2012-09-01

    Full Text Available Abstract Background The treatment strategy for gastric diffuse large cell lymphoma (DLBCL has not been standardized in such as to the cycles of chemotherapy, dose of radiation, or necessity for the surgery. Although the results of CHOP or R-CHOP treatments have demonstrated the good prognosis, the treatments have been controversial in many cases. Methods We retrospectively analyzed 40 gastric DLBCL patients receiving chemotherapy with or without radiation in our institute. Those in stages II-IV were treated with six cycles of R-CHOP without radiation; for those in stage I, we administered three cycles of R-CHOP with radiation. Results The three-year overall survival (OS and progression-free survival (PFS rates were 95.2 and 91.8%, respectively. Those in stage I obtained 100% of OS. The radiation dose prescribed was 30.6 Gy for CR cases and 39.6 to 40 Gy for PR after chemotherapy. Although survival rates tended to correlate with staging groups or age-adjusted IPI classifications, multivariate statistical analysis did not show clear differences. All 14 patients with initial bleeding were successfully managed without surgery during treatment. Conclusion R-CHOP therapy was very effective for gastric DLBCL. It may be not necessary to use more than 30.6 Gy of radiotherapy in the highly chemo-sensitive cases. Less toxic treatments should be made available to gastric DLBCL patients.

  17. DNA–PKcs–SIN1 complexation mediates low-dose X-ray irradiation (LDI)-induced Akt activation and osteoblast differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Yong; Fang, Shi-ji [The Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou 215000 (China); Zhu, Li-juan [Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, Jiangsu 215021 (China); Zhu, Lun-qing, E-mail: xiaodongwangsz@163.com [The Center of Diagnosis and Treatment for Children’s Bone Diseases, The Children’s Hospital Affiliated to Soochow University, Suzhou, Jiangsu 215000 (China); Zhou, Xiao-zhong, E-mail: zhouxz@suda.edu.cn [The Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou 215000 (China)

    2014-10-24

    Highlights: • LDI increases ALP activity, promotes type I collagen (Col I)/Runx2 mRNA expression. • LDI induces DNA–PKcs activation, which is required for osteoblast differentiation. • Akt activation mediates LDI-induced ALP activity and Col I/Runx2 mRNA increase. • DNA–PKcs–SIN1 complexation mediates LDI-induced Akt Ser-473 phosphorylation. • DNA–PKcs–SIN1 complexation is important for osteoblast differentiation. - Abstract: Low-dose irradiation (LDI) induces osteoblast differentiation, however the underlying mechanisms are not fully understood. In this study, we explored the potential role of DNA-dependent protein kinase catalytic subunit (DNA–PKcs)–Akt signaling in LDI-induced osteoblast differentiation. We confirmed that LDI promoted mouse calvarial osteoblast differentiation, which was detected by increased alkaline phosphatase (ALP) activity as well as mRNA expression of type I collagen (Col I) and runt-related transcription factor 2 (Runx2). In mouse osteoblasts, LDI (1 Gy) induced phosphorylation of DNA–PKcs and Akt (mainly at Ser-473). The kinase inhibitors against DNA–PKcs (NU-7026 and NU-7441) or Akt (LY294002, perifosine and MK-2206), as well as partial depletion of DNA–PKcs or Akt1 by targeted-shRNA, dramatically inhibited LDI-induced Akt activation and mouse osteoblast differentiation. Further, siRNA-knockdown of SIN1, a key component of mTOR complex 2 (mTORC2), also inhibited LDI-induced Akt Ser-473 phosphorylation as well as ALP activity increase and Col I/Runx2 expression in mouse osteoblasts. Co-immunoprecipitation (Co-IP) assay results demonstrated that LDI-induced DNA–PKcs–SIN1 complexation, which was inhibited by NU-7441 or SIN1 siRNA-knockdown in mouse osteoblasts. In summary, our data suggest that DNA–PKcs–SIN1 complexation-mediated Akt activation (Ser-473 phosphorylation) is required for mouse osteoblast differentiation.

  18. Therapeutic dose of green tea extract provokes liver damage and exacerbates paracetamol-induced hepatotoxicity in rats through oxidative stress and caspase 3-dependent apoptosis.

    Science.gov (United States)

    El-Bakry, Hanan A; El-Sherif, G; Rostom, Rehab M

    2017-10-17

    Green tea extract (GTE) is considered to be endowed with countless healthful properties. Nevertheless, data concerning the hepatoprotective activities of GTE and its utilization as a therapeutic intervention for paracetamol (APAP) overdose are conflicting and intriguing. The present study was undertaken to address the effect of therapeutic dose of GTE on the liver, evaluate the potential hepatoprotection of GTE against APAP-induced hepatotoxicity, asses the regenerative capacity of the liver after discontinuation of treatments, and explore the mechanisms underlying these effects. Adult male albino rats were divided into six groups (n=9 each): (1) control, (2) APAP (2g/kg, orally for one week), (3) GTE (8.5mg/kg, orally for one month), (4) APAP/GTE (APAP followed by GTE), (5) APAP recovery (for one month) and (6) APAP/GTE recovery (for one month). Administration of APAP or GTE resulted in well-documented biochemical and histopathological alterations indicating hepatotoxicity, manifested as augmented concentrations of liver enzymes, hepatocellular necrosis and degeneration, congestion, hemorrhage, inflammation, and fibrosis. The APAP group showed glycogen depletion. Consistent with these changes apoptosis (as detected by caspase-3 immunoreactivity) and oxidative stress (MDA) were greatly increased, whereas antioxidant activities (catalase and GSH) were markedly decreased. These changes were more pronounced in APAP/GTE group, and were not recovered upon cessation of treatments for one month. These results highlight that administration of therapeutic doses of GTE induces hepatotoxicity, and imply that in a situation of clinical paracetamol overdose, administration of GTE is likely to potentiate APAP-induced hepatotoxicity. Further studies are warranted given the increasing use of green tea extract as a dietary supplement. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  19. Structural changes caused by radiation-induced reduction and radiolysis: the effect of X-ray absorbed dose in a fungal multicopper oxidase

    Energy Technology Data Exchange (ETDEWEB)

    De la Mora, Eugenio [Universidad Nacional Autónoma de México, Avenida Universidad 2001, Cuernavaca, Morelos 62210 (Mexico); Lovett, Janet E. [University of Oxford, South Parks Road, Oxford OX1 3QR (United Kingdom); University of Oxford, South Parks Road, Oxford OX1 3RE (United Kingdom); EaStCHEM School of Chemistry, Joseph Black Building, The King’s Buildings, Edinburgh EH9 3JJ, Scotland (United Kingdom); Blanford, Christopher F. [University of Oxford, South Parks Road, Oxford OX1 3QR (United Kingdom); Manchester Interdisciplinary Biocentre, 131 Princess Street, Manchester M1 7DN (United Kingdom); Garman, Elspeth F. [University of Oxford, South Parks Road, Oxford OX1 3QU (United Kingdom); Valderrama, Brenda; Rudino-Pinera, Enrique, E-mail: rudino@ibt.unam.mx [Universidad Nacional Autónoma de México, Avenida Universidad 2001, Cuernavaca, Morelos 62210 (Mexico)

    2012-05-01

    Radiation-induced reduction, radiolysis of copper sites and the effect of pH value together with the concomitant geometrical distortions of the active centres were analysed in several fungal (C. gallica) laccase structures collected at cryotemperature. This study emphasizes the importance of careful interpretation when the crystallographic structure of a metalloprotein is described. X-ray radiation induces two main effects at metal centres contained in protein crystals: radiation-induced reduction and radiolysis and a resulting decrease in metal occupancy. In blue multicopper oxidases (BMCOs), the geometry of the active centres and the metal-to-ligand distances change depending on the oxidation states of the Cu atoms, suggesting that these alterations are catalytically relevant to the binding, activation and reduction of O{sub 2}. In this work, the X-ray-determined three-dimensional structure of laccase from the basidiomycete Coriolopsis gallica (Cg L), a high catalytic potential BMCO, is described. By combining spectroscopic techniques (UV–Vis, EPR and XAS) and X-ray crystallography, structural changes at and around the active copper centres were related to pH and absorbed X-ray dose (energy deposited per unit mass). Depletion of two of the four active Cu atoms as well as low occupancies of the remaining Cu atoms, together with different conformations of the metal centres, were observed at both acidic pH and high absorbed dose, correlating with more reduced states of the active coppers. These observations provide additional evidence to support the role of flexibility of copper sites during O{sub 2} reduction. This study supports previous observations indicating that interpretations regarding redox state and metal coordination need to take radiation effects explicitly into account.

  20. Lymphadenectomy exacerbates tumor growth while lymphadenectomy plus the adoptive transfer of autologous cytotoxic cells and low-dose cyclophosphamide induces regression of an established murine fibrosarcoma.

    Science.gov (United States)

    Maglioco, Andrea; Machuca, Damián; Mundiñano, Juliana; Cabrera, Gabriel; Camicia, Gabriela; Bruzzo, Juan; Camerano, Gabriela; Costa, Héctor; Ruggiero, Raúl A; Dran, Graciela I

    2011-03-01

    Tumor-draining lymph node (TDLN) ablation is routinely performed in the management of cancer; nevertheless, its usefulness is at present a matter of debate. TDLN are central sites where T cell priming to tumor antigens and onset of the antitumor immune response occur. However, tumor-induced immunosuppression has been demonstrated at TDLN, leading to downregulation of antitumor reaction and tolerance induction. Tolerance in turn is a main impairment for immunotherapy trials. We used a murine immunogenic fibrosarcoma that evolves to a tolerogenic state, to study the cellular and molecular mechanisms underlying tolerance induction at the level of TDLN and to design an appropriate immunotherapy. We determined that following a transient activation, the established tumor induces signs of immunosuppression at TDLN that coexist with local and systemic evidences of antitumor response. Therefore, we evaluated the feasibility of removing TDLN in order to eliminate a focus of immunosuppression and favor tumor rejection; but instead, a marked exacerbation of tumor growth was induced. Combining TDLN ablation with the in vivo depletion of regulatory cells by low-dose cyclophosphamide and the restoring of the TDLN-derived cells into the donor mouse by adoptive transference, resulted in lowered tumor growth, enhanced survival and a considerable degree of tumor regression. Our results demonstrate that important antitumor elements can be eliminated by lymphadenectomy and proved that the concurrent administration of low-dose chemotherapy along with the reinoculation of autologous cytotoxic cells provides protection. We suggest that this protocol may be useful, especially in the cases where lymphadenectomy is mandatory.

  1. Whole body exposure of mice to secondhand smoke induces dose-dependent and persistent promutagenic DNA adducts in the lung

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sang-In [Department of Cancer Biology, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010 (United States); Arlt, Volker M. [Section of Molecular Carcinogenesis, Institute of Cancer Research, Brookes Lawley Building, Sutton, Surrey SM2 5NG (United Kingdom); Yoon, Jae-In [Department of Cancer Biology, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010 (United States); Cole, Kathleen J. [Section of Molecular Carcinogenesis, Institute of Cancer Research, Brookes Lawley Building, Sutton, Surrey SM2 5NG (United Kingdom); Pfeifer, Gerd P. [Department of Cancer Biology, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010 (United States); Phillips, David H. [Section of Molecular Carcinogenesis, Institute of Cancer Research, Brookes Lawley Building, Sutton, Surrey SM2 5NG (United Kingdom); Besaratinia, Ahmad, E-mail: ania@coh.org [Department of Cancer Biology, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA 91010 (United States)

    2011-11-01

    Secondhand smoke (SHS) exposure is a known risk factor for lung cancer in lifelong nonsmokers. However, the underlying mechanism of action of SHS in lung carcinogenesis remains elusive. We have investigated, using the {sup 32}P-postlabeling assay, the genotoxic potential of SHS in vivo by determining the formation and kinetics of repair of DNA adducts in the lungs of mice exposed whole body to SHS for 2 or 4 months (5 h/day, 5 days/week), and an ensuing one-month recovery period. We demonstrate that exposure of mice to SHS elicits a significant genotoxic response as reflected by the elevation of DNA adduct levels in the lungs of SHS-exposed animals. The increases in DNA adduct levels in the lungs of SHS-exposed mice are dose-dependent as they are related to the intensity and duration of SHS exposure. After one month of recovery in clean air, the levels of lung DNA adducts in the mice exposed for 4 months remain significantly higher than those in the mice exposed for 2 months (P < 0.0005), levels in both groups being significantly elevated relative to controls (P < 0.00001). Our experimental findings accord with the epidemiological data showing that exposure to smoke-derived carcinogens is a risk factor for lung cancer; not only does the magnitude of risk depend upon carcinogen dose, but it also becomes more irreversible with prolonged exposure. The confirmation of epidemiologic data by our experimental findings is of significance because it strengthens the case for the etiologic involvement of SHS in nonsmokers' lung cancer. Identifying the etiologic factors involved in the pathogenesis of lung cancer can help define future strategies for prevention, early detection, and treatment of this highly lethal malignancy.

  2. Lamotrigine blocks apoptosis induced by repeated administration of high-dose methamphetamine in the medial prefrontal cortex of rats.

    OpenAIRE

    Nakato, Yasuya; Abekawa, Tomohiro; Ito,Koki; Inoue, Takeshi; Koyama, Tsukasa

    2011-01-01

    Lamotrigine (LTG) is sometimes co-administered with antipsychotic drugs for the treatment of schizophrenia. Nevertheless, the pharmacological basis of LTG use for schizophrenia has not been reported. Our group recently proposed a new psychostimulant animal model that might reflect the progressive pathophysiology of schizophrenia. Results obtained using that model show that LTG blocks the initiation and expression of repeated high-dosage methamphetamine-induced prepulse inhibition deficit in r...

  3. Effects of fixed-dose isosorbide dinitrate/hydralazine on diastolic function and exercise capacity in hypertension-induced diastolic heart failure.

    Science.gov (United States)

    Wilson, Richard M; De Silva, Deepa S; Sato, Kaori; Izumiya, Yasuhiro; Sam, Flora

    2009-09-01

    Hypertension-induced diastolic heart failure accounts for a large proportion of all heart failure presentations. Hypertension also induces left ventricular (LV) hypertrophy. Fixed-dose isosorbide dinitrate/hydralazine (HISDN) decreased mortality in human systolic heart failure but it is unknown whether it improves maladaptive myocardial remodeling. We sought to test the hypothesis that chronic HISDN modulates LV hypertrophy and myocardial remodeling in hypertension-induced diastolic heart failure. FVB mice underwent either saline (n=18) or aldosterone (n=28) infusion. All underwent uninephrectomy and drank 1% salt water for 4 weeks. Mice were randomized after surgery to regular chow or chow containing HISDN (isosorbide dinitrate: 26 mg/kg per day; hydralazine: 50 mg/kg per day) for 4 weeks. Aldosterone infusion increased tail-cuff blood pressure (161+/-3 mm Hg) versus saline-infused mice (129+/-2 mm Hg). Aldosterone induced LV hypertrophy versus saline-infused mice (LV:body weight ratio: 4.2+/-0.1 versus 3.6+/-0.1 mg/g). HISDN attenuated the aldosterone-induced increased in systolic blood pressure (137+/-5 mm Hg) and also lowered blood pressure in saline-infused mice (114+/-2 mm Hg). However, HISDN did not cause LV hypertrophy regression in aldosterone-infused mice. Aldosterone increased LV end-diastolic dimensions that were not attenuated by HISDN. Similarly, neither aldosterone infusion nor HISDN affected LV end-systolic dimensions. LV ejection fraction and wet:dry lung ratio were not different between aldosterone-untreated and aldosterone-HISDN mice. However, mitral Doppler E/A ratio (a measure of diastolic function), exercise capacity, and plasma soluble vascular cell adhesion molecule 1 levels were improved in aldosterone-HISDN hearts. In conclusion, fixed-dose HISDN improved hypertension, diastolic function, and exercise capacity and reduced soluble vascular cell adhesion molecule 1 levels. There were no reductions in LV hypertrophy, cardiac fibrosis, or

  4. Nanosilica induced dose-dependent cytotoxicity and cell type-dependent multinucleation in HepG2 and L-02 cells

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Yongbo [Capital Medical University, Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, Beijing Pediatric Research Institute, Beijing Children’s Hospital (China); Duan, Junchao; Li, Yang; Yu, Yang; Hu, Hejing; Wu, Jing; Zhang, Yannan; Li, Yanbo; CaixiaGuo; Zhou, Xianqing; Sun, Zhiwei, E-mail: zwsun@ccmu.edu.cn [Capital Medical University, School of Public Health (China)

    2016-11-15

    The prevalent exposure to nanosilica gained concerns about health effects of these particles on human beings. Although nanosilica-induced multinucleation has been confirmed previously, the underlying mechanism was still not clear; this study was to investigate the origination of multinucleated cells caused by nanosilica (62 nm) in both HepG2 and L-02 cells. Cell viability and cellular uptake was determined by MTT assay and transmission electron microscope (TEM), respectively. Giemsa staining was applied to detect multinucleation. To clarify the origination of multinucleated cells, fluorescent probes, PKH26 and PKH67, time-lapse observation were further conducted by confocal microscopy. Results indicated that nanosilica particles were internalized into cells and induced cytotoxicity in a dose-dependent manner. Quantification analysis showed that nanosilica significantly increased the rates of binucleated and multinucleated cells, which suggested mitotic catastrophe induction. Moreover, dynamic visualization verified that multinucleation resulted from cell fusion in HepG2 cells not in L-02 cells after nanosilica exposure, suggesting cell type-dependent multinucleation formation. Both multinucleation and cell fusion were involved in genetic instability, which emphasized the significance to explore the multinucleation induced by nanosilica via environmental, occupational and consumer product exposure.

  5. Gamma radiation-induced conditioned taste aversions in rats: A comparison of the protective effects of area postrema lesions with differing doses of radiation

    Energy Technology Data Exchange (ETDEWEB)

    Ossenkopp, K.P.; Giugno, L. (Univ. of Western Ontario, London (Canada))

    1989-10-01

    Lesions which destroy the area postrema (AP) and damage the adjacent nucleus of the solitary tract (NTS) attenuate or abolish conditioned taste aversions (CTA) induced by a variety of pharmacological agents as well as exposure to radiation. In the present experiment, 4 groups of male rats received lesions of AP and 4 groups were given sham lesions. One sham-lesioned and one AP-lesioned group were given a single pairing of 1-hr access to a novel 0.10% sodium saccharin solution followed immediately with exposure to 0, 100, 200, or 400 rad of gamma radiation, respectively. Four days later all groups were given daily two-bottle preference tests (saccharin vs. water) on 4 consecutive days. The sham-lesioned groups exposed to the radiation (100, 200, or 400 rad) developed profound aversions to the saccharin on all test days (p less than 0.001). In contrast, all of the AP-lesioned groups as well as the sham-irradiated (0 rad) sham-lesioned group exhibited strong, comparable (p greater than 0.30) preferences for saccharin. Thus, lesion of AP abolished the radiation-induced CTA at all dose levels of radiation. These results raise the possibility of pharmacological intervention at the level of AP to prevent radiation-induced CTA in cancer patients undergoing radiation therapy.

  6. Study on Effectiveness of Low Dose Theophylline as Add-on to Inhaled Corticosteroid for Patients with Sulfur Mustard Induced Bronchiolitis

    Directory of Open Access Journals (Sweden)

    Yunes Panahi

    2013-12-01

    Full Text Available Background: Theophylline may reverse steroid resistance and decrease inflammation in patients with chronic pulmonary disease and sulfur mustard (SM induced bronchiolitis. This study was designed to assess the effects of low-dose theophylline on improvement of pulmonary function tests (PFTs of SM exposed patients.Methods: In this comparative observational study, a group of SM-exposed victims during the Iraq-Iran war who were treated with oral slow releasing (SR theophylline, salmetrol, fluxitide, omeprazole and NAC (study group were compared to a group of age and gender matched SM-exposed patients who received same medications except oral SR theophylline (historical control group. PFTs were measured at the beginning of the study and after 8 weeks of the treatment.Results: In total, 33 subjects in the study group and 27 subjects in the control group were studied. Mean (SD age of all subjects was 51 (14.1 years. In the study group, on the 8th week post-treatment, PFTs decreased, though the differences of tests between before and after treatment were not significant. In the control group, all the tests decreased in the same period and these reductions were not also significant. However, the changes in PFTs were significantly different between the two groups. The results of most PFTs in the controls decreased in greater extents compared to theophylline treated patients. This shows that despite theophylline was unable to improve the patients; it was partially able to decelerate the reductions in PFTs.Conclusion: Theophylline may not improve PFTs of SM exposed patients but it may decelerate the progress of the underlying respiratory disease. Further studies in this setting with higher doses of theophylline and longer term of evaluation are needed to better understand the pathophysiological mechanism of SM induced bronchiolitis and the effectiveness of the treatment with theophylline.   How to cite this article: Panahi Y, Poursaleh Z, Amini-Harandi A

  7. Neutropenia induced in outbred mice by a simplified low-dose cyclophosphamide regimen: characterization and applicability to diverse experimental models of infectious diseases

    Science.gov (United States)

    Zuluaga, Andres F; Salazar, Beatriz E; Rodriguez, Carlos A; Zapata, Ana X; Agudelo, Maria; Vesga, Omar

    2006-01-01

    Background For its low cost and ease of handling, the mouse remains the preferred experimental animal for preclinical tests. To avoid the interaction of the animal immune system, in vivo antibiotic pharmacodynamic studies often employ cyclophosphamide (CPM) to induce neutropenia. Although high doses (350–450 mg/kg) are still used and their effects on mouse leukocytes have been described, a lower dose (250 mg/kg) is widely preferred today, but the characteristics and applicability of this approach in outbred mice have not been determined. Methods Fifteen female ICR mice were injected intraperitoneally with 150 and 100 mg/kg of CPM on days 1 and 4, respectively. Blood samples (~160 μL) were drawn from the retro-orbital sinus of each mouse on days 1, 4, 5, 6, 7 and 11. Leukocytes were counted manually and the number of granulocytes was based on microscopic examination of Wright-stained smears. The impact of neutropenia induced by this method was then determined with a variety of pathogens in three different murine models of human infections: pneumonia (Klebsiella pneumoniae, Streptococcus pneumoniae, Staphylococcus aureus), meningoencephalitis (S. pneumoniae), and the thigh model (S. aureus, Escherichia coli, Bacteroides fragilis). Results The basal count of leukocytes was within the normal range for outbred mice. On day 4, there was an 84% reduction in total white blood cells, and by day 5 the leukopenia reached its nadir (370 ± 84 cells/mm3). Profound neutropenia (≤10 neutrophils/mm3) was demonstrated at day 4 and persisted through days 5 and 6. Lymphocytes and monocytes had a 92% and 96% decline between days 1 and 5, respectively. Leukocytes recovered completely by day 11. Mice immunosupressed under this protocol displayed clinical and microbiological patterns of progressive and lethal infectious diseases after inoculation in different organs with diverse human pathogens. Conclusion A CPM total dose of 250 mg/kg is sufficient to induce profound and sustained

  8. A single high dose of methamphetamine induces apoptotic and necrotic striatal cell loss lasting up to 3 months in mice.

    Science.gov (United States)

    Tulloch, I; Afanador, L; Mexhitaj, I; Ghazaryan, N; Garzagongora, A G; Angulo, J A

    2011-10-13

    Methamphetamine (METH) is an addictive agent that poses a public health problem due to its toxic effects on neural tissue. We have shown that METH induces striatal lesions (cell loss) within 24 h of administration. Because cell proliferation has been found to follow excitotoxic and other types of lesions in adult brain, we tested the hypothesis that cell proliferation would follow METH-induced striatal cell death. To that end, METH (30 mg/kg i.p.) was injected into adult male mice followed by a single injection of the proliferation marker 5-bromo-2'-deoxyuridine (BrdU, 100 mg/kg i.p.) at various times post-METH up to 12 weeks. Immunohistochemical analysis of striatal tissue showed that METH-treated animals incorporated BrdU between 24-48 h post-METH. To determine the survival of the newly generated cells, a subgroup of animals received BrdU 36 h after METH and were sacrificed at various times up to 12 weeks post-METH. Morphological analysis of striatal tissue from these animals showed that by 12 weeks post-METH, approximately 42% and 30% of the newly generated cells showed pyknotic or necrotic morphology, respectively. Thus, approximately 30% of the newly generated cells survive up to 12 weeks post-METH. Striatal volume was increased by METH and normalized to control levels by 12 weeks after METH. The data demonstrate that a single bolus injection of METH induces cellular changes and responses that persist for months after exposure to METH. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

  9. Effective treatment of house dust mite-induced allergic rhinitis with 2 doses of the SQ HDM SLIT-tablet

    DEFF Research Database (Denmark)

    Demoly, Pascal; Emminger, Waltraud; Rehm, Dorte

    2016-01-01

    : The trial was a randomized, double-blind, placebo-controlled phase III trial conducted in 12 European countries including 992 adults with moderate-to-severe HDM-induced AR despite treatment with pharmacotherapy. Subjects were randomized 1:1:1 to 1 year of daily treatment with placebo, 6 SQ-HDM, or 12 SQ......-HDM. The primary end point was the total combined rhinitis score (ie, the sum of rhinitis symptom and medication scores) during the efficacy assessment period (approximately the last 8 weeks of the treatment period). Key secondary end points were rhinitis symptoms, medication scores, quality of life...

  10. A single dose of dexamethasone encapsulated in polyethylene glycol-coated polylactic acid nanoparticles attenuates cisplatin-induced hearing loss following round window membrane administration

    Science.gov (United States)

    Sun, Changling; Wang, Xueling; Zheng, Zhaozhu; Chen, Dongye; Wang, Xiaoqin; Shi, Fuxin; Yu, Dehong; Wu, Hao

    2015-01-01

    This study aimed to investigate the sustained drug release properties and hearing protection effect of polyethylene glycol-coated polylactic acid (PEG-PLA) stealth nanoparticles loaded with dexamethasone (DEX). DEX was fabricated into PEG-PLA nanoparticles using an emulsion and evaporation technique, as previously reported. The DEX-loaded PEG-PLA nanoparticles (DEX-NPs) had a hydrodynamic diameter of 130±4.78 nm, and a zeta potential of −26.13±3.28 mV. The in vitro release of DEX from DEX-NPs lasted 24 days in phosphate buffered saline (pH 7.4), 5 days in artificial perilymph (pH 7.4), and 1 day in rat plasma. Coumarin 6-labeled NPs placed onto the round window membrane (RWM) of guinea pigs penetrated RWM quickly and accumulated to the organs of Corti, stria vascularis, and spiral ganglion cells after 1 hour of administration. The DEX-NPs locally applied onto the RWM of guinea pigs by a single-dose administration continuously released DEX in 48 hours, which was significantly longer than the free DEX that was cleared out within 12 hours after administration at the same dose. Further functional studies showed that locally administrated single-dose DEX-NPs effectively preserved outer hair cells in guinea pigs after cisplatin insult and thus significantly attenuated hearing loss at 4 kHz and 8 kHz frequencies when compared to the control of free DEX formulation. Histological analyses indicated that the administration of DEX-NPs did not induce local inflammatory responses. Therefore, prolonged delivery of DEX by PEG-PLA nanoparticles through local RWM diffusion (administration) significantly protected the hair cells and auditory function in guinea pigs from cisplatin toxicity, as determined at both histological and functional levels, suggesting the potential therapeutic benefits in clinical applications. PMID:25999718

  11. Metabolic outcome of female mice exposed to a mixture of low-dose pollutants in a diet-induced obesity model.

    Directory of Open Access Journals (Sweden)

    Danielle Naville

    Full Text Available Pollutants are suspected to contribute to the etiology of obesity and related metabolic disorders. Apart from occupational exposure which concerns a subset of chemicals, humans are mostly exposed to a large variety of chemicals, all life-long and at low doses. Food ingestion is a major route of exposure and it is suggested that pollutants have a worsened impact when combined with a high-fat diet. In the experimental studies described herein, we aimed to add further evidence on the metabolic impact of food pollutants using a recently set up model in which mice are life-long fed a high-fat/high-sucrose diet (HFSD with/without common food pollutants shown to exhibit metabolic disrupting activities. Specifically, this mixture comprised bisphenol A, dioxin, polychlorobiphenyl PCB153, and phthalate and was added in HFSD at doses resulting in mice exposure at the Tolerable Daily Intake dose range for each pollutant. We herein focused on the 7-week-old females which exhibited early signs of obesity upon HFSD feeding. We observed no signs of toxicity and no additional weight gain following exposure to the mixture but alleviated HFSD-induced glucose intolerance in the absence of alteration of gluconeogenesis and steatosis. It suggested that the observed metabolic improvement was more likely due to effects on muscle and/or adipose tissues rather than on the liver. Consistently, female mice exhibited enhanced lean/fat mass ratio and skeletal muscle insulin sensitivity. Moreover, expression levels of inflammatory markers were reduced in adipose tissue at 7 but enhanced at 12 weeks of age in agreement with the inverse alterations of glucose tolerance observed at these ages upon pollutant exposure in the HFSD-fed females. Collectively, these data suggest apparent biphasic effects of pollutants upon HFSD feeding along with obesity development. These effects were not observed in males and may depend on interactions between diet and pollutants.

  12. mBAND analysis of chromosome aberrations in human epithelial cells induced by gamma-rays and secondary neutrons of low dose rate.

    Science.gov (United States)

    Hada, M; Gersey, B; Saganti, P B; Wilkins, R; Cucinotta, F A; Wu, H

    2010-08-14

    Human risks from chronic exposures to both low- and high-LET radiation are of intensive research interest in recent years. In the present study, human epithelial cells were exposed in vitro to gamma-rays at a dose rate of 17 mGy/h or secondary neutrons of 25 mGy/h. The secondary neutrons have a broad energy spectrum that simulates the Earth's atmosphere at high altitude, as well as the environment inside spacecrafts like the Russian MIR station and the International Space Station (ISS). Chromosome aberrations in the exposed cells were analyzed using the multicolor banding in situ hybridization (mBAND) technique with chromosome 3 painted in 23 colored bands that allows identification of both inter- and intrachromosome exchanges including inversions. Comparison of present dose responses between gamma-rays and neutron irradiations for the fraction of cells with damaged chromosome 3 yielded a relative biological effectiveness (RBE) value of 26+/-4 for the secondary neutrons. Our results also revealed that secondary neutrons of low dose rate induced a higher fraction of intrachromosome exchanges than gamma-rays, but the fractions of inversions observed between these two radiation types were indistinguishable. Similar to the previous findings after acute radiation exposures, most of the inversions observed in the present study were accompanied by other aberrations. The fractions of complex type aberrations and of unrejoined chromosomal breakages were also found to be higher in the neutron-exposed cells than after gamma-rays. We further analyzed the location of the breaks involved in chromosome aberrations along chromosome 3, and observed hot spots after gamma-ray, but not neutron, exposures.

  13. Protective effect of pioglitazone on cardiomyocyte apoptosis in low-dose streptozotocin & high-fat diet-induced type-2 diabetes in rats

    Directory of Open Access Journals (Sweden)

    Uma Bhandari

    2015-01-01

    Full Text Available Background & objectives: Cardiomyocyte apoptosis is one of the pathologic phenomena associated with diabetes and related conditions including obesity, insulin resistance and hyperlipidaemia. In the present study, the protective effects of pioglitazone on cardiomyocyte apoptosis was evaluated in experimental diabetes induced by low dose of streptozoticin (STZ combined with high fat diet (HFD in rats. Methods: Male Wistar rats (150-200 g were injected with low-dose STZ (45 mg/kg, i.v., single dose and orally fed with a HFD (20 g/day/rat for a period of 28 days and simultaneously treated with pioglitazone (20 mg/kg/p.o. for a period of 21 days (from 8 th day to 28 th day. On 29 th day blood was collected, serum separated and used for biochemical parameters. Heart tissue was used for cardiomyocyte apoptosis measurement and also for histopathological examination. Results: Pioglitazone treatment resulted in a decrease in cardiomyocyte apoptosis as revealed by a decrease in cardiac caspase-3, lactate dehydrogenase (LDH levels and DNA fragmentation, and an increase in Na+K+ATPase levels in diabetic rats. Cardiac histology of diabetic control rats showed dense focal fatty infiltration in the myocardial cells whereas normal architecture with regular morphology and well preserved cytoplasm was observed with pioglitazone treatment. Pioglitazone treatment significantly reduced the heart rate, mean arterial blood pressure, body mass index (BMI and levels of serum glucose, leptin, insulin, HOMA-IR, total cholesterol (TC and triglycerides (TGs, apoliproprotein-B glycosylated haemoglobin (HbA1c levels and atherogenic index, and increased the levels of serum high density lipoprotein cholesterol (HDL-C and cardiac antioxidant enzymes. Interpretation & conclusions: The present study results suggest that pioglitazone possesses cardiac anti-apoptotic potential in diabetic rat model and can be further explored for its use for treatment of diabetic cardiomyopathy.

  14. Consensus Guideline for Use of Glucarpidase in Patients with High-Dose Methotrexate Induced Acute Kidney Injury and Delayed Methotrexate Clearance

    DEFF Research Database (Denmark)

    Ramsey, Laura B; Balis, Frank M; O'Brien, Maureen M

    2018-01-01

    Acute kidney injury due to high-dose methotrexate (HDMTX) is a serious, life-threatening toxicity that can occur in pediatric and adult patients. Glucarpidase is a treatment approved by the Food and Drug Administration for high methotrexate concentrations in the context of kidney dysfunction......, but the guidelines for when to use it are unclear. An expert panel was convened to provide specific, expert consensus guidelines for the use of glucarpidase in patients who develop HDMTX-induced nephrotoxicity and delayed methotrexate excretion. The guideline provides recommendations to identify the population...... of patients who would benefit from glucarpidase rescue by more precisely defining the absolute methotrexate concentrations associated with risk for severe or life-threatening toxicity at several time points after the start of an HDMTX infusion. For an HDMTX infusion ≤24 hours, if the 36-hour concentration...

  15. Equitoxic Doses of 5-Azacytidine and 5-Aza-2 ′ Deoxycytidine Induce Diverse Immediate and Overlapping Heritable Changes in the Transcriptome

    DEFF Research Database (Denmark)

    Qiu, X.; Hother, C.; Ralfkiær, U. M.

    2010-01-01

    BACKGROUND: 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...... 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...... was observed in T24 cells. CONCLUSIONS/SIGNIFICANCE: 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....

  16. Effect of lower doses of vanadate in combination with Azadirachta indica leaf extract on hepatic and renal antioxidant enzymes in streptozotocin-induced diabetic rats.

    Science.gov (United States)

    Upreti, Jaya; Ali, Shakir; Basir, Seemi Farhat

    2013-12-01

    The present study was undertaken to investigate short-term (21 days) effects of oral administration of Azadirachta indica leaf extract and vanadate, separately and in combination, on the activities of antioxidant enzymes in streptozotocin-induced diabetic rats. Vanadate is a remarkable antidiabetic agent and shows insulin mimetic effect. However, severe toxicity is associated with vanadate when used in high concentration while at lower concentration the hypoglycemic property of vanadate is reduced. So, we used a low dose of vanadate in combination with A. indica leaf extract and evaluated their effect on the antioxidant defense system. Streptozotocin-diabetic rats were treated separately with insulin, vanadate (0.6 mg/ml), A. indica, and with combined dose of vanadate (0.2 mg/ml) and A. indica. At the end of the experiment, rats were sacrificed and serum glucose levels and activities of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase were determined in cytosolic fraction of liver and kidney. Diabetic rats showed hyperglycemic condition and alteration in antioxidant enzyme activities. Treatment with antidiabetic compounds resulted in the reduction of glucose levels and restoration of enzyme activities to normal. Results showed that combined treatment of vanadate and A. indica leaf extract was the most effective in normalizing altered antioxidant enzyme system.

  17. [Safety of reintroduction of erlotinib at low doses following hand-foot syndrome induced by erlotinib treatment for a Pancoast-Tobias tumour].

    Science.gov (United States)

    Clause, A-L; Vanderheyde, K; Pieters, T

    2014-09-01

    Erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is a targeted therapy used in first, second or third line treatment of non-small cell lung carcinoma. Several cutaneous toxicities after the use of EGFR-TKI are well-described. After 13 days of erlotinib treatment, an 82-year-old man, diagnosed with squamous cell lung carcinoma, developed an acneiform rash in parallel with hand-foot syndrome (HFS). This led to the interruption of his treatment because of the patient's distress. However, for the first time and after a total recovery of the toxidermia, we reintroduced the therapy at very low doses without any HFS recurrence being observed. The HFS is a dose-dependent toxidermia appearing within the first week following administration of the triggering cytotoxic agents (chemotherapies or target therapies). It appears that a specific pathogenic mechanism exists for each cytotoxic agent triggering the skin damage, resulting in different clinical presentations. A major aspect of HFS treatment involves the reduction or withdrawal of the treatment. We describe what is to our knowledge, the third case of erlotinib-induced HFS, a new secondary undesirable skin pathology for which, currently, exist few direct causal explanations or drug monitoring. This observation highlights the importance of broadening our knowledge of the exact mechanisms linking EGFR-TKI to the appearance of HFS in order to optimize treatment. Copyright © 2013 SPLF. Published by Elsevier Masson SAS. All rights reserved.

  18. Phenolics composition and antidiabetic property of Brachystegia eurycoma seed flur in high-fat diet, low-dose streptozotocin-induced type 2 diabetes in rats

    Directory of Open Access Journals (Sweden)

    Emmanuel Anyachukwu Irondi

    2015-06-01

    Full Text Available Objective: To quantify some major pharmacologically important flavonoids and phenolic acids in Brachystegia eurycoma seed flour (BESF and evaluate its antidiabetic activity in type 2 diabetic rats. Method: Flavonoids and phenolic acids were quantified using a reverse-phase high pressure liquid chromatrography coupled with diode array detection. Type 2 diabetes was induced in rats using high-fat diet, low-dose streptozotocin (HFD/STZ model, by feeding the rats with HFD for 2 weeks followed by single dose administration of STZ (40 mg/kg body weight, intraperitoneally. The diabetic rats were later fed BESF-supplemented (10% and 20% diets, or administered with metformin (25 mg/kg b.w. for 21 days; the control rats were fed basal diet during this period. After the dietary regimen, the rats were sacrificed, and their blood, liver and pancreas samples were collected for biochemical assays. Results: The flavonoids (catechin, rutin, quercitrin, quercetin and kaempferol and phenolic acids (gallic acid, caffeic, chlorogenic and ellagic acid were abundant in BESF. BESFsupplemented diets (BESF-SD significantly (P 0.05 with metformin administration in some of the biomarkers. Conclusion: The flavonoids and phenolic acids in BESF may have acted synergistically to produce the observed antidiabetic effects. BESF could therefore be an effective and affordable dietary therapy for the management of T2DM; and an excellent source for drug discovery.

  19. Single-Dose Metformin Enhances Bile Acid-Induced Glucagon-Like Peptide-1 Secretion in Patients With Type 2 Diabetes.

    Science.gov (United States)

    Brønden, Andreas; Albér, Anders; Rohde, Ulrich; Rehfeld, Jens F; Holst, Jens J; Vilsbøll, Tina; Knop, Filip K

    2017-11-01

    Despite a position as the first-line pharmacotherapy in type 2 diabetes, the glucose-lowering mechanisms of metformin remain to be fully clarified. Gut-derived modes of action, including suppression of bile acid reabsorption and a resulting increase in glucagon-like peptide-1 (GLP-1) secretion, have been proposed. The aim of this study was to assess the GLP-1 secretory and glucometabolic effects of endogenously released bile, with and without concomitant single-dose administration of metformin in patients with type 2 diabetes. Randomized, placebo-controlled, and double-blinded crossover study. This study was conducted at Center for Diabetes Research, Gentofte Hospital, Denmark. Fifteen metformin-treated patients with type 2 diabetes; all participants completed the study. Four experimental study days in randomized order with administration of either 1500 mg metformin or placebo in combination with intravenous infusion of cholecystokinin (0.4 pmol × kg-1 × min-1) or saline. Plasma GLP-1 excursions as measured by baseline-subtracted area under the curve. Single-dose metformin further enhanced bile acid-mediated induction of GLP-1 secretion (P = 0.02), whereas metformin alone did not increase plasma GLP-1 concentrations compared with placebo (P = 0.17). Metformin, both with (P = 0.02) and without (P = 0.02) concomitant cholecystokinin-induced gallbladder emptying, elicited reduced plasma glucose excursions compared with placebo. No GLP-1-mediated induction of insulin secretion or suppression of glucagon was observed. Metformin elicited an enhancement of the GLP-1 response to cholecystokinin-induced gallbladder emptying in patients with type 2 diabetes, whereas no derived effects on insulin or glucagon secretion were evident in this acute setting.

  20. In-vivo kinetics of ALA-induced fluorescence in the canine oral cavity: influence of drug dose and tissue type

    Science.gov (United States)

    Vaidyanathan, Vijay; Rastegar, Sohi; Fossum, Theresa W.; Flores, P.; van der Breggen, E. W. J.; Egger, N. G.; Jacques, Steven L.; Motamedi, Massoud

    1997-06-01

    Fluorescence spectroscopic detection and photodynamic therapy may provide an effective approach for early detection and treatment of oral cancer. Thus the development of a safe photosensitizer that could enhance the spectroscopic contrast between normal and neoplastic tissue, while allowing for selective photosensitization and treatment of pre-malignant and malignant lesions in the oral cavity, is highly desired. In this study, the pharmacokinetics and a safety of 5-aminolevulinic acid (ALA) that could induce an endogenous precursor of protoporphyrin IX and heme in the biosynthetic pathway was investigated. Two doses of ALA:25 and 75 mg/kg were administered intravenously to 4 and 3 dogs, respectively. A 'wash-out' period of 1 week between administration of each does was allowed to ensure against PpIX build-up. Using an optical multichannel analyzer, the fluorescence from the oral cavity was recorded at 3 sites: buccal mucosa, gums, and the tongue, and also from a remote site, the skin. A fiber optic probe was used to deliver excitation and collect the emitted fluorescence. Results showed that the ALA-induced fluorescence reached a peak at 2-4 hours, and returned to baseline in 24-31 hours. The dogs were stable during the course of the study, minimal vomiting was noted. In conclusion, the study showed that higher doses result in a higher peak at a later time.It was observed that different tissues have different pharmacokinetic response, the tongue and the gums have the highest peak fluorescence values, followed by the buccal mucosa and skin.

  1. Site specific oxidation of amino acid residues in rat lens γ-crystallin induced by low-dose γ-irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Ingu [Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502 (Japan); Saito, Takeshi [Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502 (Japan); Research Reactor Institute, Kyoto University, Kumatori, Osaka 590-0494 (Japan); Fujii, Norihiko [Radioisotope Research Center, Teikyo University, Kaga Itabashi-ku, Tokyo 173-8605 (Japan); Kanamoto, Takashi [Department of Ophthalmology, Hiroshima Memorial Hospital, Honkawacho, Naka-ku, Hiroshima 730-0802 (Japan); Chatake, Toshiyuki [Research Reactor Institute, Kyoto University, Kumatori, Osaka 590-0494 (Japan); Fujii, Noriko, E-mail: nfujii@rri.kyoto-u.ac.jp [Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502 (Japan); Research Reactor Institute, Kyoto University, Kumatori, Osaka 590-0494 (Japan)

    2015-10-30

    Although cataracts are a well-known age-related disease, the mechanism of their formation is not well understood. It is currently thought that eye lens proteins become abnormally aggregated, initially causing clumping that scatters the light and interferes with focusing on the retina, and ultimately resulting in a cataract. The abnormal aggregation of lens proteins is considered to be triggered by various post-translational modifications, such as oxidation, deamidation, truncation and isomerization, that occur during the aging process. Such modifications, which are also generated by free radical and reactive oxygen species derived from γ-irradiation, decrease crystallin solubility and lens transparency, and ultimately lead to the development of a cataract. In this study, we irradiated young rat lenses with low-dose γ-rays and extracted the water-soluble and insoluble protein fractions. The water-soluble and water-insoluble lens proteins were digested with trypsin, and the resulting peptides were analyzed by LC-MS. Specific oxidation sites of methionine, cysteine and tryptophan in rat water-soluble and -insoluble γE and γF-crystallin were determined by one-shot analysis. The oxidation sites in rat γE and γF-crystallin resemble those previously identified in γC and γD-crystallin from human age-related cataracts. Our study on modifications of crystallins induced by ionizing irradiation may provide useful information relevant to human senile cataract formation. - Highlights: • Low-dose γ-rays induced oxidation at specific residues in γE- and γF-crystallin. • The number of oxidation sites was higher in insoluble than soluble crystallins. • γ-Irradiation closely mimics the oxidation that occur in senile human cataracts.

  2. Protection by low-dose γ radiation on doxorubicin-induced nephropathy in rats pretreated with curcumin, green tea, garlic or l-carnitine

    Directory of Open Access Journals (Sweden)

    Rasha R. Radwan

    2012-12-01

    Full Text Available The protective potentials of a single exposure to 0.3 Gy of γ radiation alone or with previous treatment with certain natural products with antioxidants activity, namely curcumin (50 mg/kg, i.p., green tea (300 mg/kg, p.o., garlic (100 mg/kg, p.o. or l-carnitine (40 mg/kg, i.p. against doxorubicin (DOX-induced nephropathy in rats were studied. Natural products were administered daily for 14 successive days followed by single i.p. injection of DOX (5 mg/kg. Rats were subjected to whole body γ radiation, 1 day before DOX administration. Serum levels of creatinine, urea, uric acid, low density lipoprotein (LDL-C, high density lipoprotein (HDL-C cholesterols, total proteins and albumin as well as renal concentrations of reduced glutathione (GSH, thiobarbituric acid reactive substances (TBARS, nitric oxide (NO and calcium (Ca were determined. Irradiation provided significant protections against DOX-induced changes in all measured parameters, except renal Ca content. All the test natural products significantly improved radiation-induced protection against renal lipid peroxidation. l-Carnitine markedly augmented the protection toward changes in renal GSH, NO and Ca concentrations. Curcumin increased the protection toward changes in serum albumin and renal GSH and NO concentrations, while garlic increased the protection toward changes in serum LDL-C level. It could be concluded that low-dose γ radiation could provide prophylaxis against DOX-induced nephropathy which might be augmented by the use of certain natural antioxidants.

  3. Low doses of cholera toxin and its mediator cAMP induce CTLA-2 secretion by dendritic cells to enhance regulatory T cell conversion.

    Directory of Open Access Journals (Sweden)

    Cinthia Silva-Vilches

    Full Text Available Immature or semi-mature dendritic cells (DCs represent tolerogenic maturation stages that can convert naive T cells into Foxp3+ induced regulatory T cells (iTreg. Here we found that murine bone marrow-derived DCs (BM-DCs treated with cholera toxin (CT matured by up-regulating MHC-II and costimulatory molecules using either high or low doses of CT (CThi, CTlo or with cAMP, a known mediator CT signals. However, all three conditions also induced mRNA of both isoforms of the tolerogenic molecule cytotoxic T lymphocyte antigen 2 (CTLA-2α and CTLA-2β. Only DCs matured under CThi conditions secreted IL-1β, IL-6 and IL-23 leading to the instruction of Th17 cell polarization. In contrast, CTlo- or cAMP-DCs resembled semi-mature DCs and enhanced TGF-β-dependent Foxp3+ iTreg conversion. iTreg conversion could be reduced using siRNA blocking of CTLA-2 and reversely, addition of recombinant CTLA-2α increased iTreg conversion in vitro. Injection of CTlo- or cAMP-DCs exerted MOG peptide-specific protective effects in experimental autoimmune encephalomyelitis (EAE by inducing Foxp3+ Tregs and reducing Th17 responses. Together, we identified CTLA-2 production by DCs as a novel tolerogenic mediator of TGF-β-mediated iTreg induction in vitro and in vivo. The CT-induced and cAMP-mediated up-regulation of CTLA-2 also may point to a novel immune evasion mechanism of Vibrio cholerae.

  4. Variation in apoptosis mechanisms employed by malaria parasites: the roles of inducers, dose dependence and parasite stages

    Directory of Open Access Journals (Sweden)

    Matthews Holly

    2012-08-01

    Full Text Available Abstract Background Plasmodium berghei ookinetes exhibit an apoptotic phenotype when developing within the mosquito midgut lumen or when cultured in vitro. Markers of apoptosis increase when they are exposed to nitric oxide or reactive oxygen species but high concentrations of hydrogen peroxide cause death without observable signs of apoptosis. Chloroquine and other drugs have been used to induce apoptosis in erythrocytic stages of Plasmodium falciparum and to formulate a putative pathway involving cysteine protease activation and mitochondrial membrane permeabilization; initiated, at least in the case of chloroquine, after its accumulation in the digestive vacuole causes leakage of the vacuole contents. The lack of a digestive vacuole in ookinetes prompted the investigation of the effect of chloroquine and staurosporine on this stage of the life cycle. Finally, the suggestion that apoptosis may have evolved as a strategy employed by ookinetes to increase the fitness of surviving parasites was explored by determining whether increasing the ecological triggers parasite density and nutrient depletion induced apoptosis. Methods Ookinetes were grown in culture then either exposed to hydrogen peroxide, chloroquine or staurosporine, or incubated at different densities and in different media. The proportion of ookinetes displaying positive markers for apoptosis in treated samples was compared with controls and results were analyzed using analysis of variance followed by a Turkey’s test, or a Kruskal-Wallis test as appropriate. Results Hydrogen peroxide below 50 μM triggered apoptosis but cell membranes were rapidly compromised by higher concentrations, and the mode of death could not be defined. Both chloroquine and staurosporine cause a significant increase in ookinetes with condensed chromatin, caspase-like activity and, in the case of chloroquine, phosphatidylserine translocation and DNA fragmentation (not investigated for staurosporine. However

  5. Comparison of the expression profiles induced by genotoxic and nongenotoxic carcinogens in rat liver

    Energy Technology Data Exchange (ETDEWEB)

    Ellinger-Ziegelbauer, Heidrun [Bayer Healthcare AG, Department of Molecular and Genetic Toxicology, Aprather Weg 18a, 42096 Wuppertal (Germany)]. E-mail: heidrun.ellinger-ziegelbauer@bayerhealthcare.com; Stuart, Barry [Bayer Crop Science, Department of Toxicology, Stilwell, KS (United States); Wahle, Brad [Bayer Crop Science, Department of Toxicology, Stilwell, KS (United States); Bomann, Werner [Bayer Crop Science, Department of Toxicology, Stilwell, KS (United States); Ahr, Hans Juergen [Bayer Healthcare AG, Department of Molecular and Genetic Toxicology, Aprather Weg 18a, 42096 Wuppertal (Germany)

    2005-08-04

    Application of recently developed gene expression techniques using microarrays in toxicological studies (toxicogenomics) facilitate the interpretation of a toxic compound's mode of action and may also allow the prediction of selected toxic effects based on gene expression changes. In order to test this hypothesis, we investigated whether carcinogens at doses known to induce liver tumors in the 2-year rat bioassay deregulate characteristic sets of genes in a short term in vivo study and whether these deregulated genes represent defined biological pathways. Male Wistar rats were dosed with the four nongenotoxic hepatocarcinogens methapyrilene (MPy, 60 mg/kg/day), diethylstilbestrol (DES, 10 mg/kg/day), Wy-14643 (Wy, 60 mg/kg/day), and piperonylbutoxide (PBO, 1200 mg/kg/day). After 1, 3, 7, and 14 days, the livers were taken for histopathological evaluation and for analysis of the gene expression profiles on Affymetrix RG{sub U}34A arrays. The expression profile of the four nongenotoxic carcinogens were compared to the profiles of the four genotoxic carcinogens 2-nitrofluorene (2-NF), dimethylnitrosamine (DMN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and aflatoxin B1 (AB1) from a similar study reported previously. By using statistical and clustering tools characteristically deregulated genes were extracted and functionally classified. Distinct cellular pathways were affected by the nongenotoxic carcinogens compared to the genotoxic carcinogens which at least partly correlated with the two-stage model of carcinogenesis. Characteristic to genotoxic carcinogens were a DNA damage response and the activation of proliferative and survival signaling. Nongenotoxic carcinogens showed responses to oxidative DNA or protein damage, as well as cell cycle progression and signs of regeneration. Many of the gene alterations found with the nongenotoxic carcinogens imply compound-specific mechanisms. Although neither a single gene nor a single pathway will be

  6. A functional genomics approach using radiation-induced changes in gene expression to study low dose radiation effects in vitro and in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Fornace, Jr, A J

    2007-03-03

    Abstract for final report for project entitled A functional genomics approach using radiation-induced changes in gene expression to study low dose radiation effects in vitro and in vivo which has been supported by the DOE Low Dose Radiation Research Program for approximately 7 years. This project has encompassed two sequential awards, ER62683 and then ER63308, in the Gene Response Section in the Center for Cancer Research at the National Cancer Institute. The project was temporarily suspended during the relocation of the Principal Investigators laboratory to the Dept. of Genetics and Complex Diseases at Harvard School of Public Health at the end of 2004. Remaining support for the final year was transferred to this new site later in 2005 and was assigned the DOE Award Number ER64065. The major aims of this project have been 1) to characterize changes in gene expression in response to low-dose radiation responses; this includes responses in human cells lines, peripheral blood lymphocytes (PBL), and in vivo after human or murine exposures, as well as the effect of dose-rate on gene responses; 2) to characterize changes in gene expression that may be involved in bystander effects, such as may be mediated by cytokines and other intercellular signaling proteins; and 3) to characterize responses in transgenic mouse models with relevance to genomic stability. A variety of approaches have been used to study transcriptional events including microarray hybridization, quantitative single-probe hybridization which was developed in this laboratory, quantitative RT-PCR, and promoter microarray analysis using genomic regulatory motifs. Considering the frequent responsiveness of genes encoding cytokines and related signaling proteins that can affect cellular metabolism, initial efforts were initiated to study radiation responses at the metabolomic level and to correlate with radiation-responsive gene expression. Productivity includes twenty-four published and in press manuscripts

  7. Association of carbamazepine-induced severe cutaneous drug reactions and HLA-B*1502 allele status, and dose and treatment duration in paediatric neurology patients in Singapore.

    Science.gov (United States)

    Chong, Kok Wee; Chan, Derrick W S; Cheung, Yin Bun; Ching, Leng Kee; Hie, Szu Liang; Thomas, Terrence; Ling, Simon; Tan, Ene Choo

    2014-06-01

    To determine the association between severe cutaneous drug reactions (SCDR), HLA-B*1502 allelism, carbamazepine dose and treatment duration in a Singapore paediatric population. Case-control study of SCDR with carbamazepine and HLA-B*1502. We recruited 32 cases, 5 with Steven Johnson Syndrome/Toxic Epidermolytic Necrolysis (SJS/TEN) (2 Chinese, 3 Malay), 6 with hypersensitivity syndrome (HSS) (5 Chinese, 1 Indian), 11 with minor drug reactions (9 Chinese, 2 Malay) and 10 controls (7 Chinese, 2 Malay, 1 Indian). HLA-B*1502 allelism was assayed. HLA-B*1502 status and the type of drug reaction were compared using univariate analysis. The time-span from treatment onset to reaction and the dose-time to reaction association in the 3 groups were analysed. HLA-B*1502 was positive in: 5/5 (SJS/TEN), 0/6 (HSS), 1/11 (minor drug reactions) and 1/10 controls. OR for SJS/TEN in HLA-B*1502-positive patients relative to that in HLA-B*1502-negative patients was estimated by exact logistic regression to be 27.20 (95% CI 2.67 to ∞). Median treatment duration (days) until allergic reactions was 12 (range 11-13), 16 (range 10-37) and 11 (range 0-63) for SJS/TEN, HSS and minor drug reactions, respectively. Median dose at onset of reactions was 6.2 mg/kg/day (range 4.6-7.4), 9.8 mg/kg/day (range 7.7-12.2) and 6.7 mg/kg/day (range 3.6-20.0) for the 3 groups, respectively. HLA-B*1502 positivity increases the odds of carbamazepine-induced SCDR in Singapore children of Chinese and Malay ethnicity. Adverse drug reactions to carbamazepine occurred within 2 weeks and at low doses. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  8. Combinatorial DNA Damage Pairing Model Based on X-Ray-Induced Foci Predicts the Dose and LET Dependence of Cell Death in Human Breast Cells

    Energy Technology Data Exchange (ETDEWEB)

    Vadhavkar, Nikhil [Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States); Pham, Christopher [University of Texas, Houston, TX (United States). MD Anderson Cancer Center; Georgescu, Walter [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Div.; Deschamps, Thomas [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Div.; Heuskin, Anne-Catherine [Univ. of Namur (Belgium). Namur Research inst. for Life Sciences (NARILIS), Research Center for the Physics of Matter and Radiation (PMR); Tang, Jonathan [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Div.; Costes, Sylvain V. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Div.

    2014-09-01

    In contrast to the classic view of static DNA double-strand breaks (DSBs) being repaired at the site of damage, we hypothesize that DSBs move and merge with each other over large distances (m). As X-ray dose increases, the probability of having DSB clusters increases as does the probability of misrepair and cell death. Experimental work characterizing the X-ray dose dependence of radiation-induced foci (RIF) in nonmalignant human mammary epithelial cells (MCF10A) is used here to validate a DSB clustering model. We then use the principles of the local effect model (LEM) to predict the yield of DSBs at the submicron level. Two mechanisms for DSB clustering, namely random coalescence of DSBs versus active movement of DSBs into repair domains are compared and tested. Simulations that best predicted both RIF dose dependence and cell survival after X-ray irradiation favored the repair domain hypothesis, suggesting the nucleus is divided into an array of regularly spaced repair domains of ~;;1.55 m sides. Applying the same approach to high-linear energy transfer (LET) ion tracks, we are able to predict experimental RIF/m along tracks with an overall relative error of 12percent, for LET ranging between 30 350 keV/m and for three different ions. Finally, cell death was predicted by assuming an exponential dependence on the total number of DSBs and of all possible combinations of paired DSBs within each simulated RIF. Relative biological effectiveness (RBE) predictions for cell survival of MCF10A exposed to high-LET showed an LET dependence that matches previous experimental results for similar cell types. Overall, this work suggests that microdosimetric properties of ion tracks at the submicron level are sufficient to explain both RIF data and survival curves for any LET, similarly to the LEM assumption. Conversely, high-LET death mechanism does not have to infer linear-quadratic dose formalism as done in the LEM. In addition, the size of repair domains derived in our model

  9. Residual γH2AX foci induced by low dose x-ray radiation in bone marrow mesenchymal stem cells do not cause accelerated senescence in the progeny of irradiated cells

    OpenAIRE

    Pustovalova, Margarita; Astrelina, Тatiana A.; Grekhova, Anna; Vorobyeva, Natalia; Tsvetkova, Anastasia; Blokhina, Taisia; Nikitina, Victoria; Suchkova, Yulia; Usupzhanova, Daria; Brunchukov, Vitalyi; Kobzeva, Irina; Karaseva, Тatiana; Ozerov, Ivan V.; Samoylov, Aleksandr; Bushmanov, Andrey

    2017-01-01

    Mechanisms underlying the effects of low-dose ionizing radiation (IR) exposure (10-100 mGy) remain unknown. Here we present a comparative study of early (less than 24h) and delayed (up to 11 post-irradiation passages) radiation effects caused by low (80 mGy) vs intermediate (1000 mGy) dose X-ray exposure in cultured human bone marrow mesenchymal stem cells (MSCs). We show that γН2АХ foci induced by an intermediate dose returned back to the control value by 24 h post-irradiation. In contrast, ...

  10. Influence of the intensity of the first dose on the extent and duration of the protective effect induced in Saintpaulia ionantha (Wendl. ) leaves irradiated by gamma rays

    Energy Technology Data Exchange (ETDEWEB)

    Duron, M. (I.N.R.A., Beaucouze, 49 - Angers (France)); Dixon, B. (Centre regional de Lutte contre le Cancer, 49 - Angers (France))

    1982-09-27

    If a 24 hrs. time interval is left between two gamma-rays doses, first doses ranging from 5 to 30 Gy are efficient to protect the leaves against a challenging letal dose of 70 Gy. The duration of the protective effect increases from 6 to 21 days when the first dose increases from 5 to 30 Gy.

  11. Effect of hydroalcoholic fruit extract of Persea americana Mill. on high fat diet induced obesity: A dose response study in rats.

    Science.gov (United States)

    Monika, Padmanabhan; Geetha, Arumugam

    2016-06-01

    The fruits of Persea Americana Mill., commonly known as Avocado, are traditionally consumed for various health benefits including weight reduction. Here, we studied the effect of hydroalcoholic fruit extract of Persea americana (HAEPA) on high fat diet (HFD) induced obesity in rats. Obesity was induced in male Sprague Dawley rats by feeding HFD for 14 wk. The hypolipidemic effect was evaluated by co-administering 25, 50, 100 and 200 mg/kg body wt. of HAEPA. There was a significant increase in weight gain, body mass index (BMI), blood lipids, low density lipoproteins (LDL), lipid peroxides (LPO) and serum transaminases in HFD fed rats. HFD+HAEPA fed rats showed a significant decrease in blood lipids, LPO, liver lipids and increase in antioxidant status when compared to HFD control rats. The activity of lipid metabolic key enzymes such as fatty acid synthase and HMG CoA reductase in liver were also found to be decreased significantly in HAEPA co-administered rats. Lipoprotein lipase activity was found increased in HFD+HAEPA rats. Among the 4 doses studied, 100 mg of HAEPA/kg body wt. exhibited optimum hypolipidemic activity. Histopathological observations in liver and visceral adipose tissue added more evidence for the lipid lowering effect of HAEPA. It can be concluded that avocado fruit extract can act as hypolipidemic agent probably by modulating the activities of HMG CoA reductase and fatty acid synthase in liver.

  12. Protective Effects of Hydrogen against Low-Dose Long-Term Radiation-Induced Damage to the Behavioral Performances, Hematopoietic System, Genital System, and Splenic Lymphocytes in Mice

    Directory of Open Access Journals (Sweden)

    Jiaming Guo

    2016-01-01

    Full Text Available Molecular hydrogen (H2 has been previously reported playing an important role in ameliorating damage caused by acute radiation. In this study, we investigated the effects of H2 on the alterations induced by low-dose long-term radiation (LDLTR. All the mice in hydrogen-treated or radiation-only groups received 0.1 Gy, 0.5 Gy, 1.0 Gy, and 2.0 Gy whole-body gamma radiation, respectively. After the last time of radiation exposure, all the mice were employed for the determination of the body mass (BM observation, forced swim test (FST, the open field test (OFT, the chromosome aberration (CA, the peripheral blood cells parameters analysis, the sperm abnormality (SA, the lymphocyte transformation test (LTT, and the histopathological studies. And significant differences between the treatment group and the radiation-only groups were observed, showing that H2 could diminish the detriment induced by LDLTR and suggesting the protective efficacy of H2 in multiple systems in mice against LDLTR.

  13. Cholecystokinin-Induced Gallbladder Emptying and Single-Dose Metformin Elicit Additive Glucagon-Like Peptide-1 Responses

    DEFF Research Database (Denmark)

    Rohde, Ulrich; Sonne, David Peick; Christensen, Mikkel

    2016-01-01

    CONTEXT: Bile acids have been suggested to mediate glucagon-like peptide-1 (GLP-1) secretion via activation of the bile acid receptor TGR5 on enteroendocrine L cells. Metformin too has been shown to increase GLP-1 levels. The effect of gallbladder emptying, metformin or a combination has however...... never been studied. OBJECTIVE: We hypothesized that cholecystokinin-8 (CCK)-induced gallbladder emptying stimulates human GLP-1 secretion and that metformin would potentiate this effect. DESIGN: A double-blinded, randomized study. SETTING: The study was conducted at a specialized research unit....... PARTICIPANTS: Ten healthy male subjects with no family history of diabetes (aged 22 (range 20-32) years; body mass index 21.7 (19.3-24.2) kg/m(2); fasting plasma glucose 4.9 (4.7-5.3) mM; and HbA1c 5.1 (4.4-5.8) %). INTERVENTION: On 4 separate days, the subjects received metformin or placebo and a concomitant...

  14. Caffeine dose-dependently induces thermogenesis but restores ATP in HepG2 cells in culture.

    Science.gov (United States)

    Riedel, Annett; Pignitter, Marc; Hochkogler, Christina M; Rohm, Barbara; Walker, Jessica; Bytof, Gerhard; Lantz, Ingo; Somoza, Veronika

    2012-09-01

    Caffeine has been hypothesised as a thermogenic agent that might help to maintain a healthy body weight. Since very little is known about its actions on cellular energy metabolism, we investigated the effect of caffeine on mitochondrial oxidative phosphorylation, cellular energy supply and thermogenesis in HepG2 cells, and studied its action on fatty acid uptake and lipid accumulation in 3T3-L1 adipocytes at concentrations ranging from 30-1500 μM. In HepG2 cells, caffeine induced a depolarisation of the inner mitochondrial membrane, a feature of mitochondrial thermogenesis, both directly and after 24 h incubation. Increased concentrations of uncoupling protein-2 (UCP-2) also indicated a thermogenic activity of caffeine. Energy generating pathways, such as mitochondrial respiration, fatty acid oxidation and anaerobic lactate production, were attenuated by caffeine treatment. Nevertheless, HepG2 cells demonstrated a higher energy charge potential after exposure to caffeine that might result from energy restoration through attenuation of energy consuming pathways, as typically found in hibernating animals. In 3T3-L1 cells, in contrast, caffeine increased fatty acid uptake, but did not affect lipid accumulation. We provide evidence that caffeine stimulates thermogenesis but concomitantly causes energy restoration that may compensate enhanced energy expenditure.

  15. Psychiatric side effects induced by supraphysiological doses of combinations of anabolic steroids correlate to the severity of abuse.

    Science.gov (United States)

    Pagonis, Thomas A; Angelopoulos, Nikiforos V; Koukoulis, George N; Hadjichristodoulou, Christos S

    2006-12-01

    The objective of our study was to evaluate the psychological consequences of real-world AAS use in athletes abusing such agents, in comparison with a placebo and control group of comparable athletes, while correlating the severity of abuse with the side effects observed. The hypothesis tested by the study was that the use of AAS induces a wide range of psychological side effects whose impact and emergence is dependent upon the severity of the abuse. The study includes a substantial group of AAS abusing athletes and two more groups demographically similar to the first, one composed of athletes not using any substance and a placebo group. All athletes were stratified according to the severity of AAS abuse. Psychometric instruments were applied to all athletes in specific time intervals, dependent to the AAS abusers' regimens, providing us with a final psychological profile that was to be compared to the pre-study profile. All results were comparable (within and between groups) for statistically significant differences and correlated to the severity of the abuse. Homogeneity of all groups was safeguarded by random doping controls, monitoring of drug levels and analysis of all self obtained drugs by method of liquid chromatography/mass spectrometry. All athletes were provided with a common exercise and dietary regime, so common training and nutritional conditions were achieved. We studied a cohort of 320 body-building, amateur and recreational athletes, of whom 160 were active users of AAS (group C), 80 users administering placebo drugs (group B) and 80 not abusing any substance (Group A). Group C athletes were stratified according to AAS abuse parameters, thus providing us with three subgroups of "light, medium and heavy abuse". Athletes of groups A and B were included in a "no abuse" subgroup. The psychometric instruments used were the Symptoms Check List-90 (SCL-90) and the Hostility and Direction of Hostility Questionnaire (HDHQ). The psychometric evaluations took

  16. Systematic review and meta-analysis of vancomycin-induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter.

    Science.gov (United States)

    van Hal, S J; Paterson, D L; Lodise, T P

    2013-02-01

    In an effort to maximize outcomes, recent expert guidelines recommend more-intensive vancomycin dosing schedules to maintain vancomycin troughs between 15 and 20 mg/liter. The widespread use of these more-intensive regimens has been associated with an increase in vancomycin-induced nephrotoxicity reports. The purpose of this systematic literature review is to determine the nephrotoxicity potential of maintaining higher troughs in clinical practice. All studies pertaining to vancomycin-induced nephrotoxicity between 1996 and April 2012 were identified from PubMed, Embase, Cochrane Controlled Trial Registry, and Medline databases and analyzed according to Cochrane guidelines. Of the initial 240 studies identified, 38 were reviewed, and 15 studies met the inclusion criteria. Overall, higher troughs (≥ 15 mg/liter) were associated with increased odds of nephrotoxicity (odds ratio [OR], 2.67; 95% confidence interval [CI], 1.95 to 3.65) relative to lower troughs of liter. The relationship between a trough of ≥ 15 mg/liter and nephrotoxicity persisted when the analysis was restricted to studies that examined only initial trough concentrations (OR, 3.12; 95% CI, 1.81 to 5.37). The relationship between troughs of ≥ 15 mg/liter and nephrotoxicity persisted after adjustment for covariates known to independently increase the risk of a nephrotoxicity event. An incremental increase in nephrotoxicity was also observed with longer durations of vancomycin administration. Vancomycin-induced nephrotoxicity was reversible in the majority of cases, with short-term dialysis required only in 3% of nephrotoxic episodes. The collective literature indicates that an exposure-nephrotoxicity relationship for vancomycin exists. The probability of a nephrotoxic event increased as a function of the trough concentration and duration of therapy.

  17. Neonatal Immunization with a Single IL-4/Antigen Dose Induces Increased Antibody Responses after Challenge Infection with Equine Herpesvirus Type 1 (EHV-1) at Weanling Age.

    Science.gov (United States)

    Wagner, Bettina; Perkins, Gillian; Babasyan, Susanna; Freer, Heather; Keggan, Alison; Goodman, Laura B; Glaser, Amy; Torsteinsdóttir, Sigurbjorg; Svansson, Vilhjálmur; Björnsdóttir, Sigríður

    2017-01-01

    Neonatal foals respond poorly to conventional vaccines. These vaccines typically target T-helper (Th) cell dependent B-cell activation. However, Th2-cell immunity is impaired in foals during the first three months of life. In contrast, neonatal basophils are potent interleukin-4 (IL-4) producers. The purpose of this study was to develop a novel vaccine triggering the natural capacity of neonatal basophils to secrete IL-4 and to evaluate if vaccination resulted in B-cell activation and antibody production against EHV-1 glycoprotein C (gC). Neonatal vaccination was performed by oral biotinylated IgE (IgE-bio) treatment at birth followed by intramuscular injection of a single dose of streptavidin-conjugated gC/IL-4 fusion protein (Sav-gC/IL-4) for crosslinking of receptor-bound IgE-bio (group 1). Neonates in group 2 received the intramuscular Sav-gC/IL-4 vaccine only. Group 3 remained non-vaccinated at birth. After vaccination, gC antibody production was not detectable. The ability of the vaccine to induce protection was evaluated by an EHV-1 challenge infection after weaning at 7 months of age. Groups 1 and 2 responded to EHV-1 infection with an earlier onset and overall significantly increased anti-gC serum antibody responses compared to control group 3. In addition, group 1 weanlings had a decreased initial fever peak after infection indicating partial protection from EHV-1 infection. This suggested that the neonatal vaccination induced a memory B-cell response at birth that was recalled at weanling age after EHV-1 challenge. In conclusion, early stimulation of neonatal immunity via the innate arm of the immune system can induce partial protection and increased antibody responses against EHV-1.

  18. Effect of Low Dose Lead (Pb) Administration on Tail Immersion Test and Formalin-induced Pain in Wistar Rats: Possible Modulatory Role of Cobalt (II) Chloride.

    Science.gov (United States)

    Umar, A H; Suleiman, I; Muhammed, H

    2017-03-06

    Lead (Pb) is cheap and there is a long tradition of its use, but its toxic effects have also been recognized. There is increased public health concern regarding the hazards of low dose Pb exposure to adults and children. Studies have shown the risks for hypertension, decrements in renal function, subtle decline in cognitive function, and adverse reproductive outcome at low blood Pb level. In this study, the possible modulatory role of cobalt (II) chloride (CoCl2) on low level Pb exposure on tail immersion test and formalin induced pain was investigated. Twenty adult Wistar rats of both sexes (weight 150g to 200g) were used. The animals were divided into four groups (n = 5) and administered Pb (5mg/kg), Pb (5mg/kg) + CoCl2 (50mg/kg) and CoCl2 (50mg/kg) orally for twenty-eight days. The last group served as control and were given distilled water only. In the tail immersion test, there was no significant change in reaction time for all three groups when compared to the control. In the formalin-induced pain, pain score after five and forty-five minutes also do not show significant change for all the three groups when compared to control. This work suggested that exposure to 5mg/kg Pb for twenty-eight days do not significantly impair reaction time in tail immersion test and pain score in formalin induced pain in Wistar rats. Also, administration of 50mg/kg CoCl2 do not improve performance of the animals in the experiments.

  19. Neonatal Immunization with a Single IL-4/Antigen Dose Induces Increased Antibody Responses after Challenge Infection with Equine Herpesvirus Type 1 (EHV-1 at Weanling Age.

    Directory of Open Access Journals (Sweden)

    Bettina Wagner

    Full Text Available Neonatal foals respond poorly to conventional vaccines. These vaccines typically target T-helper (Th cell dependent B-cell activation. However, Th2-cell immunity is impaired in foals during the first three months of life. In contrast, neonatal basophils are potent interleukin-4 (IL-4 producers. The purpose of this study was to develop a novel vaccine triggering the natural capacity of neonatal basophils to secrete IL-4 and to e