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Sample records for b6c3f1 mice final

  1. A CHRONIC INHALATION STUDY OF METHYL BROMIDE TOXICITY IN B6C3F1 MICE. (FINAL REPORT TO THE NATIONAL TOXICOLOGY PROGRAM)

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    HABER, S.B.

    1987-06-26

    This report provides a detailed account of a two year chronic inhalation study of methyl bromide toxicity in B6C3Fl mice conducted for the National Toxicology Program. Mice were randomized into three dose groups (10, 33 and 100 ppm methyl bromide) and one control group (0 ppm) per sex and exposed 5 days/week, 6 hours/day, for a total of 103 weeks. Endpoints included body weight; clinical signs and mortality, and at 6, 15 and 24 months of exposure, animals were sacrificed for organ weights, hematology and histopathology. In addition, a subgroup of animals in each dosage group was monitored for neurobehavioral and neuropathological changes. After only 20 weeks of exposure, 48% of the males and 12% of the females in the 100 ppm group had died. Exposures were terminated in that group and the surviving mice were observed for the duration of the study. Exposure of B6C3Fl mice to methyl bromide, even for only 20 weeks, produced significant changes in growth rate, mortality, organ weights and neurobehavioral functioning. These changes occurred in both males and females, but were more pronounced in males.

  2. Carcinogenicity study of cochineal in B6C3F1 mice.

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    Mori, H; Iwata, H; Tanaka, T; Morishita, Y; Mori, Y; Kojima, T; Okumura, A

    1991-09-01

    The carcinogenicity of cochineal, a red colouring used in food and other products, was studied in a 2-yr bioassay in B6C3F1 mice. Groups of 50-55 mice of each sex were given 0, 3 or 6% cochineal in the diet for 2 yr. Mice of all groups developed tumours including hepatocellular adenomas or carcinomas, pulmonary adenomas or adenocarcinomas and lymphomas or lymphatic leukaemias, and the incidences of these tumours were not significantly different in treated and control groups. The results indicate that cochineal lacks carcinogenicity in mice and are consistent with those of in vitro short-term assays of cochineal and of carminic acid, an active principle of cochineal.

  3. Carcinogenicity of bisphenol-A in Fischer rats and B6C3F1 mice.

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    Huff, J

    2001-11-01

    Bisphenol-A (BP-A; 4,4'-isopropylidenediphenol) is a monomer of plastics commonly used in various consumer products, and is used as an intermediate in the manufacture of epoxy, polycarbonate, and polyester-styrene resins. A National Toxicology Program carcinogenesis bioassay of BP-A (>98% pure) was conducted by feeding diets containing 0, 1000, or 2000 ppm BP-A to groups of 50 male and 50 female Fischer (F)344 rats; 0, 1000, or 5000 ppm to groups of 50 male B6C3F1 mice; and 0, 5000, or 10,000 ppm to groups of 50 female B6C3F1 mice for 103 weeks. The mean body weights of the low- and high-dose rats and of female mice and high-dose male mice were lower than those of the controls throughout much of the study. Lower body weight gains in rats were likely caused by reduced food consumption. Survivals were comparable among groups. Regarding neoplasia, leukemias occurred at increased incidences in BP-A-dosed rats of both sexes: male, 13/50 controls vs 12/50 low-dose and 23/50 high-dose (P Toxicology Program concluded that there was no convincing evidence that BP-A was carcinogenic for rats or mice. However, the marginal increases in leukemias in male and female rats, along with increases in the combined incidence of lymphomas and leukemias in male mice, suggest that BP-A may be associated with increased cancers of the hematopoietic system. Increases in interstitial-cell tumors of the testes in rats were also evidence of carcinogenesis, as was the unusual occurrence of mammary gland fibroadenomas in male rats.

  4. Acrylonitrile is a multisite carcinogen in male and female B6C3F1 mice.

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    Ghanayem, Burhan I; Nyska, Abraham; Haseman, Joseph K; Bucher, John R

    2002-07-01

    Acrylonitrile is a heavily produced unsaturated nitrile, which is used in the production of synthetic fibers, plastics, resins, and rubber. Acrylonitrile is a multisite carcinogen in rats after exposure via gavage, drinking water, or inhalation. No carcinogenicity studies of acrylonitrile in a second animal species were available. The current studies were designed to assess the carcinogenicity of acrylonitrile in B6C3F1 mice of both sexes. Acrylonitrile was administered by gavage at 0, 2.5, 10, or 20 mg/kg/day, 5 days per week, for 2 years. Urinary thiocyanate and N-acetyl-S-(2-cyanoethyl)-L-cysteine were measured as markers of exposure to acrylonitrile. In general, there were dose-related increases in urinary thiocyanate and N-acetyl-S-(2-cyanoethyl)-L-cysteine concentrations in all dosed groups of mice and at all time points. Survival was significantly (p acrylonitrile-dosed groups. In female mice, the incidence of benign or malignant granulosa cell tumors (combined) in the ovary in the 10 mg/kg dose group was greater than that in the vehicle control group, but because of a lack of dose response, this was considered an equivocal finding. In addition, the incidences of atrophy and cysts in the ovary of the 10 and 20 mg/kg dose groups were significantly increased. The incidences of alveolar/bronchiolar adenoma or carcinoma (combined) were significantly increased in female mice treated with acrylonitrile at 10 mg/kg/day for 2 years. This was also considered an equivocal result. In conclusion, these studies demonstrated that acrylonitrile causes multiple carcinogenic effects after gavage administration to male and female B6C3F1 mice for 2 years.

  5. Glycidol modulation of the immune responses in female B6C3F1 mice.

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    Guo, T L; McCay, J A; Brown, R D; Musgrove, D L; Butterworth, L; Munson, A E; Germolec, D R; White, K L

    2000-08-01

    The immunotoxic potential of glycidol was evaluated in female B6C3F1 mice using a battery of functional assays and three host resistance models. Glycidol was administered to the animals by oral gavage as a solution in sterile distilled water daily for 14 days at doses of 25, 125 and 250 mg/kg. In tier I, we observed that glycidol exposure produced a dose-related decrease in splenocyte IgM antibody-forming cell response to sheep red blood cells (sRBC); the spleen natural killer (NK) cell activity was also decreased. A decrease in B cell proliferative responses to anti-IgM F(ab')2 and/or interleukin-4 (IL-4) was observed while the splenocyte proliferative responses to T cell mitogen ConA and B cell mitogen LPS were not affected. The splenocyte proliferative response to allogeneic cells as evaluated in the mixed leukocyte reaction (MLR) to DBA/2 spleen cells was not affected. In tier II, we found that exposure to glycidol decreased the number and percentage of B cells and the absolute number of CD4+ T cells in the spleen while the number of total T cells, CD8+ T cells and CD4+CD8+ T cells was not affected. The cytotoxic T lymphocyte (CTL) response to mitomycin C-treated P815 mastocytoma was not affected; the cytotoxic activity of peritoneal macrophages was not suppressed. Moreover, the host resistance to Listeria monocytogenes was not affected although a slight increase in host resistance to Streptococcus pneumoniae was observed. However, exposure to glycidol decreased host resistance to the B16F10 melanoma tumor model with the maximal tumor formation in lung observed in the high dose group. Overall, these dada support the finding that glycidol is an immunosuppressive agent in female B6C3F1 mice.

  6. Carcinogenicity of glycidol in F344 rats and B6C3F1 mice.

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    Irwin, R D; Eustis, S L; Stefanski, S; Haseman, J K

    1996-01-01

    Glycidol, a simple aliphatic epoxide, was administered by gavage in water to groups of male and female F344/N rats and B6C3F1 mice. Rats received 0, 37.5 or 75 mg kg-1 and mice received 0, 25 or 50 mg kg-1 daily, 5 days per week for 2 years. Exposure to glycidol was associated with dose-related increases in the incidences of neoplasms in numerous tissues in both rats and mice. Survival of rats that received glycidol was markedly reduced compared to the control because of the early induction of neoplastic disease. In male rats, mesothelioma arising in the tunica vaginalis and frequently metastasizing to the peritoneum were considered the major cause of early death. Early deaths in female rats were associated with mammary gland neoplasms. Survival of female mice that received 50 mg kg-1 was lower than the control after week 101 due primarily to euthanasia of moribund animals with mammary gland neoplasms. Survival of male mice and female mice that received 25 mg kg-1 was comparable to the control. In mice, exposure to glycidol was associated with increased incidences of neoplasms of the harderian gland in males and females, the forestomach in males and the mammary gland in females.

  7. Benzene-induced hematotoxicity and bone marrow compensation in B6C3F1 mice.

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    Farris, G M; Robinson, S N; Gaido, K W; Wong, B A; Wong, V A; Hahn, W P; Shah, R S

    1997-04-01

    Long-term inhalation exposure of benzene has been shown to cause hematotoxicity and an increased incidence of acute myelogenous leukemia in humans. The progression of benzene-induced hematotoxicity and the features of the toxicity that may play a major role in the leukemogenesis are not known. We report the hematological consequences of benzene inhalation in B6C3F1 mice exposed to 1, 5, 10, 100, and 200 ppm benzene for 6 hr/day, 5 days/week for 1, 2, 4, or 8 weeks and a recovery group. There were no significant effects on hematopoietic parameters from exposure to 10 ppm benzene or less. Exposure of mice to 100 and 200 ppm benzene reduced the number of total bone marrow cells, progenitor cells, differentiating hematopoietic cells, and most blood parameters. Replication of primitive progenitor cells in the bone marrow was increased during the exposure period as a compensation for the cytotoxicity induced by 100 and 200 ppm benzene. In mice exposed to 200 ppm benzene, the primitive progenitor cells maintained an increased percentage of cells in S-phase through 25 days of recovery compared with controls. The increased replication of primitive progenitor cells in concert with the reported genotoxicity induced by benzene provides the components necessary for producing an increased incidence of lymphoma in mice. Furthermore, we propose this mode of action as a biologically plausible mechanism for benzene-induced leukemia in humans exposed to high concentrations of benzene.

  8. Comparison of Methods of Identifying Helicobacter hepaticus in B6C3F1 Mice Used in a Carcinogenesis Bioassay

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    Fox, James G.; MacGregor, Judith A.; Shen, Zeli; Li, Xiantang; Lewis, Robert; Dangler, Charles A.

    1998-01-01

    In a long-term rodent bioassay evaluating the carcinogenicity of triethanolamine, there was equivocal evidence of carcinogenic activity in male B6C3F1 mice, based on a marginal increase in the number of hepatocellular adenomas and hepatoblastomas. Interpretation was complicated by the presence of Helicobacter hepaticus in selected silver-stained liver sections which also had histological evidence of karyomegaly and oval cell hyperplasia. An increase in numbers of liver tumors, as evidence of ...

  9. Genistein modulation of streptozotocin diabetes in male B6C3F1 mice can be induced by diet

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    Guo, Tai L., E-mail: tlguo1@uga.edu [Department of Biosciences and Diagnostic Imaging, College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7382 (United States); Wang, Yunbiao [Department of Biosciences and Diagnostic Imaging, College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7382 (United States); Key Laboratory of Wetland Ecology and Environment, Northeast Institute of Geography and Agroecology, Chinese Academy of Sciences, Changchun 130102 (China); Xiong, Tao [College of Animal Science, Yangtze University, Jingzhou City, Hubei Province 434025 (China); Ling, Xiao [Institute for Food and Drug Control of Shandong Province, Jinan City, Shandong 250012 (China); Zheng, Jianfeng [Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298-0613 (United States)

    2014-11-01

    Diet and phytoestrogens affect the development and progression of diabetes. The objective of the present study was to determine if oral exposure to phytoestrogen genistein (GE) by gavage changed blood glucose levels (BGL) through immunomodulation in streptozotocin (STZ)-induced diabetic male B6C3F1 mice fed with three different diets. These three diets were: NTP-2000 diet (NTP), soy- and alfalfa-free 5K96 diet (SOF) and high fat diet (HFD) with 60% of kcal from fat, primarily rendered fat of swine. The dosing regimen for STZ consisted of three 100 mg/kg doses (i.p.): the first dose was administered at approximately 2 weeks following the initiation of daily GE (20 mg/kg) gavage, and the second dose was on day 19 following the first dose, and the third dose was on day 57 following the first dose. In mice on the NTP diet, GE treatment decreased BGL with statistical significances observed on days 33 and 82 following the first STZ injection. In mice fed the HFD diet, GE treatment produced a significant decrease and a significant increase in BGL on days 15 and 89 following the first STZ injection, respectively. In mice fed the SOF diet, GE treatment had no significant effects on BGL. Although GE treatment affected phenotypic distributions of both splenocytes (T cells, B cells, natural killer cells and neutrophils) and thymocytes (CD4/CD8 and CD44/CD25), and their mitochondrial transmembrane potential and generation of reactive oxygen species, indicators of cell death (possibly apoptosis), GE modulation of neutrophils was more consistent with its diabetogenic or anti-diabetic potentials. The differential effects of GE on BGL in male B6C3F1 mice fed with three different diets with varied phytoestrogen contents suggest that the estrogenic properties of this compound may contribute to its modulation of diabetes. - Highlights: • Diets affected streptozotocin-induced diabetes in male B6C3F1 mice. • Genistein modulation of streptozotocin diabetes can be induced by diet.

  10. Absorption and metabolism of triclosan after application to the skin of B6C3F1 mice.

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    Fang, Jia-Long; Vanlandingham, Michelle; da Costa, Gonçalo Gamboa; Beland, Frederick A

    2016-05-01

    Triclosan is used as an antimicrobial agent in personal care products, household items, medical devices, and clinical settings. Humans can receive lifelong exposures to triclosan; however, data on the toxicity and carcinogenicity after topical application are lacking. This study determined the absorption, distribution, metabolism, and excretion of triclosan after application to the skin of B6C3F1 mice. [(14)C(U)]triclosan (10 or 100 mg triclosan/kg body weight) was administered topically to mice in two separate experiments: a vehicle selection experiment using propylene glycol, ethanol, and a generic cosmetic cream, and a toxicokinetic experiment. Mice were killed up to 72 h after triclosan administration, and excreta and tissues were analyzed for radioactivity. Ethanol had the best properties of the vehicles evaluated. Maximum absorption was obtained at approximately 12 h after dosing. Radioactivity appeared in the excreta and in all tissues examined, with the highest levels in the gall bladder and the lowest levels in the brain. Triclosan was metabolized to triclosan sulfate, triclosan glucuronide, 2,4-dichlorophenol, and hydroxytriclosan. The metabolite profile was tissue-dependent and the predominant route of excretion was fecal. The AUC(0-∞) and the Cmax of plasma and liver in females were greater than those in males. Slightly lower absorption was observed in mice with Elizabethan collars.

  11. Toxicity of divinylbenzene-55 for B6C3F1 mice in a two-week inhalation study.

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    Morgan, D L; Mahler, J F; Wilson, R E; Moorman, M P; Price, H C; O'connor, R W

    1997-10-01

    Divinylbenzene (DVB) is a crosslinking monomer used primarily for copolymerization with styrene to produce ion-exchange resins. The toxicity of inhaled DVB was investigated because of the potential for worker exposure and the structural similarity of DVB to styrene, a potential carcinogen. Male and female B6C3F1 mice were exposed to 0, 25, 50, or 75 ppm DVB for 6 hr/day, 5 days/week for up to 2 weeks. Six mice/sex/dose group were killed after 3, 5, and 10 exposures and six mice/sex in the 75 ppm group were killed 7 days after 10 exposures. The most severe effects occurred in the nasal cavity and liver, with less severe effects occurring in the kidneys. In the nasal cavity olfactory epithelium acute necrosis and inflammation were present at early time points followed by regeneration, architectural reorganization, and focal respiratory metaplasia by 7 days after the last exposure. Olfactory epithelial changes were concentration-dependent with extensive involvement at 75 ppm and peripheral sparing at 25 ppm. There was also necrosis and regeneration of olfactory-associated Bowman's glands as well as the lateral nasal (Steno's) glands. Hepatocellular centrilobular (CL) necrosis was observed only in the 75 ppm dose group and was similar to that caused by styrene. A time-dependent progression was observed, characterized by CL degeneration after 1 exposure, necrosis after 3 and 5 exposures, and chronic inflammation with CL karyomegaly after 10 exposures and 7 days after the 10th exposure. Hepatic GSH levels were decreased in a dose-dependent manner. In the kidneys, transient tubular damage was observed in some male mice exposed to 75 ppm, and appeared to be a response to DVB-induced tubular epithelial injury.

  12. Early metabolomics changes in heart and plasma during chronic doxorubicin treatment in B6C3F1 mice.

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    Schnackenberg, Laura K; Pence, Lisa; Vijay, Vikrant; Moland, Carrie L; George, Nysia; Cao, Zhijun; Yu, Li-Rong; Fuscoe, James C; Beger, Richard D; Desai, Varsha G

    2016-11-01

    The present study aimed to identify molecular markers of early stages of cardiotoxicity induced by a potent chemotherapeutic agent, doxorubicin (DOX). Male B6C3F1 mice were dosed with 3 mg kg(-1) DOX or saline via tail vein weekly for 2, 3, 4, 6 or 8 weeks (cumulative DOX doses of 6, 9, 12, 18 or 24 mg kg(-1) , respectively) and euthanized a week after the last dose. Mass spectrometry-based and nuclear magnetic resonance spectrometry-based metabolic profiling were employed to identify initial biomarkers of cardiotoxicity before myocardial injury and cardiac pathology, which were not noted until after the 18 and 24 mg kg(-1) cumulative doses, respectively. After a cumulative dose of 6 mg kg(-1) , 18 amino acids and four biogenic amines (acetylornithine, kynurenine, putrescine and serotonin) were significantly increased in cardiac tissue; 16 amino acids and two biogenic amines (acetylornithine and hydroxyproline) were significantly altered in plasma. In addition, 16 acylcarnitines were significantly increased in plasma and five were significantly decreased in cardiac tissue compared to saline-treated controls. Plasma lactate and succinate, involved in the Krebs cycle, were significantly altered after a cumulative dose of 6 mg kg(-1) . A few metabolites remained altered at higher cumulative DOX doses, which could partly indicate a transition from injury processes at 2 weeks to repair processes with additional injury happening concurrently before myocardial injury at 8 weeks. These altered metabolic profiles in mouse heart and plasma during the initial stages of injury progression due to DOX treatment may suggest these metabolites as candidate early biomarkers of cardiotoxicity. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

  13. Comparison of methods of identifying Helicobacter hepaticus in B6C3F1 mice used in a carcinogenesis bioassay.

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    Fox, J G; MacGregor, J A; Shen, Z; Li, X; Lewis, R; Dangler, C A

    1998-05-01

    In a long-term rodent bioassay evaluating the carcinogenicity of triethanolamine, there was equivocal evidence of carcinogenic activity in male B6C3F1 mice, based on a marginal increase in the number of hepatocellular adenomas and hepatoblastomas. Interpretation was complicated by the presence of Helicobacter hepaticus in selected silver-stained liver sections which also had histological evidence of karyomegaly and oval cell hyperplasia. An increase in numbers of liver tumors, as evidence of carcinogenic activity, was also noted in female mice. However, H. hepaticus was not considered a complicating factor, because the livers of the female mice did not have histological features compatible with H. hepaticus infection. A retrospective analysis of 51 liver tissue samples from the original carcinogenicity study was conducted to determine the incidence of H. hepaticus infection and to evaluate different diagnostic approaches for assessing the presence of H. hepaticus in livers lacking characteristic lesions. In an initial evaluation of seven mice with liver tumors, argyrophilic bacteria resembling H. hepaticus were observed in liver sections, associated with characteristic liver lesions of hepatocytic karyomegaly and oval cell hyperplasia. Frozen liver tissue was available from four of these mice; all were confirmed to be infected with H. hepaticus by culture and PCR. In a larger subsequent analysis using frozen liver tissues from 44 mice without characteristic hepatic lesions, H. hepaticus-specific DNA was amplified from the livers of 21 of 44 of the mice (47%), compared to 14 of 44 of the mice (32%) having H. hepaticus cultured from their frozen liver tumors. The results of H. hepaticus culture and H. hepaticus-specific PCR concurred (i.e., both positive and negative results) in 84% of the cases. Microscopic detection of immunofluorescence-labeled or silver-stained bacteria in liver sections was relatively insensitive compared to either culture or PCR detection. This

  14. Subchronic toxicity of triethylenetetramine dihydrochloride in B6C3F1 mice and F344 rats.

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    Greenman, D L; Morrissey, R L; Blakemore, W; Crowell, J; Siitonen, P; Felton, P; Allen, R; Cronin, G

    1996-02-01

    Triethylenetetramine dihydrochloride (trien-2HCl; CAS No. 38260-01-04), a chelating agent used to treat Wilson's disease patients who are intolerant of the drug of choice, was tested for subchronic toxicity in B6C3F1 mice and F344 rats. Mice and rats received trien-2HCl in the drinking water at concentrations of 0, 120, 600, or 3000 ppm for up to 92 days. Twenty mice and 18 rats of each sex were assigned to each dose group fed either a cereal-based (NIH-31) or a purified (AIN-76A) diet, both containing nutritionally adequate levels of copper. An additional control group of rats and mice received a Cu-deficient AIN-76A diet. This low copper diet resulted in Cu-deficiency symptoms, such as anemia, liver periportal cytomegaly, pancreatic atrophy and multifocal necrosis, spleen hematopoietic cell proliferation, and increased heart weight, together with undetectable levels of plasma copper in rats but not in mice. Trien-2HCl lowered plasma copper levels some-what (at 600 and 3000 ppm) in rats fed the AIN-76A diet, but did not induce the usual signs of copper deficiency. Trien-2HCl caused an increased frequency of uterine dilatation at 3000 ppm in rats fed AIN-76A diet that was not noted in females fed the Cu-deficient diet. Trien-2HCl toxicity occurred only in mice in the highest dose group fed an AIN-76A diet. Increased frequencies of inflammation of the lung interstitium and liver periportal fatty infiltration were seen in both sexes, and hematopoietic cell proliferation was seen in the spleen of males. Kidney and body weights were reduced in males as was the incidence of renal cytoplasmic vacuolization. There were no signs of copper deficiency in mice exposed to trien-2HCl. The only effect of trien-2HCl in animals fed the NIH-31 diet was a reduced liver copper level in both rat sexes, noted at 3000 ppm.

  15. Characterization of hepatocellular resistance and susceptibility to styrene toxicity in B6C3F1 mice.

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    Mahler, J F; Price, H C; O'Connor, R W; Wilson, R F; Eldridge, S R; Moorman, M P; Morgan, D L

    1999-03-01

    Short-term inhalation exposure of B6C3F1 mice to styrene causes necrosis of centrilobular (CL) hepatocytes. However, in spite of continued exposure, the necrotic parenchyma is rapidly regenerated, indicating resistance by regenerated cells to styrene toxicity. These studies were conducted to test the hypothesis that resistance to repeated styrene exposure is due to sustained cell proliferation, with production of hepatocytes that have reduced metabolic capacity. Male mice were exposed to air or 500 ppm styrene (6 h/day); hepatotoxicity was evaluated by microscopic examination, serum liver enzyme levels, and bromodeoxyuridine (BrdU)-labeling index (LI). Metabolism was assessed by measurement of blood styrene and styrene oxide. Both single and repeated exposures to styrene resulted in mortality by Day 2; in mice that survived, there was CL necrosis with elevated BrdU LI at Day 6, and complete restoration of the necrotic parenchyma by Day 15. The BrdU LI in mice given a single exposure had returned to control levels by Day 15. Re-exposure of these mice on Day 15 resulted in additional mortality and hepatocellular necrosis, indicating that regenerated CL cells were again susceptible to the cytolethal effect of styrene following a 14-day recovery. However, in mice repeatedly exposed to styrene for 14 days, the BrdU LI remained significantly increased on Day 15, with preferential labeling of CL hepatocytes with enlarged nuclei (karyomegaly). If repeated exposures were followed by a 10-day recovery period, CL karyomegaly persisted, but the BrdU LI returned to control level and CL hepatocytes became susceptible again to styrene toxicity as demonstrated by additional mortality and acute necrosis after a challenge exposure. These findings indicated a requirement for continued styrene exposure and DNA synthesis in order to maintain this resistant phenotype. Analyses of proliferating-cell nuclear-antigen (PCNA) labeling were conducted to further characterize the cell cycle

  16. EFFECT OF TRICHLOROETHYLENE ON DNA METHYLATION AND EXPRESSION OF EARLY-INTERMEDIATE PROTOONCOGENES IN THE LIVER OF B6C3F1 MICE. (R825384)

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    Trichloroethylene (TCE) is a multimedia environmental pollution that is carcinogenic in mouse liver. The ability of TCE to modulate DNA methylation and the expression of immediate-early protooncogenes was evaluated. Female B6C3F1 mice were administered 1000 mg/kg TCE by gavage 5 ...

  17. NTP Toxicology and Carcinogenesis Studies of Isobutene (CAS No. 115-11-7) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

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    1998-12-01

    Isobutene is produced during the fractionation of refinery gases or through the catalytic cracking of methyl-t-butyl ether. Isobutene is primarily used to produce diisobutylene, trimers, butyl rubber, and other polymers. In addition, it is used in the production of isooctane, high-octane aviation gasoline, methyl-t-butyl ether, and copolymer resins with butadiene and acrylonitrile. Isobutene was selected for evaluation because of the potential for human exposure due to its large production volume and the lack of adequate data on its carcinogenic potential. The toxicity and carcinogenicity of isobutene were determined in male and female F344/N rats and B6C3F1 mice exposed to isobutene (greater than 98% pure) by inhalation for 14 weeks or 2 years. The mutagenicity of isobutene was assessed in Salmonella typhimurium, and the frequency of micronuclei was determined in the peripheral blood of mice exposed by inhalation for 14 weeks. 14-WEEK STUDIES: Groups of 10 male and 10 female F344/N rats and B6C3F1 mice were exposed to isobutene at concentrations of 0, 500, 1,000, 2,000, 4,000, or 8,000 ppm 6 hours per day, 5 days per week, for 14 weeks. Concentrations greater than 8,000 ppm isobutene were not used because of the danger of explosion. All rats and mice survived to the end of the study. The final mean body weights and body weight gains of all exposed groups were similar to those of the chamber controls. No exposure-related gross lesions were observed in male or female rats or mice at necropsy. Microscopically, minimal hypertrophy of goblet cells lining the nasopharyngeal duct in the most caudal nose section was observed in some rats in each exposed group of males and females. 2-YEAR STUDIES: Based on the lack of significant exposure-related toxicologic effects in the 14-week rat and mouse studies, 8,000 ppm was selected as the highest exposure concentration in the 2-year studies. Concentrations of 0, 500, 2,000, and 8,000 ppm were selected for rats and mice with the

  18. NTP Toxicology and Carcinogenesis Studies of Glycidol (CAS No. 556-52-5) In F344/N Rats and B6C3F1 Mice (Gavage Studies).

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    1990-03-01

    Glycidol is a viscous liquid that is used as a stabilizer in the manufacture of vinyl polymers, as an additive for oil and synthetic hydraulic fluids, and as a diluent in some epoxy resins. NTP Toxicology and Carcinogenesis studies were conducted by administering glycidol (94% pure, containing 1.2% 3-methoxy-1,2-propanediol, 0.4% 3-chloro-1,2-propanediol, 2.8% diglycidyl ether, and 1.1% 2,6-dimethanol-1,4-dioxane) in water by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary (CHO) cells, Drosophila melanogaster, and the bone marrow of male B6C3F1 mice. Sixteen-Day Studies: Glycidol doses for groups of five rats or five mice of each sex ranged from 37.5 to 600 mg/kg; vehicle controls received distilled water. All rats that received 600 mg/kg died between days 3 and 13. Edema and degeneration of the epididymal stroma, atrophy of the testis, and granulomatous inflammation of the epididymis occurred in males that received 300 mg/kg. All mice that received 600 mg/kg and two males and two females that received 300 mg/kg died by day 4 of the studies. Focal demyelination in the medulla and thalamus of the brain occurred in all female mice that received 300 mg/kg. Thirteen-Week Studies: Doses for groups of 10 rats ranged from 25 to 400 mg/kg, and doses for groups of 10 mice ranged from 19 to 300 mg/kg; vehicle controls received distilled water. All rats that received 400 mg/kg died by week 2; three males and one female that received 200 mg/kg died during weeks 11-12. Final mean body weights of male rats that received 50, 100, or 200 mg/kg were 96%-85% that of vehicle controls; final mean body weights of female rats receiving the same doses were 95%-89% that of vehicle controls. Sperm count and sperm motility were reduced in male rats that received 100 or 200 mg/kg. Necrosis of the cerebellum, demyelineation in the medulla of the brain

  19. Genetic Alterations in K-ras and p53 Cancer Genes in Lung Neoplasms From B6C3F1 Mice Exposed to Cumene

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    Hong, Hue-Hua L.; Ton, Thai-Vu T.; Kim, Yongbaek; Wakamatsu, Nobuko; Clayton, Natasha P.; Chan, Po-Chuen; Sills, Robert C.; Lahousse, Stephanie A.

    2008-01-01

    The incidences of alveolar/bronchiolar adenomas and carcinomas in cumene-treated B6C3F1 mice were significantly greater than those of the controls. We evaluated these lung neoplasms for point mutations in the K-ras and p53 genes that are often mutated in humans. K-ras and p53 mutations were detected by cycle sequencing of PCR-amplified DNA isolated from paraffin-embedded neoplasms. K-ras mutations were detected in 87 % cumene-induced lung neoplasms, and the predominant mutations were exon 1 c...

  20. Reevaluation and Classification of Duodenal Lesions in B6C3F1 Mice and F344 Rats from 4 Studies of Hexavalent Chromium in Drinking Water.

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    Cullen, John M; Ward, Jerrold M; Thompson, Chad M

    2016-02-01

    Thirteen-week and 2-year drinking water studies conducted by the National Toxicology Program (NTP) reported that hexavalent chromium (Cr(VI)) induced diffuse epithelial hyperplasia in the duodenum of B6C3F1 mice but not F344 rats. In the 2-year study, Cr(VI) exposure was additionally associated with duodenal adenomas and carcinomas in mice only. Subsequent 13-week Cr(VI) studies conducted by another group demonstrated non-neoplastic duodenal lesions in B6C3F1 mice similar to those of the NTP study as well as mild duodenal hyperplasia in F344 rats. Because intestinal lesions in mice are the basis for proposed safety standards for Cr(VI), and the histopathology data are relevant to the mode of action, consistency (an important Hill criterion for causality) was assessed across the aforementioned studies. Two veterinary pathologists applied uniform diagnostic criteria to the duodenal lesions in rats and mice from the 4 repeated-dose studies. Comparable non-neoplastic intestinal lesions were evident in mice and rats from all 4 studies; however, the incidence and severity of intestinal lesions were greater in mice than rats. These findings demonstrate consistency across studies and species and highlight the importance of standardized nomenclature for intestinal pathology. The differences in the severity of non-neoplastic lesions also likely contribute to the differential tumor response.

  1. Immunotoxicological profile of chloramine in female B6C3F1 mice when administered in the drinking water for 28 days.

    Science.gov (United States)

    Guo, Tai L; Germolec, Dori R; Collins, Bradley J; Luebke, Robert W; Auttachoat, Wimolnut; Smith, Matthew J; White, Kimber L

    2011-01-01

    Monochloramine has been used to provide a disinfecting residual in water distribution systems where it is difficult to maintain an adequate free-chlorine residual or where disinfection by-product formation is of concern. The goal of this study was to characterize the immunotoxic effects of chloramine in female B(6)C(3)F(1) mice when administered via the drinking water. Mice were exposed to chloramine-containing deionized tap water at 2, 10, 20, 100, or 200 ppm for 28 days. No statistically significant differences in drinking water consumption, body weight, body weight gain, organ weights, or hematological parameters between the exposed and control animals were noted during the experimental period. There were no changes in the percentages and numbers of total B-lymphocytes, T-lymphocytes, CD4(+) and CD8(+) T-lymphocytes, natural killer (NK) cells, and macrophages in the spleen. Exposure to chloramine did not affect the IgM antibody-forming cell response to sheep red blood cells (SRBC) or anti-SRBC IgM antibody production. Minimal effects, judged to be biologically insignificant, were observed in the mixed-leukocyte response and NK activity. In conclusion, chloramine produced no toxicological and immunotoxic effects in female B(6)C(3)F(1) mice when administered for 28 days in the drinking water at concentrations ranging from 2-200 ppm.

  2. Importance of Dichloroacetate and Trichloroacetate to the Hepatocarcinogenic Response to Trichloroeylene in B6C3F1 Mice

    Science.gov (United States)

    1989-10-15

    Phenobarbital. 0.5 g/L No. of foci 0 0 No. mice with foci 0/5 0/5 Foci/lateral lobe 0 0 No. mice with tumors 0/5 0/5 041 C41 > 000 P-4 5 zn 04 41 3 0...1981) Morphological changes in mouse spermatozoa after exposure to inhalation anesthetics during early spermatogenesis. Anesthesiolocgv 5:53- 56

  3. Disposition and metabolism of cumene in F344 rats and B6C3F1 mice.

    Science.gov (United States)

    Chen, Ling-Jen; Wegerski, Christopher J; Kramer, Daniel J; Thomas, Leslie A; McDonald, Jacob D; Dix, Kelly J; Sanders, J Michael

    2011-03-01

    Cumene is a high-production volume chemical that has been shown to be a central nervous system depressant and has been implicated as a long-term exposure carcinogen in experimental animals. The absorption, distribution, metabolism, and excretion of [(14)C]cumene (isopropylbenzene) was studied in male rats and mice of both sexes after oral or intravenous administration. In both species and sexes, urine accounted for the majority of the excretion (typically ≥ 70%) by oral and intravenous administration. Enterohepatic circulation of cumene and/or its metabolites was indicated because 37% of the total dose was excreted in bile in bile duct-cannulated rats with little excreted in normal rats. The highest tissue (14)C levels in rats were observed in adipose tissue, liver, and kidney with no accumulation observed after repeat dosing up to 7 days. In contrast, mice contained the highest concentrations of (14)C at 24 h after dosing in the liver, kidney, and lung, with repeat dosing accumulation of (14)C observed in these tissues as well as in the blood, brain, heart, muscle, and spleen. The metabolites in the expired air, urine, bile, and microsomes were characterized with 16 metabolites identified. The volatile organics in the expired air comprised mainly cumene and up to 4% α-methylstyrene. The major urinary and biliary metabolite was 2-phenyl-2-propanol glucuronide, which corresponded with the main microsomal metabolite being 2-phenyl-2-propanol.

  4. NTP Toxicology and Carcinogenesis Studies of Propylene (CAS No. 115-07-1) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

    Science.gov (United States)

    1985-11-01

    data discrepancies were found that influenced the final interpretations. Under the conditions of these studies, there was no evidence of carcinogenicity in male and female F344/N rats or in male and female B6C3F1 mice exposed to propylene by inhalation at concentrations of 5,000 or 10,000 ppm for 103 weeks. In the nasal cavity, propylene induced squamous metaplasia of the respiratory epithelium in male and female rats and epithelial hyperplasia in female rats. Synonyms: propene; methylethylene; methylethene

  5. NTP Toxicology and Carcinogenesis Studies of Pentachloroanisole (CAS No. 1825-21-4) in F344 Rats and B6C3F1 Mice (Feed Studies).

    Science.gov (United States)

    1993-04-01

    Pentachloroanisole is a chlorinated aromatic compound which is widely distributed at low levels in the environment and in food products. Formation of pentachloroanisole in the environment may result from the degradation of structurally related, commercially important, ubiquitous chlorinated aromatic compounds such as pentachlorophenol and pentachloronitrobenzene which are known rodent toxins or carcinogens. Toxicology and carcinogenesis studies were conducted by administering pentachloroanisole (>99% pure) in corn oil by gavage to groups of male and female F344/N rats and B6C3F1 mice for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium strains, mouse lymphoma cells, and Chinese hamster ovary cells. 16-DAY STUDIES IN RATS: Groups of five male and five female F344/N rats were administered pentachloroanisole in corn oil by gavage once per day, 5 days per week, for 16 days at doses of 0, 100, 125, 150, 175, or 200 mg/kg body weight. Deaths occurred during days 2 and 3 in rats receiving doses of 125 mg/kg or greater; these deaths were considered directly related to pentachloroanisole administration. No biologically significant changes in mean body weight gains or final body weights were noted in the 100 mg/kg groups of rats. Because of the high early mortality rate, valid comparisons of body weight differences in other dose groups could not be made. Inactivity was noted in all dose groups. Rats administered doses of 125 mg/kg or greater also exhibited dyspnea. 16-DAY STUDIES IN MICE: Groups of five male and five female B6C3F1 mice were administered pentachloroanisole in corn oil by gavage once per day, 5 days per week, for 16 days at doses of 0, 100, 175, 250, 325, or 400 mg/kg. Deaths occurred during days 2 and 3 in mice receiving doses of 175 mg/kg or greater; these deaths were considered directly related to chemical administration. No biologically significant changes in mean body weight gains or final body weights

  6. NTP Toxicology and Carcinogenesis Studies of Tetrafluoroethylene (CAS No. 116-14-3) in F344 Rats and B6C3F1 Mice (Inhalation Studies).

    Science.gov (United States)

    1997-04-01

    Tetrafluoroethylene is used in the production of polytetrafluoroethylene (Teflon(R)) and other polymers. Tetrafluoroethylene was nominated by the National Cancer Institute for toxicity and carcinogenicity studies based on the potential for human exposure to the chemical due to the large production volume and on the lack of adequate data for tetrafluoroethylene in the literature. Male and female F344/N rats and B6C3F1 mice were exposed to tetrafluoroethylene (98% to 99% pure) by whole body inhalation exposure for 16 days, 13 weeks, or 2 years. Genetic toxicity studies were conducted in mouse peripheral blood erythrocytes. 16-DAY STUDY IN RATS: Groups of five male and five female F344/N rats were exposed to 0, 312, 625, 1,250, 2,500, or 5,000 ppm tetrafluoroethylene by inhalation for 6 hours per day, 5 days per week for a total of 12 exposures during a 16-day period. All rats survived to the end of the study. The final mean body weights and body weight gains of males and females exposed to 5,000 ppm were significantly less than those of the controls. The mean body weight gain of females exposed to 2,500 ppm was also significantly less than that of the controls. There were no exposure-related clinical findings in male or female rats. There were no significant differences in hematology parameters that were considered to be related to tetrafluoroethylene exposure. Absolute and relative kidney weights of all exposed groups of males were significantly greater than those of the controls, as were those of females in the 2,500 and 5,000 ppm groups. The absolute kidney weight of females exposed to 1,250 ppm was also significantly greater than that of the controls. The relative liver weights of all exposed groups of males and the absolute liver weights of males in the 625 and 2,500 ppm groups were significantly greater than those of the controls. Increased incidences of renal tubule degeneration occurred in males and females exposed to 625 ppm or greater; this lesion was

  7. Characterization of the toxicity, mutagenicity, and carcinogenicity of methacrylonitrile in F344 Rats and B6C3F1 mice.

    Science.gov (United States)

    Nyska, Abraham; Ghanayem, Burhan I

    2003-04-01

    Methacrylonitrile is an unsaturated aliphatic nitrile. It is widely used in the preparation of homopolymers and copolymers, elastomers, and plastics, and as a chemical intermediate in the preparation of acids, amides, amines, esters, and other nitriles. Methacrylonitrile was nominated for study by the National Cancer Institute (USA) because of the potential for human exposure, structural similarity to the known carcinogen acrylonitrile, and a lack of toxicity and carcinogenicity data. Doses selected for the 2-year study were based on the results of the 13-week gavage studies. Groups of 50 male and 50 female animals were exposed by gavage to 0, 3, 10, or 30 mg/kg in F344 rats, and 0, 1.5, 3 or 6 mg/kg in B6C3F1 mice, 5 days per week for 2 years. Urinary excretion of N-acetyl- S-(2-cyanopropyl)- l-cysteine (NACPC) and N-acetyl- S-(2-hydroxypropyl)- l-cysteine (NAHPC) were measured as markers of exposure at various time points after methacrylonitrile administration, and demonstrated that exposure of animals to methacrylonitrile occurred as intended. Urinary excretion of NACPC and NAHPC increased in rats and mice in a dose-dependent manner. In contrast to observations in rats, the ratios of NACPC/creatinine were generally higher in female than in male mice. Further, the ratios of NAHPC/creatinine in rats were significantly greater at all time points and all doses than the corresponding ratios of NACPC/creatinine in male and female mice. In both rats and mice, survival was not affected by treatment. In rats, mean body weights of the 30 mg/kg groups were less than those of the vehicle controls after weeks 21 and 37 for males and females, respectively. No treatment-related effect on body weight was seen in mice. There were no neoplasms (in either species) or non-neoplastic lesions (mice only) that were attributed to methacrylonitrile administration. In rats, the incidences of olfactory epithelial atrophy and metaplasia of the nose were significantly greater in 30 mg

  8. Toxic responses in F344 rats and B6C3F1 mice given roxarsone in their diets for up to 13 weeks.

    Science.gov (United States)

    Abdo, K M; Elwell, M R; Montgomery, C A; Thompson, M B; Thompson, R B; Prejean, J D

    1989-01-01

    Thirteen-week toxicity studies were conducted in groups of 10 F344 rats and B6C3F1 mice of each sex fed roxarsone at 0, 50, 100, 200, 400, or 800 ppm in the diet. Arsenic levels in blood, urine, kidneys, and liver of rats were measured in additional animals of each sex dosed with 100 or 400 ppm roxarsone. Compound-related mortality occurred in both sexes of rats at 800 ppm and mice at 800 and 400 ppm. Significant body weight gain depression occurred in both sexes of rats at 200, 400, and 800 ppm and mice at 800 ppm. Clinical signs of toxicity (trembling, ataxia, and pale skin) were seen primarily in rats and mice at 800 ppm. Lesions associated with roxarsone administration were noted only in the kidney of rats and were characterized by tubular necrosis and mineralization at the corticomedullary junction. Arsenic levels in urine, blood, liver, and kidneys increased over time and were directly proportional to the level of roxarsone in feed. These levels were greater than 6 times higher in rats than in mice and were about 2 time higher in males than in females. The no-observable-effect level for roxarsone toxicity was estimated at 100 ppm for rats and 200 ppm for mice. No hematology or clinical chemistry effects were found in rats or mice of either sex.

  9. Genetic alterations in K-ras and p53 cancer genes in lung neoplasms from B6C3F1 mice exposed to cumene.

    Science.gov (United States)

    Hong, Hue-Hua L; Ton, Thai-Vu T; Kim, Yongbaek; Wakamatsu, Nobuko; Clayton, Natasha P; Chan, Po-Chuen; Sills, Robert C; Lahousse, Stephanie A

    2008-07-01

    The incidences of alveolar/bronchiolar adenomas and carcinomas in cumene-treated B6C3F1 mice were significantly greater than those of the control animals. We evaluated these lung neoplasms for point mutations in the K-ras and p53 genes that are often mutated in humans. K-ras and p53 mutations were detected by cycle sequencing of PCR-amplified DNA isolated from paraffin-embedded neoplasms. K-ras mutations were detected in 87% of cumene-induced lung neoplasms, and the predominant mutations were exon 1 codon 12 G to T transversions and exon 2 codon 61 A to G transitions. P53 protein expression was detected by immunohistochemistry in 56% of cumene-induced neoplasms, and mutations were detected in 52% of neoplasms. The predominant mutations were exon 5, codon 155 G to A transitions, and codon 133 C to T transitions. No p53 mutations and one of seven (14%) K-ras mutations were detected in spontaneous neoplasms. Cumene-induced lung carcinomas showed loss of heterozygosity (LOH) on chromosome 4 near the p16 gene (13%) and on chromosome 6 near the K-ras gene (12%). No LOH was observed in spontaneous carcinomas or normal lung tissues examined. The pattern of mutations identified in the lung tumors suggests that DNA damage and genomic instability may be contributing factors to the mutation profile and development of lung cancer in mice exposed to cumene.

  10. NTP Toxicology and Carcinogenesis Studies of Roxarsone (CAS No. 121-19-7) in F344/N Rats and B6C3F1 Mice (Feed Studies).

    Science.gov (United States)

    1989-03-01

    Roxarsone is a veterinary drug used as a growth promoter and as an anticoccidial agent and for treatment of swine dysentery. Toxicology and carcinogenesis studies were conducted by administering roxarsone (greater than 99.4% pure) in feed to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Fourteen-Day and Thirteen-Week Studies: In the 14-day studies, the diets fed to rats contained 0 or 100-1,600 ppm roxarsone, and those fed to mice contained 0 or 60-1,000 ppm. Deaths occurred in rats and mice that received the highest doses. Rats that received 800 or 1,600 ppm lost weight. Male mice that received 1,000 ppm and female mice that received 500 ppm lost weight. In the first 13-week studies, roxarsone was fed to rats and mice at dietary concentrations of 0 or 50-800 ppm. Decreases (more than 10%) in final mean body weights of dosed rats relative to those of controls were observed for males that received 200, 400, or 800 ppm and for females that received 400 or 800 ppm. Deaths occurred in groups that received 800 ppm. Clinical signs of toxicity (trembling, ataxia, and pale skin) were seen primarily in rats that received 800 ppm. Kidney lesions were observed in rats that received 800 ppm. These lesions were characterized by tubular necrosis and mineralization in the rats that died during the studies and by tubular dilatation and casts, interstitial inflammation, and tubular epithelial cell regeneration in the rats that lived to the end of the studies. Additional 13-week studies were conducted in rats at dietary concentrations of 0, 100, or 400 ppm to demonstrate the absorption of roxarsone from the gastrointestinal tract; to determine its distribution in liver, kidney, and blood; and to study its effects on various hematologic and clinical chemical values. No deaths occurred. Renal lesions of minimal severity observed in male rats that received 400 ppm were characterized by tubular epithelial cell degeneration and regeneration, tubular

  11. NTP Toxicology and Carcinogenesis Studies of Diethanolamine (CAS No. 111-42-2) in F344/N Rats and B6C3F1 Mice (Dermal Studies).

    Science.gov (United States)

    1999-07-01

    Diethanolamine is widely used in the preparation of diethanolamides and diethanolamine salts of long-chain fatty acids that are formulated into soaps and surfactants used in liquid laundry and dishwashing detergents, cosmetics, shampoos, and hair conditioners. Diethanolamine is also used in textile processing, in industrial gas purification to remove acid gases, as an anticorrosion agent in metalworking fluids, and in preparations of agricultural chemicals. Aqueous diethanolamine solutions are used as solvents for numerous drugs that are administered intravenously. Diethanolamine was selected for evaluation because its large-scale production and pattern of use indicate the potential for widespread human exposure. Male and female F344/N rats and B6C3F1 mice received dermal applications of diethanolamine in 95% ethanol for 2 years. Genetic toxicology studies were performed in Salmonella typhimurium, L5178Y mouse lymphoma cells, cultured Chinese hamster ovary cells, and B6C3F1 mouse peripheral blood erythrocytes. RATS: Groups of 50 male rats were administered 0, 16, 32, or 64 mg diethanolamine/kg body weight in ethanol dermally for 2 years. Groups of 50 female rats were administered 0, 8, 16, or 32 mg/kg in ethanol dermally for 2 years. Survival, Body Weights, and Clinical Findings Survival of vehicle control and dosed male and female rats was similar. Mean body weights of 64 mg/kg males were less than those of the vehicle controls beginning week 8, and mean body weights of females were generally similar to those of the vehicle control group. The only clinical finding attributed to diethanolamine administration was irritation of the skin at the site of application. Pathology Findings: Minimal to mild nonneoplastic lesions occurred at the site of application in the epidermis of dosed male and female rats. The incidence of acanthosis in 64 mg/kg males, the incidences of hyperkeratosis in 32 and 64 mg/kg males and in all dosed female groups, and the incidences of exudate

  12. NTP Toxicology and Carcinogenesis Studies of Two Pentachlorophenol Technical-Grade Mixtures (CAS No. 87-86-5) in B6C3F1 Mice (Feed Studies).

    Science.gov (United States)

    1989-03-01

    Toxicology studies of pentachlorophenol, a biocide used primarily as a wood preservative, were conducted by feeding diets containing a technical-grade composite, Dowicide EC-7 (a technical grade formulation), or pure pentachlorophenol to groups of B6C3F1 mice for 30 days. These three grades plus another commercial grade of pentachlorophenol (DP-2) were used in 6-month studies. These studies were followed by 2-year carcinogenicity studies of technical-grade pentachlorophenol and of Dowicide EC-7 in feed. Genetic toxicology studies were conducted in Salmonella typhimurium and in Chinese hamster ovary (CHO) cells. Thirty-Day and Sixteen-Month Studies: Groups of 19 male mice and 5-15 female mice were fed diets containing 0, 20, 100, 500, 2,500, or 12,500 ppm technical-grade pentachlorophenol, Dowicide EC-7, or pure pentachlorophenol for 30 consecutive days. Necropsies and histopathologic examinations were performed on all animals. Selected organs were weighed. Supplemental analyses included hematology, serum chemistry, urinalysis, immunology, and hepatic enzyme induction. Compound-related deaths were observed at the highest dose (12,500 ppm) with all three materials and at 2,500 ppm with EC-7 and pure pentachlorophenol (males only). Decreases in body weight gain were also observed in the groups in which deaths occurred. Diffuse centrilobular cytomegaly, karyomegaly, nuclear atypia, degeneration, or necrosis of the liver were compound-related lesions observed in all groups that received pure pentachlorophenol, technical-grade pentachlorophenol, or EC-7 at 500 ppm and above. Serum enzymes associated with liver injury were increased. In the 6-month studies, groups of 10 male and 10 female mice were given diets containing the various grades of pentachlorophenol at the following dietary concentrations: 200, 600, or 1,800 ppm technical-grade pentachlorophenol; 200, 600, or 1,200 ppm DP-2 (not used in the 30-day studies); 200, 600, or 1,200 ppm EC-7; or 200, 500, or 1,500 ppm

  13. NTP Toxicology and Carcinogenesis Studies of Salicylazosulfapyridine (CAS No. 599-79-1) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

    Science.gov (United States)

    1997-05-01

    Salicylazosulfapyridine is widely used for the treatment of ulcerative colitis and Crohn's disease. It has been beneficial in the treatment of psoriasis and rheumatoid arthritis, and it has been used in veterinary medicine for the treatment of granulomatous colitis. Salicylazosulfapyridine was nominated for toxicity and carcinogenicity testing by the National Cancer Institute on the basis of its widespread use in humans and because it is a representative chemical from a class of aryl sulfonamides. Salicylazosulfapyridine is a suspect carcinogen because reductive cleavage of the azo linkage yields a p-amino aryl sulfonamide (sulfapyridine), and a related p-amino aryl sulfonamide (sulfamethoxazole) has been shown to produce thyroid neoplasms in rats. Toxicology and carcinogenicity studies were conducted in F344/N rats and B6C3F1 mice. Rats and mice were administered salicylazosulfapyridine (96% to 98% pure) in corn oil by gavage for 16 days, 13 weeks, or 2 years. The gavage route of administration was selected for these studies because it approximates the typical route of human exposure to the chemical. Genetic toxicology studies were conducted in vitro in Salmonella typhimurium and cultured Chinese hamster ovary cells and in vivo in rat and mouse bone marrow and mouse peripheral blood cells. 16-DAY STUDY IN RATS: Groups of five male and five female rats were administered 0, 675, 1,350, or 2,700 mg salicylazosulfapyridine/kg body weight in corn oil by gavage for 16 days excluding weekends. All rats survived to the end of the study. With the exception of the 675 mg/kg male group, the final mean body weights of all dosed groups of males and females were significantly lower than those of controls. Mean body weight gains of all dosed groups were less than those of controls. Clinical findings included ruffled fur and distended abdomens in male and female rats receiving 2,700 mg/kg. Hypothyroidism, evidenced by decreased serum triiodothyronine and thyroxine concentrations

  14. Immunotoxic effects of sodium tungstate dihydrate on female B6C3F1/N mice when administered in drinking water.

    Science.gov (United States)

    Frawley, Rachel P; Smith, Matthew J; White, Kimber L; Elmore, Susan A; Herbert, Ron; Moore, Rebecca; Staska, Lauren M; Behl, Mamta; Hooth, Michelle J; Kissling, Grace E; Germolec, Dori R

    2016-09-01

    Tungsten is a naturally occurring, high-tensile strength element that has been used in a number of consumer products. Tungsten has been detected in soil, waterways, groundwater, and human tissue and body fluids. Elevated levels of tungsten in urine were reported for populations exposed to tungstate in drinking water in areas where natural tungsten formations were prevalent. Published reports indicated that sodium tungstate may modulate hematopoiesis, immune cell populations, and immune responses in rodent models. The objective of this study was to assess potential immunotoxicity of sodium tungstate dihydrate (STD), a drinking water contaminant. Female B6C3F1/N mice received 0-2000 mg STD/L in their drinking water for 28 d, and were evaluated for effects on immune cell populations in spleen and bone marrow, and humoral-mediated, cell-mediated, and innate immunity. Three different parameters of cell-mediated immunity were similarly affected at 1000 mg STD/L. T-cell proliferative responses against allogeneic leukocytes and anti-CD3 were decreased 32%, and 21%, respectively. Cytotoxic T-lymphocyte activity was decreased at all effector:target cell ratios examined. At 2000 mg STD/L, the absolute numbers of CD3(+) T-cell progenitor cells in bone marrow were increased 86%, but the alterations in B-lymphocyte and other progenitor cells were not significant. There were no effects on bone marrow DNA synthesis or colony forming capabilities. STD-induced effects on humoral-mediated immunity, innate immunity, and splenocyte sub-populations were limited. Enhanced histopathology did not detect treatment-related lesions in any of the immune tissues. These data suggest exposure to STD in drinking water may adversely affect cell-mediated immunity.

  15. Investigation of the DNA adducts formed in B6C3F1 mice treated with benzene: Implications for molecular dosimetry

    Energy Technology Data Exchange (ETDEWEB)

    Bodell, W.J.; Pathak, D.N.; Levay, G. [Univ. of California, San Francisco, CA (United States)] [and others

    1996-12-01

    We have investigated the formation of DNA adducts in the bone marrow and white blood cells of male B6C3F1 mice treated with benzene using P1-enhanced {sup 32}P-postlabeling. No adducts were detected in the bone marrow of controls or mice treated with various doses of benzene once a day. After twice-daily treatment for 1 to 7 days with benzene, 440 mg/kg, one major (no. 1) and UP to two minor DNA adducts were detected in both the bone marrow and white blood cells. The relative adduct levels in these cells ranged from 0.06 to 1.46 x 10{sup -7}. A significant correlation (r 0.95) between levels of adducts in bone marrow and white blood cells was observed. After a 7-day treatment with benzene, 440 mg/kg twice a day, the number of cells per femur decreased from 1.6 x 10{sup 7} to 0.85 X 10{sup 7}, indicating myelotoxicity. In contrast, administration of benzene once a day produced only a small decrease in bone marrow cellularity. The observed induction of toxicity in bone marrow was paralleled by formation of DNA adducts. In vitro treatment of bone marrow with hydroquinone (HQ) for 24 hr produced the same DNA adducts as found after treatment of mice with benzene, suggesting that HQ is the principal metabolite of benzene leading to DNA adduct formation in vivo. Using {sup 32}P-postlabeling the principal DNA adduct formed in vivo was compared with N{sup 2}-(4-hydroxyphenyl)-2-deoxyguanosine-3-phosphate. The results of this comparison demonstrates that the DNA adduct formed in vivo co-chromatographs with N{sup 2}-(4-hydroxyphenyl)-2-deoxyguanosine-3{prime}-phosphate. These studies indicate that metabolic activation of benzene leads to the formation of DNA adducts in bone marrow and white blood cells and suggest that measurement of DNA adducts in white blood cells may be an indicator of biological effect following benzene exposure. 34 refs., 4 figs., 2 tabs.

  16. NTP Carcinogenesis Bioassay of Propyl Gallate (CAS No. 121-79-9) in F344/N Rats and B6C3F1 Mice (Feed Study).

    Science.gov (United States)

    1982-12-01

    Propyl gallate is a white to nearly white odorless powder having a slightly bitter taste. Solutions of propyl gallate turn dark in the presence of iron or iron salts. Propyl gallate has been used since 1948 as an antioxidant to stabilize cosmetics, food packaging materials, and foods containing fats. As an additive, it may be found in edible fats, oils, mayonnaise, shortening, baked goods, candy, dried meat, fresh pork sausage, and dried milk, and it is used in hair grooming products, pressure-sensitive adhesives, lubricating oil additives, and transforming oils. A NTP Carcinogenesis bioassay of propyl gallate was conducted by feeding diets containing 6,000 or 12,000 ppm propyl gallate to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex for 103 weeks. Groups of 50 untreated rats and 50 untreated mice of each sex served as controls. Survival of rats and mice was not adversely affected by propyl gallate, but mean body weights of dosed rats and mice of each sex were lower than those of the controls. At 104 weeks, mean body weights of low-and high-dose rats were 4% and 8% lower than those of the controls for males and 11% and 19% lower than those of the controls for females. Similarly, mean body weights of low-and high-dose mice were 5% and 8% lower than those of the controls for males and 11% (both dose groups) lower than those of the controls for females. Thyroid follicular-cell adenomas or carcinomas (combined) occurred in male rats with a statistically significant (P<0.05) positive trend, but the incidences in the dosed groups were not statistically significant in direct comparisons with the control groups. Moreover, the incidence of high-dose male rats with follicular-cell tumors (3/50, 6%) was not statistically different from the historical control rate (14/584, 2.4%) for the laboratory that conducted this bioassay. Rare tumors (an astrocytoma or a glioma) were found in the brains of two low-dose female rats. The incidence of all brain tumors in the

  17. NTP Toxicity Studies of Cyclohexanone Oxime Administered by Drinking Water to B6C3F1 Mice (CAS No. 100-64-1).

    Science.gov (United States)

    1996-04-01

    Cyclohexanone oxime is used primarily as a captive intermediate in the synthesis of caprolactam for the production of polycaprolactam (Nylon-6) fibers and plastics and also in a variety of industrial applications. Cyclohexanone oxime was selected for study because of the potential for human exposure and the interest in oximes as a chemical class. Toxicity studies of cyclohexanone oxime (approximately 99% pure) were carried out in male and female B6C3F1 mice; the compound was administered in drinking water for 2 weeks or 13 weeks. In addition, the genetic toxicity of cyclohexanone oxime was evaluated by determining mutagenicity in Salmonella typhimurium and induction of chromosomal aberrations in cultured Chinese hamster ovary cells in vitro, with and without S9 activation. The frequency of micronucleated normochromatic erythrocytes in the bone marrow and peripheral blood of mice from the 13-week study was also determined. In the 2-week study, groups of five male and five female mice were given drinking water containing 0, 106, 312, 625, 1,250, or 2,500 ppm cyclohexanone oxime. No deaths occurred, and there was no decrease in weight gain in any group. No gross lesions were observed; there were significant increases in relative spleen weights of males and females in the 2,500 ppm group and increases in the relative liver weight of male mice exposed to 312 ppm or greater. In the 13-week studies, groups of 10 male and 10 female mice were given drinking water containing 625, 1,250, 2,500, 5,000 or 10,000 ppm cyclohexanone oxime. Deaths occurred in the 10,000 ppm groups and weight gain was depressed in males and females given 10,000 ppm and in females given 5,000 ppm. There were significant increases in relative spleen weight at exposure levels of 5,000 and 10,000 ppm and significant increases in the relative liver weights of males and females that received 10,000 ppm. Microscopically, hematopoietic cell proliferation was observed in the spleen of males and females in

  18. Toxicology and carcinogenesis studies of 1-bromopropane (CAS No. 106-94-5) in F344/N rats and B6C3F1 mice (inhalation studies).

    Science.gov (United States)

    2011-08-01

    In the early to mid 1990s, 1-bromopropane was used primarily as an intermediate in the production of pesticides, quaternary ammonium compounds, flavors and fragrances, pharmaceuticals, and other chemicals in well-controlled, closed processes. In the mid to late 1990s, it was introduced as a less toxic replacement for methylene chloride in emissive applications such as vapor and immersion degreasing operations and critical cleaning of electronics and metals. 1-Bromopropane was also introduced as a nonflammable, nontoxic, fast-drying, and inexpensive solvent for adhesive resins, and has been marketed as a replacement for ozone depleting refrigerants. 1-Bromopropane was nominated for study by the Occupational Safety and Health Administration based on the potential for widespread occupational and environmental exposure and a lack of toxicity and carcinogenicity data. Male and female F344/N rats and B6C3F1 mice were exposed to 1-bromopropane (99% or greater pure) by inhalation for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Escherichia coli and mouse peripheral blood. 2-WEEK STUDY IN RATS: Groups of five male and five female rats were exposed to 1-bromopropane vapor at concentrations of 0, 125, 250, 500, 1,000, or 2,000 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 16 days. All rats survived to the end of the study except one 500 ppm male. Mean body weights of 2,000 ppm rats were significantly less than those of the chamber controls. The absolute kidney weight of 1,000 ppm males, relative kidney weights of all exposed groups of males, and absolute and relative kidney weights of all exposed groups of females were significantly increased. The absolute and relative liver weights of 1,000 ppm males, relative liver weights of 500 and 2,000 ppm males, and absolute and relative liver weights of 500 ppm or greater females were significantly increased. Nasal lesions included suppurative inflammation in

  19. Point mutations of K-ras and H-ras genes in forestomach neoplasms from control B6C3F1 mice and following exposure to 1,3-butadiene, isoprene or chloroprene for up to 2-years.

    Science.gov (United States)

    Sills, R C; Hong, H L; Boorman, G A; Devereux, T R; Melnick, R L

    2001-06-01

    1,3 Butadiene (BD), isoprene (IP) and chloroprene (CP) are structural analogs. There were significantly increased incidences of forestomach neoplasms in B6C3F1 mice exposed to BD, IP or CP by inhalation for up to 2-years. The present study was designed to characterize genetic alterations in K- and H-ras proto-oncogenes in a total of 52 spontaneous and chemically induced forestomach neoplasms. ras mutations were identified by restriction fragment length polymorphism, single strand conformational polymorphism analysis, and cycle sequencing of PCR-amplified DNA isolated from paraffin-embedded forestomach neoplasms. A higher frequency of K- and H-ras mutations was identified in BD-, IP- and CP-induced forestomach neoplasms (83, 70 and 57%, respectively, or combined 31/41, 76%) when compared to spontaneous forestomach neoplasms (4/11, 36%). Also a high frequency of H-ras codon 61 CAA-->CTA transversions (10/41, 24%) was detected in chemically induced forestomach neoplasms, but none were present in the spontaneous forestomach neoplasms examined. Furthermore, an increased frequency (treated 13/41, 32% versus untreated 1/11, 9%) of GGC-->CGC transversion at K-ras codon 13 was seen in BD-, and IP-induced forestomach neoplasms, similar to the predominant K-ras mutation pattern observed in BD-induced mouse lung neoplasms. These data suggest that the epoxide intermediates of the structurally related chemicals (BD, IP, and CP) may cause DNA damage in K-ras and H-ras proto-oncogenes of B6C3F1 mice following inhalation exposure and that mutational activation of these genes may be critical events in the pathogenesis of forestomach neoplasms induced in the B6C3F1 mouse.

  20. Toxicity and Carcinogenicity of Ozone in Combination with 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone and Dibutyl Phthalate in B6C3F1 Mice for 16 and 32 Weeks

    Institute of Scientific and Technical Information of China (English)

    MIN YOUNG KIM; M YUNG CHO

    2009-01-01

    Objective To evaluate the toxic and carcinogenic potential of ozone alone or in combination with 4-(N-methyl-N-nitrosamino)-1-(3-pyddyl)-1-butanone (NNK) and/or dibutyl phthalate (DBP). Methods Male and female B6C3F1 mice were exposed,through inhalation,intravenous administration and diet,to 0.5 ppm of ozone,1.0 mg/kg of NNK and 5000 ppm of DBP,individually and in combination for 16 and 32 weeks. Results No treatment-related death was seen,but significant differences in body and organ weights between control and treated mice were observed during the study.No incidence of lung tumor incidence was recorded in mice exposed to either ozone alone or combined treatment.Oviductal carcinomas were observed in female mice exposed to ozone or DBP alone for 16 weeks and ozone in combination with NNK and DBP for 32 weeks. Conclusion Although ozone alone and in conjunction with NNK and/or DBP does not induce lung cancer under our experimental conditions,they induce oviductal carcinomas in B6C3F1 mice.

  1. In vitro exposure of DE-71, a penta-PBDE mixture, on immune endpoints in bottlenose dolphins (Tursiops truncatus) and B6C3F1 mice.

    Science.gov (United States)

    Wirth, Jena R; Peden-Adams, Margie M; White, Natasha D; Bossart, Gregory D; Fair, Patricia A

    2015-02-01

    Polybrominated diphenyl ethers (PBDEs) are an emerging contaminant of concern with low level exposures demonstrating toxicity in laboratory animals and wildlife, although immunotoxicity studies have been limited. Bottlenose dolphin peripheral blood leukocytes (PBLs) and mouse splenocytes were exposed to environmentally relevant DE-71 (a penta-PBDE mixture) concentrations (0-50 µg ml(-1) ) in vitro. Natural killer (NK) cell activity and lymphocyte (B and T cell) proliferation were evaluated using the parallelogram approach for risk assessment. This study aimed to substantiate results from field studies with dolphins, assess the sensitivities between the mouse model and dolphins, and to evaluate risk using the parallelogram approach. In mouse cells, NK cell activity increased at in vitro doses 0.05, 0.5 and 25 µg DE-71 ml(-1) , whereas proliferation was not modulated. In dolphin cells, NK cell activity and lymphocyte proliferation was not altered after in vitro exposure. In vitro exposure of dolphin PBLs to DE-71 showed similar results to correlative field studies; NK cell activity in mice was more sensitive to in vitro exposure than dolphins, and the parallelogram approach showed correlation with all three endpoints to predict risk in bottlenose dolphins.

  2. NTP Toxicology and Carcinogenesis Studies of Lauric Acid Diethanolamine Condensate (CAS NO. 120-40-1) in F344/N Rats and B6C3F1 Mice (Dermal Studies).

    Science.gov (United States)

    1999-07-01

    Lauric acid diethanolamine condensate is widely used in cosmetics, shampoos, soaps, and related consumer products, to which there is extensive human exposure. Because of the lack of information about potential risks associated with long-term exposure, lauric acid diethanolamine condensate, coconut oil acid diethanolamine condensate, and oleic acid diethanolamine condensate were selected as representative of the class of diethanolamides for evaluation of prechronic toxicity and carcinogenic potential. Male and female F344/N rats and B6C3F1 mice were exposed to lauric acid diethanolamine condensate dermally for 14 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, L5178Y mouse lymphoma cells, cultured Chinese hamster ovary cells, and mouse peripheral blood erythrocytes. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were admin istered 0, 25, 50, 100, 200, or 400 mg lauric acid diethanolamine condensate/kg body weight in ethanol by dermal application for 14 weeks. All animals survived until study termination. Final mean body weights and body weight gains of males receiving 200 or 400 mg/kg were significantly less than those of the vehicle control group. Irritation of the skin at the site of application was observed in males receiving 100 mg/kg or greater and in females receiving 200 or 400 mg/kg. Kidney weights of females administered 200 or 400 mg/kg were significantly greater than those of the vehicle control group. There were dose-dependent increases in the incidences of nonneoplastic lesions of the skin at the site of application, including epidermal and sebaceous gland hyperplasia, chronic inflammation, parakeratosis, and ulcer. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were admin istered 0, 50, 100, 200, 400, or 800 mg lauric acid diethanolamine condensate/kg body weight in ethanol by dermal application for 14 weeks. All animals survived until the end of the study, and final mean body weights and

  3. NTP Toxicology and Carcinogenesis Studies of Oleic Acid Diethanolamine Condensate (CAS No. 93-83-4) in F344/N Rats and B6C3F1 Mice (Dermal Studies).

    Science.gov (United States)

    1999-07-01

    Oleic acid diethanolamine condensate is widely used as an emollient, thickener, and foam stabilizer present in cosmetic formulations of bath additives, shampoos, conditioners, lipsticks, and hair dyes. Male and female F344/N rats and B6C3F1 mice received dermal applications of diethanolamine in 95% ethanol for 13 weeks or 2 years. Genetic toxicology studies were performed in Salmonella typhimurium and L5178Y mouse lymphoma cells. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were admin istered 0, 25, 50, 100, 200, or 400 mg oleic acid diethanolamine condensate/kg body weight in ethanol dermally for 13 weeks. All male and female rats survived until the end of the study. The final mean body weights and body weight gains of 200 and 400 mg/kg males and the mean body weight gain of 400 mg/kg females were significantly less than those of the vehicle controls. The only chemical-related clinical finding was irritation of the skin at the site of application in most males administered 100 mg/kg or greater and in all females administered 50 mg/kg or greater. Segmented neutrophil counts were increased relative to the vehicle controls in the 400 mg/kg male group on days 5 and 19, in the 200 mg/kg female group on day 19 and at week 13, and in the 400 mg/kg female group on days 5 and 19 and at week 13. Alkaline phosphatase concentrations were significantly increased in the 200 mg/kg male group on day 19, the 200 mg/kg female group at week 13, and in the 400 mg/kg groups of males and females at week 13. Kidney weights of 200 and 400 mg/kg females were significantly greater than those of the vehicle controls. Lesions of the skin at the site of application included epidermal hyperplasia, parakeratosis, chronic active dermal inflammation, suppurative epidermal inflammation, and sebaceous gland hypertrophy in dosed rats. The severities of these lesions generally increased with increasing dose. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were admin istered

  4. Gene expression analysis of livers from female B6C3F1 mice exposed to carcinogenic and non-carcinogenic doses of furan, with or without bromodeoxyuridine (BrdU treatment

    Directory of Open Access Journals (Sweden)

    Anna Francina Webster

    2014-12-01

    Full Text Available Standard methodology for identifying chemical carcinogens is both time-consuming and resource intensive. Researchers are actively investigating how new technologies can be used to identify chemical carcinogens in a more rapid and cost-effective manner. Here we performed a toxicogenomic case study of the liver carcinogen furan. Full study and mode of action details were previously published in the Journal of Toxicology and Applied Pharmacology. Female B6C3F1 mice were sub-chronically treated with two non-carcinogenic (1 and 2 mg/kg bw and two carcinogenic (4 and 8 mg/kg bw doses of furan for 21 days. Half of the mice in each dose group were also treated with 0.02% bromodeoxyuridine (BrdU for five days prior to sacrifice [13]. Agilent gene expression microarrays were used to measure changes in liver gene and long non-coding RNA expression (published in Toxicological Sciences. Here we describe the experimental and quality control details for the microarray data. We also provide the R code used to analyze the raw data files, produce fold change and false discovery rate (FDR adjusted p values for each gene, and construct hierarchical clustering between datasets.

  5. Gene expression analysis of livers from female B6C3F1 mice exposed to carcinogenic and non-carcinogenic doses of furan, with or without bromodeoxyuridine (BrdU) treatment.

    Science.gov (United States)

    Webster, Anna Francina; Williams, Andrew; Recio, Leslie; Yauk, Carole L

    2014-12-01

    Standard methodology for identifying chemical carcinogens is both time-consuming and resource intensive. Researchers are actively investigating how new technologies can be used to identify chemical carcinogens in a more rapid and cost-effective manner. Here we performed a toxicogenomic case study of the liver carcinogen furan. Full study and mode of action details were previously published in the Journal of Toxicology and Applied Pharmacology. Female B6C3F1 mice were sub-chronically treated with two non-carcinogenic (1 and 2 mg/kg bw) and two carcinogenic (4 and 8 mg/kg bw) doses of furan for 21 days. Half of the mice in each dose group were also treated with 0.02% bromodeoxyuridine (BrdU) for five days prior to sacrifice [13]. Agilent gene expression microarrays were used to measure changes in liver gene and long non-coding RNA expression (published in Toxicological Sciences). Here we describe the experimental and quality control details for the microarray data. We also provide the R code used to analyze the raw data files, produce fold change and false discovery rate (FDR) adjusted p values for each gene, and construct hierarchical clustering between datasets.

  6. Ntp technical report on toxicity, reproductive, and developmental studies of 60-Hz magnetic fields, administered by whole body exposure to F344/N rats, Sprague-Dawley rats, and B6C3F1 mice. Toxicity report series

    Energy Technology Data Exchange (ETDEWEB)

    Boorman, G.A.

    1996-09-01

    Electric and magnetic fields are associated with the production, transmission, and use of electricity; thus the potential for human exposure is high. These electric and magnetic fields are predominantly of low frequency (60 Hz) and generally of low intensity. The prevailing view among physicists is that exposure to these low-frequency, low-intensity fields does not pose a health hazard. However, this view has been challenged by reports linking magnetic field exposure to the development of leukemia and other cancers. Because multiple epidemiologic studies suggested a potential for increased cancer rates with increasing exposure, and because of public concern, the effects of 60-Hz magnetic field exposure were examined in F344/N rats and B6C3F1 mice in 8-week full-body-exposure studies. Animals were evaluated for hematology and clinical chemistry (rats only) parameters, pineal gland hormone concentrations, and histopathology. Additional studies were performed in Sprague-Dawley rats to examine teratologic and reproductive effects of magnetic field exposure.

  7. NTP Toxicology and Carcinogenesis Studies of alpha-Methyldopa Sesquihydrate (CAS No. 41372-08-1) in F344/N Rats and B6C3F1 Mice (Feed Studies).

    Science.gov (United States)

    1989-03-01

    a-Methyldopa sesquihydrate is used in the treatment of hypertension; over 20 million prescriptions are written annually for a -methyldopa or a-methyldopa sesquihydrate in the United States. a-Methyldopa sesquihydrate (USP grade, greater than 99% pure) was selected for study because of widespread human exposure and the lack of carcinogenicity studies on this compound. Fourteen-day, 13-week, and 2-year studies were conducted in F344/N rats and B6C3F1 mice. The chemical was administered in feed because human exposure is primarily by the oral route. Short-term studies were performed in bacteria and mammalian cells to evaluate the potential for genetic damage. Fourteen-Day and Thirteen-Week Studies: In the 14-day studies, the chemical was administered at dietary concentrations of 0 and 6,250-100,000 ppm. All rats receiving 100,000 ppm and 2/5 female rats receiving 50,000 ppm died. All mice lived until the end of the studies. Final mean body weights of dosed male rats were 14%-43% lower than that of controls, and those of dosed female rats were 9%-24% lower. Feed consumption by dosed male and female rats was reduced. Final mean body weights of dosed mice were generally within 10% of those of controls; feed consumption by dosed groups was lower than that by controls during the first week of the studies. In the 13-week studies, the chemical was administered at dietary concentrations of 0 and 3,100-50,000 ppm. Deaths occurred in 4/10 male rats, 7/10 female rats, and 2/10 female mice at 50,000 ppm and in 1/10 female rats at 25,000 ppm. Final mean body weights of dosed rats were 6%-46% lower than those of controls. Feed consumption by dosed rat groups was lower than that by controls. Final mean body weights of male mice at 25,000 and 50,000 ppm and female mice at 50,000 ppm were reduced 12%-19%. Feed consumption by dosed and control mice was comparable. Rats and mice receiving 25,000 and 50,000 ppm exhibited clinical signs of toxicity including lethargy, hyperexcitability

  8. NTP technical report on the toxicity studies of Castor Oil (CAS No. 8001-79-4) in F344/N Rats and B6C3F1 Mice (Dosed Feed Studies).

    Science.gov (United States)

    Irwin, R

    1992-03-01

    Castor oil is a natural oil derived from the seeds of the castor bean, Ricinus communis. It is comprised largely of triglycerides with a high ricinolin content. Toxicity studies with castor oil were performed by incorporating the material at concentrations as high as 10% in diets given to F344/N rats and B6C3F1 mice of both sexes for 13 weeks. Genetic toxicity studies also were performed and were negative for mutation induction in Salmonella typhimurium, for induction of sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells, and for induction of micronuclei in the peripheral blood erythrocytes of mice evaluated at the end of the 13-week studies. Exposure to castor oil at dietary concentrations as high as 10% in 13-week studies did not affect survival or body weight gains of rats or mice (10 per sex and dose). There were no biologically significant effects noted in hematologic analyses in rats. Mild increases in total bile acids and in serum alkaline phosphatase were noted at various times during the studies in rats receiving the higher dietary concentrations of castor oil. Liver weights were increased in male rats receiving the 10% dietary concentration and in male and female mice receiving diets containing 5% or 10% castor oil. However, there were no histopathologic lesions associated with these liver changes, nor were there any compound-related morphologic changes in any organ in rats or mice. No significant changes were noted in a screening for male reproductive endpoints, including sperm count and motility, and no changes were observed in the length of estrous cycles of rats or mice given diets containing castor oil. Thus, no significant adverse effects of castor oil administration were noted in these studies. Synonyms: Ricinus Oil, oil of Palma Christi, tangantangan oil, phorboyl, Neoloid.

  9. NTP Toxicology and Carcinogenesis Studies of d-Limonene (CAS No. 5989-27-5) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

    Science.gov (United States)

    1990-01-01

    Toxicology and carcinogenesis studies of d-limonene, a naturally occurring monoterpene found in many volatile oils, especially in citrus oils, were conducted because of its widespread use as a flavor and fragrance additive for food and household cleaning products and its increasing use as an industrial solvent. The d-limonene used in these studies was more than 99% pure and was administered in corn oil by gavage. Short-term studies were conducted in F344/N rats and B6C3F1 mice to identify toxic effects and affected sites and to help establish doses for the 2-year studies. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse L5178Y cells, and Chinese hamster ovary (CHO) cells. The doses selected for the 16-day studies ranged from 413 to 6,600 mg/kg for both rats and mice; deaths and reduction in body weight gain occurred at the two highest doses. No compound-related clinical signs or histopathologic lesions were observed in any of the surviving dose groups. In the 13-week studies, doses of d-limonene ranged from 150 to 2,400 mg/kg for rats and from 125 to 2,000 mg/kg for mice. Deaths occurred in the high dose group of each species and sex. Greater than 10% reductions in body weight gain were observed in the two highest dose groups of male rats and male mice and the high dose female rats. Rough hair coats and decreased activity were observed at the two highest doses in both rats and mice. There were no chemical-related histopathologic lesions in female rats or in mice of either sex. A compound-related increased severity of nephropathy was observed in the kidney of male rats. This lesion was characterized by degeneration of epithelial cells in the convoluted tubules, granular casts in the outer stripe of the outer medulla, and epithelial regeneration. These lesions have been described as reasonably characteristic of the hyaline droplet nephropathy that is associated with an accumulation of liver-generated a2u-globulin in the cytoplasm of tubular

  10. NTP Toxicology and Carcinogenesis Studies of Tris(2-chloroethyl) Phosphate (CAS No. 115-96-8) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

    Science.gov (United States)

    1991-05-01

    Tris(2-chloroethyl) phosphate (TRCP), a flame-retardant plasticizer used in plastics, polymeric foams, and synthetic fibers, was studied as part of the National Toxicology Program's class study of trisalkyl phosphate flame retardants. Toxicology and carcinogenesis studies were conducted by administering TRCP (approximately 98% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 16 weeks, or 2 years. Genetic toxicology studies were performed in Salmonella typhimurium and Chinese hamster ovary (CHO) cells. 16-Day Studies: There were no chemical-related deaths, differences in final mean body weight, or histopathological lesions in rats receiving 22 to 350 mg/kg TRCP or in mice receiving 44 to 700 mg/kg TRCP for 12 doses over 16 days. Serum cholinesterase activity in female rats receiving 175 or 350 mg/kg TRCP was reduced slightly (80% of control levels), but enzyme activity in dosed male rats and in mice was similar to that in controls. 16-Week Studies: Rats received 22 to 350 mg/kg TRCP for 16 weeks (female) or 18 weeks (male). Several male and female rats in the 175 or 350 mg/kg dose groups died from chemical toxicity. Final mean body weights of female rats receiving 350 mg/kg were 20% greater than those of controls; final mean body weights of the remaining groups of dosed female rats and dosed male rats were similar. Chemical-related neuronal necrosis occurred in the hippocampus and thalamus of female rats and, to a lesser extent, of male rats. Serum cholinesterase activity was reduced in females receiving 175 or 350 mg/kg TRCP. There were no chemical-related deaths, differences in final mean body weight, or differences in cholinesterase activity in mice receiving 44 to 700 mg/kg TRCP for 16 weeks. Tubule epithelial cells with enlarged nuclei (cytomegaly and karyomegaly) were observed in the kidneys of high-dose (700 mg/kg) male and female mice. 2-Year Studies: The 2-year studies in rats were conducted by administering 0

  11. Toxicology and carcinogenesis studies of acrylamide (CASRN 79-06-1) in F344/N rats and B6C3F1 mice (feed and drinking water studies).

    Science.gov (United States)

    2012-07-01

    Acrylamide, a water-soluble α,β-unsaturated amide, is a contaminant in baked and fried starchy foods, including french fries, potato chips, and bread, as a result of Maillard reactions involving asparagine and reducing sugars. Additional sources of acrylamide exposure include cigarettes, laboratory procedures involving polyacrylamide gels, and various occupations (e.g, monomer production and polymerization processes). Acrylamide is carcinogenic in experimental animals. To obtain data for developing quantitative risk assessments for dietary exposures to acrylamide, the Food and Drug Administration nominated acrylamide for an in-depth toxicological evaluation by the National Toxicology Program. As part of this evaluation, male and female B6C3F1/Nctr (C57BL/6N x C3H/HeN MTV-) mice and male and female F344/N Nctr rats were exposed to acrylamide (at least 99.4% pure) in drinking water for 2 years. 2-WEEK STUDY IN RATS: Groups of four male and four female F344/N rats were administered 0, 0.14, 0.35, 0.70, 1.41, 3.52, or 7.03 mM acrylamide in the drinking water (0, 10, 25, 50, 100, 250, or 500 ppm acrylamide) or 0.0, 7.4, 18.5, 37, 74, 185, or 370 mg acrylamide per kg diet for 14 days. One male rat administered 7.03 mM acrylamide in the drinking water died on day 14. Male and female rats receiving 7.03 mM acrylamide weighed 56% and 64% of controls, respectively. Male and female rats fed 370 mg acrylamide per kg diet weighed 74% and 83% of controls, respectively. Female rats receiving 3.52 mM acrylamide in drinking water and male rats fed 185 mg acrylamide per kg diet weighed 85% and 89% of controls, respectively. Rats receiving 7.03 mM acrylamide in drinking water or 370 mg acrylamide per kg diet exhibited hind-leg paralysis on day 14. Mild to moderate dilatation of the urinary bladder was observed in all rats given 370 mg acrylamide per kg diet, and in three of four male rats and all four female rats given 7.03 mM acrylamide in drinking water, and in one of four male

  12. NTP Toxicology and Carcinogenesis Studies of Tetrachloroethylene (Perchloroethylene) (CAS No. 127-18-4) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

    Science.gov (United States)

    1986-08-01

    Tetrachloroethylene is used primarily as a dry cleaning agent, an industrial solvent for fats, oils, tars, rubber, and gums, and a metal degreasing agent. Tetrachloroethylene had antihelminthic uses, particularly for hookworms (1.6-8 g/60 kg), and was formerly used in combination with some grain protectants and fumigants. Toxicology and carcinogenesis studies of tetrachloroethylene (99.9% pure) were conducted by inhalation exposure of groups of 50 male and 50 female F344/N rats and B6C3F1 mice 6 hours per day, 5 days per week, for 103 weeks. The exposure concentrations used (0, 200, or 400 ppm for rats and 0, 100, or 200 ppm for mice) were selected on the basis of results from 13-week inhalation studies in which groups of 10 rats and 10 mice of each sex were exposed to tetrachloroethylene at 100-1,600 ppm for 6 hours per day, 5 days per week. During the 13-week studies, 1,600 ppm tetrachloroethylene was lethal to 20%-70% of the rats and mice and reduced the final body weights of survivors. In rats, tetrachloroethylene at 200-800 ppm caused minimal to mild hepatic congestion. In dosed male and female mice, minimal to mild hepatic leukocytic infiltration, centrilobular necrosis, bile stasis (400-1,600 ppm), and mitotic alteration (200-1,600 ppm) were produced. Tetrachloroethylene exposure also caused minimal renal tubular cell karyomegaly in mice at concentrations as low as 200 ppm. During the 2-year studies, exposure to tetrachloroethylene did not consistently affect body weight gains in either rats or mice. Exposure at 400 ppm tetrachloroethylene reduced the survival of male rats (control, 23/50; low dose, 20/50; high dose, 12/50). This reduced survival may have been related to an increased incidence of mononuclear cell leukemia. Tetrachloroethylene at both exposure concentrations reduced the survival of male mice (46/50; 25/50; 32/50), whereas exposure at 200 ppm reduced female mouse survival (36/50; 31/50; 19/50). Early deaths in mice may have been related to the

  13. Hepatocarcinogenic potential of the glucocorticoid antagonist RU486 in B6C3F1 mice: effect on apoptosis, expression of oncogenes and the tumor suppressor gene p53

    Directory of Open Access Journals (Sweden)

    Badr Mostafa Z

    2003-01-01

    Full Text Available Abstract Background Glucocorticoids inhibit hepatocellular proliferation and modulate the expression of oncogenes and tumor suppressor genes via mechanisms involving the glucocorticoid receptor. Glucocorticoids also produce a receptor-mediated inhibitory effect on both basal and hormone-stimulated expression of a newly discovered family of molecules important for shutting off cytokine action. We therefore hypothesized that inhibiting glucocorticoid receptors may disturb hepatocellular growth and apoptosis. Consequently, we investigated the effect of RU486, a potent antagonist of the glucocorticoid receptor, on basal levels of hepatocellular proliferation and apoptosis in male B6C3F1 mice. Furthermore, we evaluated the effect of this compound on cellular genes involved in the regulation of these important processes. Results Data show that treatment of male B6F3C1 mice with RU486 (2 mg/kg/d, ip for 7 days dramatically inhibited liver cell proliferation by about 45% and programmed hepatocellular death by approximately 66%. RU 486 also significantly increased hepatic expression of the oncogenes mdm2 and JunB, while reducing that of the tumor suppressor gene p53. Conclusion Exposure to RU486 may ultimately enhance the susceptibility of the liver to cancer risk by diminishing its ability to purge itself of pre-cancerous cells via apoptosis. This effect may be mediated through increases in the hepatic expression of the oncogene mdm2, coupled with decreases in that of the tumor suppressor gene p53. The decrease in hepatocellular proliferation caused by RU 486 may be related to effects other than its anti-glucocorticoid activity.

  14. NTP technical report on the toxicity studies of Riddelliine (CAS No. 23246-96-0) Administered by Gavage to F344 Rats and B6C3F1 Mice.

    Science.gov (United States)

    Chan, Po

    1993-12-01

    Riddelliine is a naturally occurring pyrrolizidine alkaloid, a class of compounds occurring in rangeland plants of the genera Crotalaria, Amsinckia, and Senecio. Two-week and 13-week rodent toxicity studies of riddelliine were conducted because riddelliine can be a contaminant of foodstuffs, such as meat, grains, seeds, milk, herbal tea, and honey. In addition to histopathology, evaluations included clinical pathology and reproductive toxicity. In vitro genetic toxicity studies included assessments of mutagenicity in Salmonella typhimurium and of the induction of chromosomal aberrations and sister chromatid exchanges in Chinese hamster ovary cells. Riddelliine was also evaluated in vivo for the induction of micronuclei in mouse bone marrow and in peripheral blood and for the induction of S-phase synthesis and unscheduled DNA synthesis in the liver of rats and mice. In the 2-week studies, groups of five male and five female F344/N rats and B6C3F1 mice were administered riddelliine in 0.1 M phosphate buffer by gavage at dose levels of 0, 0. 33, 1.0, 3.3, 10, or 25 mg/kg body weight five times per week, for a total of 12 doses. Four of five male rats in the 25 mg/kg group died or were killed moribund before the end of the study. Mean body weight gains of male rats in the 10 and 25 mg/kg groups were depressed. No deaths or body weight effects were observed in female rats. Male rats had dose-related hemorrhagic centrilobular hepatic necrosis, hepatocytic karyomegaly and cytologic alterations, pulmonary hemorrhage and/or edema, splenic extramedullary hematopoiesis, and pancreatic edema. Female rats exhibited fewer and less severe lesions than identically treated male rats. Heart weights of treated male and female rats were lower than those of the controls. No deaths or effects on body weight were observed in treated mice. Dose-related increases in absolute and relative liver weights and increased incidences of hepatic cytomegaly were the only treatment-related findings

  15. Toxicokinetics of α-thujone following intravenous and gavage administration of α-thujone or α- and β-thujone mixture in male and female F344/N rats and B6C3F1 mice

    Energy Technology Data Exchange (ETDEWEB)

    Waidyanatha, Suramya, E-mail: waidyanathas@niehs.nih.gov [Division of National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 (United States); Johnson, Jerry D.; Hong, S. Peter [Battelle Memorial Institute, Columbus, OH 43201 (United States); Robinson, Veronica Godfrey [Division of National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 (United States); Gibbs, Seth; Graves, Steven W. [Battelle Memorial Institute, Columbus, OH 43201 (United States); Hooth, Michelle J.; Smith, Cynthia S. [Division of National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 (United States)

    2013-09-01

    Plants containing thujone have widespread use and hence have significant human exposure. α-Thujone caused seizures in rodents following gavage administration. We investigated the toxicokinetics of α-thujone in male and female F344/N rats and B6C3F1 mice following intravenous and gavage administration of α-thujone or a mixture of α- and β-thujone (which will be referred to as α,β-thujone). Absorption of α-thujone following gavage administration was rapid without any dose-, species-, sex- or test article-related effect. Absolute bioavailability of α-thujone following administration of α-thujone or α,β-thujone was generally higher in rats than in mice. In rats, females had higher bioavailability than males following administration of either test article although a sex difference was not observed in mice. C{sub max} and AUC{sub ∞} increased greater than proportional to the dose in female rats following administration of α-thujone and in male and female mice following administration of α,β-thujone suggesting possible saturation of elimination kinetics with increasing dose. Dose-adjusted AUC{sub ∞} for male and female rats was 5- to 15-fold and 3- to 24-fold higher than mice counterparts following administration of α-thujone and α,β-thujone, respectively (p-value < 0.0001 for all comparisons). Following both intravenous and gavage administration, α-thujone was distributed to the brains of rats and mice with females, in general, having higher brain:plasma ratios than males. These data are in support of the observed toxicity of α-thujone and α,β-thujone where females were more sensitive than males of both species to α-thujone-induced neurotoxicity. In general there was no difference in toxicokinetics between test articles when normalized to α-thujone concentration. - Highlights: • Absorption of α-thujone following gavage administration was rapid in rats and mice. • Rats undergo higher exposure to α-thujone than mice. • α-Thujone brain

  16. NTP technical report on the toxicity studies of Cupric Sulfate (CAS No. 7758-99-8) Administered in Drinking Water and Feed to F344/N Rats and B6C3F1 Mice.

    Science.gov (United States)

    Hebert, Charles

    1993-07-01

    Cupric sulfate is an inorganic salt which is widely used in industry, agriculture, and veterinary medicine. Its applications include use as an algicide in potable waters and as a feed additive and therapeutic agent in swine, sheep, and cattle. Because copper salts are found in human water supplies, toxicity studies of cupric sulfate pentahydrate were conducted in male and female F344/N rats and B6C3F1 mice by the drinking water (2-week studies only) and dosed feed routes (2-week and 13-week studies). Animals were evaluated for hematology, clinical chemistry, urinalysis, reproductive toxicity, tissue metal accumulation, and histopathology. In the 2-week drinking water studies, groups of five rats and five mice per sex received cupric sulfate at concentrations of 300 to 30,000 ppm for 15 days. One female rat, one male mouse, and three female mice in the 3000 ppm groups and all rats and mice in the 10,000 and 30,000 ppm groups died before the end of the studies. The remaining mice and rats in the 3000 ppm groups gained little or lost weight. Water consumption in the three highest dose groups of both species was reduced by more than 65%. Clinical signs observed in these groups were typical of those seen in moribund animals and were attributed to dehydration. The only gross or microscopic change specifically related to cupric sulfate toxicity was an increase in the size and number of cytoplasmic protein droplets in the epithelium of the renal proximal convoluted tubule in male rats from the 300 and 1000-ppm groups. In the 2-week feed studies, groups of five rats and five mice per sex were fed diets containing 1000 to 16,000 ppm cupric sulfate. No chemical-related deaths occurred in any dose group. Compared to the controls, rats and mice in the two highest dose groups had reduced body weight gains which were attributed to decreased feed consumption. Hyperplasia with hyperkeratosis of the squamous epithelium on the limiting ridge of the forestomach was seen in rats and

  17. NTP Toxicology and Carcinogenesis Studies of Gallium Arsenide (CAS No. 1303-00-0) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

    Science.gov (United States)

    2000-09-01

    Gallium arsenide is used primarily to make light- emitting diodes, lasers, laser windows, and photodetectors and in the photoelectronic transmission of data through optical fibers. Gallium arsenide was nominated for study because of its widespread use in the microelectronics industry, the potential for worker exposure, and the absence of chronic toxicity data. Male and female F344/N rats and B6C3F1 mice were exposed to gallium arsenide particles (greater than 98% pure; mass median aerodynamic diameter = 0.8 to 1.0 &mgr;m) by inhalation for 16 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, and the frequency of micronuclei was determined in the peripheral blood of mice exposed to gallium arsenide for 14 weeks. 16-DAY STUDY IN RATS: Groups of five male and five female rats were exposed to particulate aerosols of gallium arsenide with a mass median aerodynamic diameter of approximately 1 &mgr;m at concentrations of 0, 1, 10, 37, 75, or 150 mg/m(3) by inhalation, 6 hours per day, 5 days per week, for 16 days. All rats survived to the end of the study. The final mean body weights of all exposed groups of males and females were similar to those of the chamber controls. Compared to chamber controls, the liver and lung weights of males exposed to 1 mg/m(3) or greater and females exposed to 10 mg/m(3) or greater were increased; the thymus weights of all exposed groups of males were decreased. Gallium arsenide particles were visible in the alveolar spaces and, to a lesser extent, within alveolar macrophages of exposed rats. Moderate proteinosis (surfactant mixed with small amounts of fibrin) and minimal histiocytic cellular infiltrate were observed in the alveoli of exposed males and females. Epithelial hyperplasia and squamous metaplasia of the larynx were observed primarily in males exposed to 150 mg/m(3). 16-DAY STUDY IN MICE: Groups of five male and four or five female mice were exposed to particulate aerosols of gallium

  18. NTP toxicity studies of toxicity studies of 2,4-decadienal (CAS No. 25152-84-5) administered by gavage to F344/N Rats and B6C3F1 mice.

    Science.gov (United States)

    Chan, P C

    2011-01-01

    2,4-Decadienal is used as a synthetic flavoring and fragrance material and has been evaluated as a corrosion inhibitor for steel in oil field operations. 2,4-Decadienal was nominated by the National Cancer Institute for toxicity testing because the dienaldehydes occur naturally in a variety of foods and food components, are used as food additive/flavoring agents, and the potential for human exposure is high. In the toxicity studies, male and female F344/N rats and B6C3F1 mice received 2,4-decadienal (at least 93% pure) in corn oil by gavage for 2 weeks or 3 months. Genetic toxicology studies were conducted in Salmonella typhimurium, rat and mouse bone marrow cells, and mouse peripheral blood erythrocytes. In the 2-week studies, groups of five male and five female rats and mice received 2,4-decadienal in corn oil by gavage at doses of 0, 45, 133, 400, 1,200, or 3,600 mg 2,4-decadienal/kg body weight 5 days per week for 16 days. All animals in the 3,600 mg/kg groups were found dead or sacrificed moribund by day 3 (rats) or day 9 (mice). One 133 mg/kg female rat was found dead on day 8, and one male and one female mouse in the 1,200 mg/kg groups were found dead on days 12 and 16, respectively. At 1,200 mg/kg, treatment-related ulceration of the forestomach was observed in male and female rats and mice. Focal necrosis of the forestomach occurred in a 1,200 mg/kg female mouse. Mean body weights of all 1,200 mg/kg groups were less than those of the vehicle controls, and 1,200 mg/kg female mice lost weight during the study. Diarrhea, lethargy, abnormal breathing (rats), and thinness (mice) occurred in the 1,200 and 3,600 mg/kg groups. Gross lesions seen at necropsy included ulcerations of the forestomach in 1,200 mg/kg rats and 1,200 and 3,600 mg/kg mice. Adhesions involving the stomach and other abdominal organs were also seen in 1,200 and 3,600 mg/kg mice. In the 3-month studies, groups of 10 male and 10 female rats and mice received 2,4-decadienal in corn oil by gavage

  19. Toxicology and carcinogenesis studies of Ginkgo biloba extract (CAS No. 90045-36-6) in F344/N rats and B6C3F1/N mice (Gavage studies).

    Science.gov (United States)

    2013-03-01

    Ginkgo biloba extract has been used primarily as a medicinal agent in the treatment or prevention of cardiovascular and cerebrovascular dysfunction. Ginkgo biloba extract was nominated for study by the National Cancer Institute because of its widespread use as an herbal supplement to promote mental function and the limited availability of toxicity and carcinogenicity data. Furthermore, one of the major ingredients in Ginkgo biloba extract, quercetin, is a known mutagen. The Ginkgo biloba extract used in the current studies was procured from a supplier known to provide material to United States companies and contained 31.2% flavonol glycosides, 15.4% terpene lactones (6.94% bilo-balide, 3.74% ginkgolide A, 1.62% ginkgolide B, 3.06% ginkgolide C), and 10.45 ppm ginkgolic acid. Male and female F344/N rats and B6C3F1/N mice were administered Ginkgo biloba extract in corn oil by gavage for 3 months or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were administered 0, 62.5, 125, 250, 500, or 1,000 mg Ginkgo biloba extract/kg body weight in corn oil by gavage, 5 days per week for 14 weeks. Additional groups of 10 male and 10 female rats (clinical pathology study) were administered the same doses, 5 days per week for 23 days. All rats survived to the end of the study. Mean body weights of all dosed groups were similar to those of the vehicle control groups. Liver weights of all dosed groups of males and females were significantly greater than those of the vehicle control groups. The incidences of hepatocyte hypertrophy in all dosed groups of males and in 500 and 1,000 mg/kg females were significantly greater than those in the vehicle control groups; there was a dose-related increase in severity of this lesion in males. Hepatocyte fatty change occurred in all dosed males. The incidences of thyroid gland follicular cell

  20. NTP Toxicology and Carcinogenesis of 1,2,3-Trichloropropane (CAS No. 96-18-4) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

    Science.gov (United States)

    1993-08-01

    1,2,3-Trichloropropane is a colorless liquid used as a paint and varnish remover, solvent, and degreasing agent, and as a crosslinking agent in the synthesis of polysulfides and hexafluoropropylene. 1,2,3-Trichloropropane may be found as an impurity in certain nematocides and soil fumigants and as a contaminant of drinking and ground water. Studies on the toxic and carcinogenic effects of 1,2,3-trichloropropane were initiated because of the close structural relationship of this chemical to other short-chain halogenated compounds that were demonstrated to be carcinogenic in experimental animals, and because of the potential for human exposure. Toxicology and carcinogenicity studies were conducted by administering 1,2,3-trichloropropane (greater than 99% pure) in corn oil by gavage to groups of F344/N rats and B6C3FI mice for 17 weeks and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium strains, mouse lymphoma cells, and Chinese hamster ovary cells. 17-Week Studies: Groups of 20 male and 20 female rats received 1,2,3-trichloropropane in corn oil by gavage at doses of 8, 16, 32, 63, 125, or 250 mg/kg body weight 5 days per week for up to 17 weeks; 30 male and 30 female rats received corn oil alone and served as controls. Animals were evaluated at 8 or 17 weeks. All rats in the 250 mg/kg groups died by week 5. One male and four female rats in the 125 mg/kg groups died during the study. The mean body weight gains and final mean body weights of males receiving 63 mg/kg and of males and females receiving 125 mg/kg were lower than those of the controls. Hematocrit values, hemoglobin concentrations, and erythrocyte counts decreased with dose in males and females. Serum alanine aminotransferase, aspartate aminotransferase, and sorbitol dehydrogenase activities were significantly increased in some female rats receiving 125 mg/kg. Serum pseudocholinesterase activity decreased with dose in females. Increases in kidney and liver weights were related

  1. Whole Body Inhalation Exposure to 1-Bromopropane Suppresses the IgM Response to Sheep Red Blood Cells in Female B6C3F1 Mice and Fisher 344/N Rats

    Science.gov (United States)

    Anderson, Stacey. E.; Munson, Albert E.; Butterworth, Leon F.; Germolec, Dori; Morgan, Daniel L.; Roycroft, Joseph A.; Dill, Jeffrey; Meade, B. J.

    2010-01-01

    1-Bromopropane (1-BP) is categorized as a high-production volume chemical currently used in the manufacture of pharmaceuticals, pesticides and other chemicals. Its usage is estimated to be around 5 million pounds/year resulting in the potential for widespread exposure in the workplace. Case reports and animal studies have suggested exposure to this compound may cause adverse reproductive and neurological effects. Using a battery of immunological assays, the immunotoxicity of 1-BP after whole body inhalation exposure in both mice and rats was evaluated. Significant decreases in the spleen IgM response to SRBC were observed in both mice (125-500 ppm) and rats (1000 ppm) after exposure to 1-BP for 10 weeks. In addition, total spleen cells and T-cells were significantly decreased after approximately 4 weeks of 1-BP exposure in both mice (125-500 ppm) and rats (1000 ppm). No change in natural killer (NK) cell activity was observed. The observed alterations in spleen cellularity, phenotypic subsets and impairment of humoral immune function across species, raises further concern about human exposure to 1-BP and demonstrates the need for additional investigations into potential adverse health effects. PMID:20041805

  2. Whole-body inhalation exposure to 1-bromopropane suppresses the IgM response to sheep red blood cells in female B6C3F1 mice and Fisher 344/N rats.

    Science.gov (United States)

    Anderson, Stacey E; Munson, Albert E; Butterworth, Leon F; Germolec, Dori; Morgan, Daniel L; Roycroft, Joseph A; Dill, Jeffrey; Meade, B J

    2010-02-01

    1-Bromopropane (1-BP) is categorized as a high-production-volume chemical and is currently used in the manufacture of pharmaceuticals, pesticides, and other chemicals. Its usage is estimated to be around 5 million pounds per year, resulting in the potential for widespread exposure in the workplace. Case reports and animal studies have suggested exposure to this compound may cause adverse reproductive and neurological effects. Using a battery of immunological assays, the immunotoxicity of 1-BP after whole body inhalation exposure in both mice and rats was evaluated. Significant decreases in the spleen immunoglobulin (Ig) M response to sheep red blood cells (SRBC) were observed in both mice (125-500 ppm) and rats (1000 ppm) after exposure to 1-BP for 10 wk. In addition, total spleen cells and T cells were significantly decreased after approximately 4 wk of 1-BP exposure in both mice (125-500 ppm) and rats (1000 ppm). No change in natural killer (NK) cell activity was observed. The observed alterations in spleen cellularity, phenotypic subsets, and impairment of humoral immune function across species raise further concern about human exposure to 1-BP and demonstrate the need for additional investigations into potential adverse health effects.

  3. Characterization of the myelotoxicity of chloramphenicol succinate in the B6C3F1 mouse.

    Science.gov (United States)

    Turton, John A; Fagg, Rajni; Sones, William R; Williams, Thomas C; Andrews, C Michael

    2006-04-01

    Chloramphenicol (CAP) is haemotoxic in man, inducing two types of toxicity. First, a dose-related, reversible anaemia with reticulocytopenia, sometimes seen in conjunction with leucopenia and thrombocytopenia; this form of toxicity develops during drug treatment. The second haemotoxicity is aplastic anaemia (AA) which is evident in the blood as severe pancytopenia. AA development is not dose-related and occurs weeks or months after treatment. We wish, in the longer term, to investigate CAP-induced AA in the busulphan-pretreated mouse. However, as a prelude to that study, we wanted to characterize in detail the reversible haemotoxicity of CAP succinate (CAPS), administered at high dose levels in the mouse, and follow the recovery of the bone marrow in the post-dosing period. Female B6C3F1 mice were gavaged with CAPS at 0, 2500 and 3500 mg/kg, daily, for 5 days and sampled (n = 5) at 1, 7, 14 and 21 days post-dosing. Blood, bone marrow and spleen samples were analysed and clonogenic assays carried out. At day 1 post-dosing, at both CAPS dose levels, decreases were seen in erythrocytes and erythrocyte precursors; marrow erythroid cells were reduced. Reductions were also evident in splenic nucleated cell counts, blood high fluorescence ratio (HFR) reticulocyte counts and total reticulocyte counts; burst-forming units-erythroid and colony-forming units-erythroid showed decreases. At day 7 post-dosing (2500 mg/kg CAPS), there was regeneration of erythrocyte production, with marked splenic erythropoietic activity, and raised blood HFR reticulocytes. At day 7, at 3500 mg/kg CAPS, erythrocyte and reticulocyte parameters remained depressed. At 14 days post-dosing (2500 mg/kg CAPS), many erythrocyte parameters had returned to normal; at 3500 mg/kg CAPS, there was erythroid regeneration. By 21 days post-dosing, at both CAPS dose levels, most erythrocytic parameters were equivalent to control values. For leucocyte parameters, there was some depression at day 1 post-dosing (at

  4. Metabolism of methapyrilene by Fischer-344 rat and B6C3F1 mouse hepatocytes.

    Science.gov (United States)

    Kelly, D W; Holder, C L; Korfmacher, W A; Getek, T A; Lay, J O; Casciano, D A; Shaddock, J G; Duhart, H M; Slikker, W

    1992-12-01

    1. Suspension cultures of freshly isolated F344 rat and B6C3F1 mouse hepatocytes were compared for their ability to transform various concentrations of methapyrilene (MP). 2. MP metabolites were isolated and purified by h.p.l.c., and were identified by comparing their chromatographic and mass spectral properties with those of authentic standards. 3. Both rat and mouse hepatocytes transformed MP to tentatively identified 2-thiophenecarboxylic acid (I), and definitively identified mono-N-desmethyl methapyrilene glucuronide (II), methapyrilene glucuronide (III), methapyrilene N-oxide (V), and mono-N-desmethyl methapyrilene (VII).

  5. Trichloroethylene-induced gene expression and DNA methylation changes in B6C3F1 mouse liver.

    Directory of Open Access Journals (Sweden)

    Yan Jiang

    Full Text Available Trichloroethylene (TCE, widely used as an organic solvent in the industry, is a common contaminant in air, soil, and water. Chronic TCE exposure induced hepatocellular carcinoma in mice, and occupational exposure in humans was suggested to be associated with liver cancer. To understand the role of non-genotoxic mechanism(s for TCE action, we examined the gene expression and DNA methylation changes in the liver of B6C3F1 mice orally administered with TCE (0, 100, 500 and 1000 mg/kg b.w. per day for 5 days. After 5 days TCE treatment at a dose level of 1000 mg/kg b.w., a total of 431 differentially expressed genes were identified in mouse liver by microarray, of which 291 were up-regulated and 140 down-regulated. The expression changed genes were involved in key signal pathways including PPAR, proliferation, apoptosis and homologous recombination. Notably, the expression level of a number of vital genes involved in the regulation of DNA methylation, such as Utrf1, Tet2, DNMT1, DNMT3a and DNMT3b, were dysregulated. Although global DNA methylation change was not detected in the liver of mice exposed to TCE, the promoter regions of Cdkn1a and Ihh were found to be hypo- and hypermethylated respectively, which correlated negatively with their mRNA expression changes. Furthermore, the gene expression and DNA methylation changes induced by TCE were dose dependent. The overall data indicate that TCE exposure leads to aberrant DNA methylation changes, which might alter the expression of genes involved in the TCE-induced liver tumorgenesis.

  6. Trichloroethylene-induced gene expression and DNA methylation changes in B6C3F1 mouse liver.

    Science.gov (United States)

    Jiang, Yan; Chen, Jiahong; Tong, Jian; Chen, Tao

    2014-01-01

    Trichloroethylene (TCE), widely used as an organic solvent in the industry, is a common contaminant in air, soil, and water. Chronic TCE exposure induced hepatocellular carcinoma in mice, and occupational exposure in humans was suggested to be associated with liver cancer. To understand the role of non-genotoxic mechanism(s) for TCE action, we examined the gene expression and DNA methylation changes in the liver of B6C3F1 mice orally administered with TCE (0, 100, 500 and 1000 mg/kg b.w. per day) for 5 days. After 5 days TCE treatment at a dose level of 1000 mg/kg b.w., a total of 431 differentially expressed genes were identified in mouse liver by microarray, of which 291 were up-regulated and 140 down-regulated. The expression changed genes were involved in key signal pathways including PPAR, proliferation, apoptosis and homologous recombination. Notably, the expression level of a number of vital genes involved in the regulation of DNA methylation, such as Utrf1, Tet2, DNMT1, DNMT3a and DNMT3b, were dysregulated. Although global DNA methylation change was not detected in the liver of mice exposed to TCE, the promoter regions of Cdkn1a and Ihh were found to be hypo- and hypermethylated respectively, which correlated negatively with their mRNA expression changes. Furthermore, the gene expression and DNA methylation changes induced by TCE were dose dependent. The overall data indicate that TCE exposure leads to aberrant DNA methylation changes, which might alter the expression of genes involved in the TCE-induced liver tumorgenesis.

  7. Quantitative Assessment of Peroxisome Proliferation in B6C3F1 Mouse Liver after Subchronic Exposure to Trichloroethylene by Gavage.

    Science.gov (United States)

    1997-07-01

    be genotoxic (reviewed in ECETOC , 1994). The others are considered non-genotoxic carcinogens. Mechanisms of non-genotoxic carcinogenesis have been...the B6C3F1 mouse. Toxicol. Lett. 49, 255-265. ECETOC (European Centre for Ecotoxicology and Toxicology of Chemicals) (1994). Trichloroethylene

  8. Differential MicroRNA Profiles of Spontaneous and Induced Hepatocellular Carcinomas in Male B6C3F1 Mice.

    Science.gov (United States)

    Epigenetic processes have key roles in regulating transcriptional patterns and cellular functions related to chemical carcinogenesis. MicroRNAs (miRNAs) are attractive epigenetic biomarkers given their mechanistic roles in tumorigenesis, tissue-specificity, and small size, whi...

  9. DICHLOROACETATE TOXICOKINETICS AND DISRUPTION OF TYROSINE CATABOLISM IN B6C3F1 MICE: DOSE RESPONSE RELATIONSHIPS AND AGE AS A MODIFYING FACTOR. (R825954)

    Science.gov (United States)

    Dichloroacetate (DCA) is a rodent carcinogen commonly found in municipal drinking water supplies. Toxicokinetic studies have established that elimination of DCA is controlled by liver metabolism, which occurs by the cytosolic enzyme glutathione-S-transferase-zeta (GST-z...

  10. Galacto-oligosaccharides Protect the Intestinal Barrier by Maintaining the Tight Junction Network and Modulating the Inflammatory Responses after a Challenge with the Mycotoxin Deoxynivalenol in Human Caco-2 Cell Monolayers and B6C3F1 Mice

    NARCIS (Netherlands)

    Akbari, Peyman; Braber, Saskia; Alizadeh, Arash; Verheijden, Kim; Schoterman, Margriet Hc; Kraneveld, Aletta D; Garssen, Johan; Fink-Gremmels, Johanna

    2015-01-01

    BACKGROUND: The integrity of the epithelial layer in the gastrointestinal tract protects organisms from exposure to luminal antigens, which are considered the primary cause of chronic intestinal inflammation and allergic responses. The common wheat-associated fungal toxin deoxynivalenol acts as a sp

  11. Whole Body Inhalation Exposure to 1-Bromopropane Suppresses the IgM Response to Sheep Red Blood Cells in Female B6C3F1 Mice and Fisher 344/N Rats

    OpenAIRE

    2010-01-01

    1-Bromopropane (1-BP) is categorized as a high-production volume chemical currently used in the manufacture of pharmaceuticals, pesticides and other chemicals. Its usage is estimated to be around 5 million pounds/year resulting in the potential for widespread exposure in the workplace. Case reports and animal studies have suggested exposure to this compound may cause adverse reproductive and neurological effects. Using a battery of immunological assays, the immunotoxicity of 1-BP after whole ...

  12. Determination of the Chronic Mammalian Toxicological Effects of TNT (twenty-Four Month Chronic Toxicity/Carcinogenicity Study of Trinitrotoluene (TNT) in the B6C3F1 Hybrid Mouse). Volume 1

    Science.gov (United States)

    1984-12-01

    negative results. Serum antibody titer was determined for the following diseases: GD-VII virus , K virus , Mouse Adenovirus, Sendal virus , Reovirus 3...Pneumonia virus of mice, Lyrphocytic Chorlomeningitis, Polyoma vIrus , MInute vIrus of mice, Mouse Hepatitis and Ectomella. These antibody titers were...0I0 w l o N C I -I--a))CO-o 0)-000 ) ~ -~ -OWNOON 3 iN N. NN -N N -CN---.N(- N C V(NNNN NN (N- ( NCV (\\(N ( IN C () N ( N D C0 C N N -N N - - -I))( N U

  13. Determination of the Chronic Mammalian Toxicological Effects of RDX. Twenty-Four Month Chronic Toxicity/Carcinogenicity Study of Hexahydro-1,3,5- Trinitro-1,3,5-Triazine (RDX) in the B6C3F1 Hybrid Mouse. Phase 6. Volume 1

    Science.gov (United States)

    1984-04-01

    viruses : GD-VII virus , K virus , Mouse Adenovirus, Sendai virus , Reovirus 3...Pneumonia virus of mice, Lymphocytic Choriomeningitis, Polyoma virus , Minute virus of mice, Mouse Hepatitis and Ectomelia. These tests for antibody...OC" " N " N " NN C. C% N " C" N " C’ C" N N N C" C’ C, C" C" 04 C"J C" N C" C" N N" C"d N C" 04 04 C" CS C" C’) NCV C" cc I-XLU -I 0 1c Mc -tm WrL

  14. Effects of the Geiji-Bokryung-Hwan on carrageenan-induced inflammation in mice and cyclooxygenase-2 in hepatoma cells of HepG2 and Hep3B.

    Science.gov (United States)

    Park, Won-Hwan; Joo, Shin-Tak; Park, Kwan-Kyu; Chang, Young-Chae; Kim, Cheorl-Ho

    2004-02-01

    We investigated the effects of a Korean traditional prescription, Geiji-Bokryung-Hwan (GBH) consisting of five herbs of Cinnamomi Ramulus (Korean name Geiji), Poria cocos (Bokryung), Moutan Cortex Radicis (Modanpi). Paeoniae Radix (Jakyak) and Persicae Semen (Doin) on tumor growth-inhibitory activity and cancer chemopreventive activity in assays representing three major stages of carcinogenesis. Effects of the GBH extracts on carrageenan-induced edema inflammation using female (C57BL/6XC3H) F1 (B6C3F1) mice and tumorigenesis were examined. Finally, cyclooxygenase metabolites were determined after extracts treatment. These data suggest that GBH extracts merits investigation as a potential cancer chemopreventive agent in humans.

  15. Impaired fertility in T-stock female mice after superovulation

    Energy Technology Data Exchange (ETDEWEB)

    Wyrobek, A J; Bishop, J B; Marchetti, F; Zudova, D

    2003-12-05

    Superovulation of female mice with exogenous gonadotrophins is routinely used for increasing the number of eggs ovulated by each female in reproductive and developmental studies. We report an unusual effect of superovulation on fertilization in mice. In vivo matings of superovulated T-stock females with B6C3F1 males resulted in a 2-fold reduction (P<0.001) in the frequencies of fertilized eggs compared to control B6C3F1 matings. In addition, {approx}22 hr after mating only 15% of fertilized eggs recovered in T-stock females had reached the metaphase stage of the first cleavage division versus 87% in B6C3F1 females (P < 0.0001). Matings with T-stock males did not improve the reproductive performance of T-stock females. To investigate the possible cause(s) for the impaired fertilization and zygotic development, the experiments were repeated using in vitro fertilization. Under these conditions, the frequencies of fertilized eggs were not different in superovulated T-stock and B6C3F1 females (51.7% {+-} 6.0 and 64.5% {+-}3.8, P=0.10). There was a 7-fold increase in the frequencies of fertilized T-stock eggs that completed the first cell cycle of development after in vitro versus in vivo fertilization. These results rule out an intrinsic deficiency of the T-stock oocyte as the main reason for the impaired fertility after in vivo matings and suggest that superovulation of T-stock females induces a hostile oviductal and uterine environment with dramatic effects on fertilization and zygotic development.

  16. Hyperplasia of the lymphoepithelium of NALT in rats but not in mice upon 28-day exposure to 15 ppm formaldehyde vapor

    OpenAIRE

    Frieke Kuper, C.; Van Oostrum, Lidy; Ma-Hock, Lan; Durrer, Stefan; Woutersen, Ruud A.

    2010-01-01

    Abstract To investigate if local lymphoid tissues are a target of FA, nasopharynx-associated lymphoid tissues (NALT) and upper-respiratory tract-draining lymph nodes were examined in a 28-day inhalation study with FA vapor in Fischer-344 rats and B6C3F1 mice. Paraffin-embedded tissues were sectioned and stained with H&E or stained immunohistochemically for cell proliferation (BrdU incorporation). Light microscopy revealed simple hyperplasia of NALT lymphoepith...

  17. Response, thermal regulatory threshold and thermal breakdown threshold of restrained RF-exposed mice at 905 MHz

    Energy Technology Data Exchange (ETDEWEB)

    Ebert, S [Swiss Federal Institute of Technology (ETH), Zurich, 8092 Zurich (Switzerland); Eom, S J [Swiss Federal Institute of Technology (ETH), Zurich, 8092 Zurich (Switzerland); Schuderer, J [Foundation for Research on Information Technologies in Society (IT' IS), Zeughausstrasse 43, 8004 Zurich (Switzerland); Apostel, U [Fraunhofer Institute for Toxicology and Experimental Medicine, Nicolai-Fuchs-Strasse 1, 30625 Hannover (Germany); Tillmann, T [Fraunhofer Institute for Toxicology and Experimental Medicine, Nicolai-Fuchs-Strasse 1, 30625 Hannover (Germany); Dasenbrock, C [Fraunhofer Institute for Toxicology and Experimental Medicine, Nicolai-Fuchs-Strasse 1, 30625 Hannover (Germany); Kuster, N [Swiss Federal Institute of Technology (ETH), Zurich, 8092 Zurich (Switzerland)

    2005-11-07

    The objective of this study was the determination of the thermal regulatory and the thermal breakdown thresholds for in-tube restrained B6C3F1 and NMRI mice exposed to radiofrequency electromagnetic fields at 905 MHz. Different levels of the whole-body averaged specific absorption rate (SAR 0, 2, 5, 7.2, 10, 12.6 and 20 W kg{sup -1}) have been applied to the mice inside the 'Ferris Wheel' exposure setup at 22 {+-} 2 {sup 0}C and 30-70% humidity. The thermal responses were assessed by measurement of the rectal temperature prior, during and after the 2 h exposure session. For B6C3F1 mice, the thermal response was examined for three different weight groups (20 g, 24 g, 29 g), both genders and for pregnant mice. Additionally, NMRI mice with a weight of 36 g were investigated for an interstrain comparison. The thermal regulatory threshold of in-tube restrained mice was found at SAR levels between 2 W kg{sup -1} and 5 W kg{sup -1}, whereas the breakdown of regulation was determined at 10.1 {+-} 4.0 W kg{sup -1}(K = 2) for B6C3F1 mice and 7.7 {+-} 1.6 W kg{sup -1}(K = 2) for NMRI mice. Based on a simplified power balance equation, the thresholds show a clear dependence upon the metabolic rate and weight. NMRI mice were more sensitive to thermal stress and respond at lower SAR values with regulation and breakdown. The presented data suggest that the thermal breakdown for in-tube restrained mice, whole-body exposed to radiofrequency fields, may occur at SAR levels of 6 W kg{sup -1}(K = 2) at laboratory conditions.

  18. Contact hypersensitivity response to isophorone diisocyanate in mice

    Energy Technology Data Exchange (ETDEWEB)

    Stern, M.L.; Brown, T.A.; Brown, R.D.; Munson, A.E. (Virginial Commonwealth Univ., Richmond (USA))

    1989-09-01

    Isophorone diisocyanate was evaluated for its potential as a sensitizing agent for allergic contact hypersensitivity in mice. Female B6C3F1 mice were sensitized with 0.1, 0.3, and 1.0% isophorone diisocyanate and challenged with 3.0% isophorone diisocyanate. Doses of isophorone diisocyanate were selected from assays for primary irritancy. Mice received 20 microliters by direct dermal application, for 5 days, to sites prepared by shaving, dermabrading and, in some mice, with intra dermal injection of complete Freund's adjuvant. The rest period was 7 days. Measurement of the contact hypersensitivity response in mice was by radioisotopic assay two days after challenge and mouse ear swelling one and two days after challenge. Mice demonstrated statistically significant dose-dependent contact hypersensitivity responses to isophorone diisocyanate with or without adjuvant pretreatment.

  19. Mutations Induced by Benzo[a]pyrene and Dibenzo[a,l]pyrene in lacI Transgenic B6C3F1 Mouse Lung Result from Stable DNA Adducts

    Science.gov (United States)

    Dibenzo[a,l]pyrene (DB[a,l]P) and benzo[a]pyrene (B[a]P) are carcinogenic polycyclic aromatic hydrocarbons (PAH) that are each capable of forming a variety of covalent adducts with DNA. Some of the DNA adducts formed by these PAHs have been demonstrated to spontaneously depurina...

  20. Reduction of benzene metabolism and toxicity in mice that lack CYP2E1 expression.

    Science.gov (United States)

    Valentine, J L; Lee, S S; Seaton, M J; Asgharian, B; Farris, G; Corton, J C; Gonzalez, F J; Medinsky, M A

    1996-11-01

    Transgenic CYP2E1 knockout mice (cyp2e1-/-) were used to investigate the involvement of CYP2E1 in the in vivo metabolism of benzene and in the development of benzene-induced toxicity. After benzene exposure, absence of CYP2E1 protein was confirmed by Western blot analysis of mouse liver samples. For the metabolism studies, male cyp2e1-/- and wild-type control mice were exposed to 200 ppm benzene, along with a radiolabeled tracer dose of [14C]benzene (1.0 Ci/mol) by nose-only inhalation for 6 hr. Total urinary radioactivity and all radiolabeled individual metabolites were reduced in urine of cyp2e1-/- mice compared to wild-type controls during the 48-hr period after benzene exposure. In addition, a significantly greater percentage of total urinary radioactivity could be accounted for as phenylsulfate conjugates in cyp2e1-/- mice compared to wild-type mice, indicating the importance of CYP2E1 in oxidation of phenol following benzene exposure in normal mice. For the toxicity studies, male cyp2e1-/-, wild-type, and B6C3F1 mice were exposed by whole-body inhalation to 0 ppm (control) or 200 ppm benzene, 6 hr/day for 5 days. On Day 5, blood, bone marrow, thymus, and spleen were removed for evaluation of micronuclei frequencies and tissue cellularities. No benzene-induced cytotoxicity or genotoxicity was observed in cyp2e1-/- mice. In contrast, benzene exposure resulted in severe genotoxicity and cytotoxicity in both wild-type and B6C3F1 mice. These studies conclusively demonstrate that CYP2E1 is the major determinant of in vivo benzene metabolism and benzene-induced myelotoxicity in mice.

  1. Multisite carcinogenicity and respiratory toxicity of inhaled 1-bromopropane in rats and mice.

    Science.gov (United States)

    Morgan, Daniel L; Nyska, Abraham; Harbo, Sam Jens; Grumbein, Sondra L; Dill, Jeffrey A; Roycroft, Joseph H; Kissling, Grace E; Cesta, Mark F

    2011-10-01

    Two-year 1-bromopropane (1-BP) inhalation studies were conducted because of the potential for widespread exposure, the lack of chronic toxicity and carcinogenicity data, and the known carcinogenicity of structurally related compounds. Male and female F344/N rats and B6C3F1/N mice were exposed by inhalation to 0, 62.5 (mice only), 125, 250, or 500 (rats only) ppm 1-BP for 6 hr/day, 5 days/week for 105 weeks. Exposure of male and female rats to 1-BP resulted in significantly increased incidences of adenomas of the large intestine and skin neoplasms. In male rats, the incidence of malignant mesothelioma of the epididymis was statistically significantly increased at 500 ppm, but the biological significance of this common lesion is unclear. Incidences of pancreatic islet adenoma in male rats were significantly increased at all concentrations relative to concurrent controls but were within the historical control range for inhalation studies. There was no evidence of carcinogenic activity of 1-BP in male B6C3F1 mice; however, significantly increased incidences of alveolar/bronchiolar neoplasms of the lung were present in female mice. Exposure to 1-BP also resulted in increased incidences of nonneoplastic lesions in the nose of rats and mice, the larynx of rats and male mice, the trachea of female rats and male and female mice, and the lungs of mice. Inflammatory lesions with Splendore Hoeppli (S-H) material were present primarily in the nose and skin of exposed male and female rats, indicating that 1-BP caused immunosuppression.

  2. Respiratory tract changes in guinea pigs, rats, and mice following a single six-hour exposure to methyl isocyanate vapor.

    OpenAIRE

    Fowler, E H; Dodd, D E

    1987-01-01

    Groups of male and female Fischer 344 rats, B6C3F1 mice, and Hartley guinea pigs were exposed once for 6 hr to mean concentrations of 10.5, 5.4, 2.4, 1.0, or 0 (control) ppm of methyl isocyanate (MIC) vapor. Rats and mice were also exposed to 20.4 ppm of MIC. The majority of deaths occurred during postexposure days 1 through 3. The 6-hr LC50 values (with 95% confidence limits) were 6.1 (4.6 to 8.2) ppm for rats, 12.2 (8.4 to 17.5) ppm for mice, and 5.4 (4.4 to 6.7) ppm for guinea pigs. Notabl...

  3. Immunocytochemical localization of the surfactant apoprotein and Clara cell antigen in chemically induced and naturally occurring pulmonary neoplasms of mice.

    Science.gov (United States)

    Ward, J. M.; Singh, G.; Katyal, S. L.; Anderson, L. M.; Kovatch, R. M.

    1985-01-01

    The localization of surfactant apoprotein (SAP) and the Clara cell antigen(s) (CCA) was studied in naturally occurring and experimentally induced pulmonary hyperplasias and neoplasms by avidin-biotin peroxidase complex (ABC) immunocytochemistry. Lungs of B6C3F1 and A strain mice with naturally occurring lesions, B6C3F1 mice given injections of N-nitrosodiethylamine (DEN), BALB/c nu/nu or nu/+ mice exposed transplacentally on Day 16 of gestation to ethylnitrosourea (ENU), or BALB/c nu/+ mice exposed to ENU at 8-12 weeks of age were preserved in formalin or Bouin's fixative. After ABC immunocytochemistry, SAP was found in the cytoplasm of normal alveolar Type II cells; in the majority of cells in focal alveolar and solid hyperplasias originating in peribronchiolar or peripheral locations; and in solid, tubular, papillary, and mixed adenomas and carcinomas. The larger mixed-pattern neoplasms and small or large tubular neoplasms usually had the least number of cells with SAP. The majority of large papillary adenomas and carcinomas in BALB/c mice exposed to ENU and in untreated A strain mice contained SAP in the nuclei of many neoplastic cells but only in the cytoplasm of a few neoplastic cells. CCA was found in normal Clara cells of bronchi and bronchioles but not in any hyperplastic or neoplastic lesion of any mouse studied. This study provided immunocytochemical evidence that the vast majority of naturally occurring and experimentally induced pulmonary neoplasms of mice are alveolar Type II cell adenomas and carcinomas. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 PMID:3883798

  4. Comparison of gene expressions in the 2-cell embryos produced in vitro from blocking and non-blocking strain mice%阻滞和非阻滞品系小鼠体外发育2-细胞胚基因表达水平的比较

    Institute of Scientific and Technical Information of China (English)

    林翠英; 史河秀; 张燕琴; 姜雨飞; 初晨凤; 王世鄂

    2012-01-01

    Objective:To investigate the differential expression of genes in the 2-cell embryos produced in vitro from bloc king (KM) and non-blocking (B6C3F1) strain mice. Methods:KM and B6C3F1 1-cell embryos got from two kinds of hybrids were cultured in Ml 6 media. The different expressions of genes were monitored by gene chip test and real-time PCR verification. Results:Three hundred and three genes were differently expressed between KM and B6C3F1 mice in vitro 2-cell embryos, including 168 up-regulated genes and 135 down-regulated genes for KM mouse in vitro 2-cell em bryos. The genes involved in signal transduction, cell structure and motility, cell proliferation and differentiation, cell cycle and developmental processes were up-regulated in KM mouse in vitro 2-cell embryos. While the genes involved in electron transport, protein metabolism and modification, amino acid metabolism, protein targeting and localization were down-regulated in KM mouse in vitro 2-cell embryos. Conclusion: The failure supply of energy and the shortage of pro tein synthesis for the embryonic development process might be the cause of 2-cell block of KM mouse preimplantation embryo in vitro.%目的:检测阻滞品系昆明小鼠和非阻滞品系B6C3F1小鼠体外发育2-细胞胚内基因表达水平的差异,探讨昆明小鼠植入前胚体外发育阻滞与哪些基因表达调控有关.方法:分别收集昆明小鼠和B6C3F1小鼠体外培养2-细胞胚,运用基因芯片分析和Real-time PCR验证.结果:基因芯片检测共筛出差异表达基因303个,其中昆明小鼠2-细胞胚表达上调基因有168个;下调基因有135个.昆明小鼠2细胞胚表达上调的基因以信号转导、细胞周期、细胞结构和运动、细胞增殖和分化以及发育进程等为主;而下调基因与电子转移、蛋白质代谢和修饰、氨基酸代谢以及蛋白质靶向运输和定位等相关.结论:胚内能量供应不足和蛋白质合成障碍可

  5. A physiological model for simulation of benzene metabolism by rats and mice.

    Science.gov (United States)

    Medinsky, M A; Sabourin, P J; Lucier, G; Birnbaum, L S; Henderson, R F

    1989-06-15

    Studies conducted by the National Toxicology Program on the chronic toxicity of benzene indicated that B6C3F1 mice are more sensitive to the toxic effects of benzene than are F344 rats. A physiological model was developed to describe the uptake and metabolism of benzene in rats and mice and to determine if the observed differences in toxic effects could be explained by differences in the pathways for metabolism of benzene or by differences in uptake of benzene. Major pathways for elimination of benzene included metabolism to hydroquinone glucuronide or hydroquinone sulfate, phenyl glucuronide or phenyl sulfate, muconic acid, and prephenyl mercapturic acid or phenyl mercapturic acid. Model simulations for total benzene metabolized and for profiles of benzene metabolites were conducted for oral or inhalation exposure and compared to data for urinary excretion of benzene metabolites after exposure of rats and mice to [14C]- or [3H]-benzene by inhalation or gavage. Results for total amount of benzene metabolized, expressed per kilogram body weight, indicated that for inhalation exposure concentrations up to 1000 ppm, mice metabolized at least two to three times as much benzene as did rats. Simulations of oral exposure to benzene resulted in more benzene metabolized per kilogram body weight by rats at oral exposures of greater than 50 mg/kg. Patterns of metabolites formed after either route of exposure were very different for F344/N rats and B6C3F1 mice. Rats primarily formed the detoxification metabolite, phenyl sulfate. Mice formed hydroquinone glucuronide and muconic acid in addition to phenyl sulfate. Hydroquinone and muconic acid are associated with pathways leading to the formation of the putative toxic metabolites of benzene. Metabolic rate parameters, Vmax and Km, were very different for hydroquinone conjugate and muconic acid formation compared to formation of phenyl conjugates and phenyl mercapturic acids. Putative toxication pathways could be characterized as

  6. Effects of doxylamine succinate on thyroid hormone balance and enzyme induction in mice.

    Science.gov (United States)

    Bookstaff, R C; Murphy, V A; Skare, J A; Minnema, D; Sanzgiri, U; Parkinson, A

    1996-12-01

    The effects of doxylamine (as the succinate salt) on microsomal enzyme activity and serum thyroid hormone levels were examined in B6C3F1 mice following dietary exposure for 7 or 15 days (0, 40, 375, 750, or 1500 ppm in diet, expressed as free base doxylamine). In addition, the hepatic P450 enzyme inducer sodium phenobarbital (375 ppm, expressed as free acid phenobarbital) was used as a positive control for CYP2B induction. Exposure of mice to doxylamine produced dose-related increases in liver weight at both time points. Liver weights were also increased in the phenobarbital-treated mice. Doxylamine treatment caused a dose-dependent increase (up to 2.6-fold) in liver microsomal cytochrome P450 in both male and female mice, at both time points. Analyses of the activities of various hepatic microsomal cytochromes P450 indicated that doxylamine caused a marked induction of CYP2B enzymes. This was demonstrated by a large increase in the O-dealkylation of 7-pentoxyresorufin (up to 38-fold) and the 16beta-hydroxylation of testosterone (up to 6.9-fold), both of which are indicative of CYP2B induction. In addition, like phenobarbital, doxylamine treatment resulted in a modest induction of CYP3A and CYP2A enzymes and approximately a 50% increase in thyroxine-glucuronosyltransferase activity. Doxylamine did not appear to induce P450 enzymes in the CYP1A, CYP2E, or CYP4A enzyme subfamilies. None of the enzyme-inducing effects of doxylamine could be distinguished from those of phenobarbital. These results suggest that doxylamine is a phenobarbital-type inducer of liver microsomal cytochrome P450 in B6C3F1 mice. Exposure to either doxylamine or phenobarbital also resulted in decreases in serum thyroxine (T4) levels (approximately 80% of control) with compensatory increases in serum thyroid-stimulating hormone levels (approximately 4-fold). No clear changes in serum triiodothyronine levels were apparent. These findings are consistent with the hypothesis that doxylamine increases

  7. Pathobiology of aging mice and GEM: background strains and experimental design.

    Science.gov (United States)

    Brayton, C F; Treuting, P M; Ward, J M

    2012-01-01

    The use of induced and spontaneous mutant mice and genetically engineered mice (and combinations thereof) to study cancers and other aging phenotypes to advance improved functional human life spans will involve studies of aging mice. Genetic background contributes to pathology phenotypes and to causes of death as well as to longevity. Increased recognition of expected phenotypes, experimental variables that influence phenotypes and research outcomes, and experimental design options and rationales can maximize the utility of genetically engineered mice (GEM) models to translational research on aging. This review aims to provide resources to enhance the design and practice of chronic and longevity studies involving GEM. C57BL6, 129, and FVB/N strains are emphasized because of their widespread use in the generation of knockout, transgenic, and conditional mutant GEM. Resources are included also for pathology of other inbred strain families, including A, AKR, BALB/c, C3H, C57L, C58, CBA, DBA, GR, NOD.scid, SAMP, and SJL/J, and non-inbred mice, including 4WC, AB6F1, Ames dwarf, B6, 129, B6C3F1, BALB/c,129, Het3, nude, SENCAR, and several Swiss stocks. Experimental strategies for long-term cross-sectional and longitudinal studies to assess causes of or contributors to death, disease burden, spectrum of pathology phenotypes, longevity, and functional healthy life spans (health spans) are compared and discussed.

  8. Partial Return Yoke for MICE Step IV and Final Step

    Energy Technology Data Exchange (ETDEWEB)

    Witte, Holger [Brookhaven; Plate, Stephen [Brookhaven; Berg, J.Scott [Brookhaven; Tarrant, Jason [Rutherford; Bross, Alan [Fermilab

    2015-06-01

    This paper reports on the progress of the design and construction of a retro-fitted return yoke for the international Muon Ionization Cooling Experiment (MICE). MICE is a proof-of-principle experiment aiming to demonstrate ionization cooling experimentally. In earlier studies we outlined how a partial return yoke can be used to mitigate stray magnetic field in the experimental hall; we report on the progress of the construction of the partial return yoke for MICE Step IV. We also discuss an extension of the Partial Return Yoke for the final step of MICE; we show simulation results of the expected performance.

  9. Partial return yoke for MICE step IV and final step

    Energy Technology Data Exchange (ETDEWEB)

    Witte, H. [Brookhaven National Lab. (BNL), Upton, NY (United States); Plate, S. [Brookhaven National Lab. (BNL), Upton, NY (United States); Berg, J. S. [Brookhaven National Lab. (BNL), Upton, NY (United States); Tarrant, J. [Science and Technology Facilities Council (STFC), Oxford (United Kingdom). Rutherford Appleton Lab. (RAL); Bross, A. [Fermi National Accelerator Lab. (FNAL), Batavia, IL (United States)

    2015-05-03

    This paper reports on the progress of the design and construction of a retro-fitted return yoke for the international Muon Ionization Cooling Experiment (MICE). MICE is a proof-of-principle experiment aiming to demonstrate ionization cooling experimentally. In earlier studies we outlined how a partial return yoke can be used to mitigate stray magnetic field in the experimental hall; we report on the progress of the construction of the partial return yoke for MICE Step IV. We also discuss an extension of the Partial Return Yoke for the final step of MICE; we show simulation results of the expected performance.

  10. Echinomycin decreases induction of vascular endothelial growth factor and hepatocyte regeneration in acetaminophen toxicity in mice.

    Science.gov (United States)

    Milesi-Hallé, Alessandra; McCullough, Sandra; Hinson, Jack A; Kurten, Richard C; Lamps, Laura W; Brown, Aliza; James, Laura P

    2012-04-01

    Up-regulation of vascular endothelial growth factor (VEGF) is important to hepatocyte regeneration in the late stages of acetaminophen (APAP) toxicity in the mouse. This study was conducted to examine the relationship of hypoxia-inducible factor 1α (HIF-1α) to VEGF and hepatocyte regeneration in APAP toxicity using an inhibitor of HIF-1α DNA-binding activity, echinomycin (EC). B6C3F1 male mice were treated with APAP (200 mg/kg IP), followed by EC (0.15 mg IP) and killed at 4 hr. Serum alanine aminotransferase (ALT), necrosis, hepatic glutathione (GSH) and APAP protein adducts were comparable in the APAP/EC and the APAP/veh mice at 4 hr. Additional studies showed that high dose EC (0.3 mg) reduced hepatic VEGF but also lowered hepatic GSH. Subsequent studies were performed using the 0.15-mg dose of EC. Although EC 0.15 mg had no effect on hepatic VEGF levels at 8 hr, by 24 hr VEGF levels were decreased by 40%. Toxicity (ALT and histopathology) was comparable in the APAP and APAP/EC groups at 24 and 48 hr. Proliferating cell nuclear antigen expression was reduced by both Western blot analysis and immunohistochemical staining in the APAP/EC mice at 48 hr. The data support the hypothesis that induction of HIF-1α, its binding to DNA and subsequent expression of VEGF are important factors in hepatocyte regeneration in APAP toxicity in the mouse.

  11. An in vitro and in vivo toxicologic evaluation of a stabilized aloe vera gel supplement drink in mice.

    Science.gov (United States)

    Sehgal, Inder; Winters, Wallace D; Scott, Michael; Kousoulas, Konstantine

    2013-05-01

    Aloe vera gel is increasingly consumed as a beverage dietary supplement. The purpose of this study was to determine potential toxicity of a stabilized aloe vera gel derived from the inner gel fillet and marketed as a drink. The gel juice was assessed through assays of genotoxicity in vivo and acute and subchronic toxicity in B6C3F1 mice. Aloe vera did not increase the SOS DNA repair response in Escherichia coli and at 1× and 0.25× it did not increase mutagenesis of Salmonella TA100 resulting in histidine biosynthesis. At 3 and 14days following acute exposure, male and female mice gavaged with the stabilized aloe gel had daily appearances, total body weight gain, selected organ weights, necropsy and hematology tests similar to control mice gavaged with water. After a 13-week aloe gel feed study, male and female mice evaluated by the same criteria as the acute study plus feed consumption and serum chemistry tests were found to be equivalent to control groups. These data indicate that a commercial stabilized aloe gel consumed as a beverage was not genotoxic or toxic in vivo. These results contrast with those obtained using preparations containing aloe latex phenolic compounds such as anthraquinones.

  12. No Evidence of Effect on Male Mice Germ Cells After Acute Treatment With Thiram

    Institute of Scientific and Technical Information of China (English)

    1994-01-01

    Thiram is a dithiocarbamate compound widely used for industrial processes and agriculture.Animal studies reveal that this compound may affect the male reproductive system.Aim of this study was to test,using sensitive testicular parameters,whether thiram directly affects germinal cells.For this purpose,B6C3F1 mice were intraperitoneally injected with thiram in oil(single dose:75mg/kg;repeated five daily doses:25mg/k).Although both reatments were toxic ,none of the parameters examined.i.e.,testis weight,spermatid head number,specific enzyme levels at different times after treatment(14,28,35,56days)showed significant variations form the controls.On the contrary,in the positive controls(treated with chlorambuci),a marked reduction of sperm head number as well as a decrease of lactate dehydrogenasex and sorbitol dehydrogenase activity levels were evidenced at day 28,with a tendency to recover at day 35.Under these conditions thiram did not cause cytotoxicity on diferentiating spermatogonia and on late spermatocyte stages of mice gonads.

  13. Evaluation of DNA damage by alkaline elution technique after inhalation exposure of rats and mice to 1,3-butadiene.

    Science.gov (United States)

    Vangala, R R; Laib, R J; Bolt, H M

    1993-01-01

    The alkaline filter elution technique was used to evaluate single strand breaks (SSB), DNA-DNA (DDCL) and DNA-protein cross-links (DPCL) in liver and lung of male rats (Sprague-Dawley) and male mice (B6C3F1) after exposure to 2000 ppm 1,3-butadiene (BD) for 7 days (7 h/day and/or to 100, 250, 500, 1000) 2000 ppm BD for 7 h. SSB were detected in liver DNA of both species at 2000 ppm. Cross-links are more pronounced in mouse lung than in mouse liver. Elution rates of lung DNA from mice exposed for 7 h to different concentrations of BD revealed an increase in cross-links between 250 and 500 ppm, and a further increase in cross-links up to 2000 ppm. No such signs of genotoxicity could be observed for the lung of rats. Our data support the involvement of reactive metabolites (epoxybutene and especially diepoxybutane) in butadiene-induced carcinogenesis in the mouse but not to that extent in the rat.

  14. Effect of trifluoperazine on toxicity, HIF-1α induction and hepatocyte regeneration in acetaminophen toxicity in mice

    Energy Technology Data Exchange (ETDEWEB)

    Chaudhuri, Shubhra, E-mail: SCHAUDHURI@uams.edu [Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States); Arkansas Children' s Hospital Research Institute, Little Rock, AR (United States); McCullough, Sandra S., E-mail: mcculloughsandras@uams.edu [Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States); Arkansas Children' s Hospital Research Institute, Little Rock, AR (United States); Hennings, Leah, E-mail: lhennings@uams.edu [Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States); Arkansas Children' s Hospital Research Institute, Little Rock, AR (United States); Brown, Aliza T., E-mail: brownalizat@uams.edu [Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States); Arkansas Children' s Hospital Research Institute, Little Rock, AR (United States); Li, Shun-Hwa [Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI (United States); Simpson, Pippa M., E-mail: psimpson@mcw.edu [Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI (United States); Hinson, Jack A., E-mail: hinsonjacka@uams.edu [Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, Arkansas Children' s Hospital Research Institute, Little Rock, AR (United States); James, Laura P., E-mail: jameslaurap@uams.edu [Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States); Arkansas Children' s Hospital Research Institute, Little Rock, AR (United States); Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, Arkansas Children' s Hospital Research Institute, Little Rock, AR (United States)

    2012-10-15

    Oxidative stress and mitochondrial permeability transition (MPT) are important mechanisms in acetaminophen (APAP) toxicity. The MPT inhibitor trifluoperazine (TFP) reduced MPT, oxidative stress, and toxicity in freshly isolated hepatocytes treated with APAP. Since hypoxia inducible factor-one alpha (HIF-1α) is induced very early in APAP toxicity, a role for oxidative stress in the induction has been postulated. In the present study, the effect of TFP on toxicity and HIF-1α induction in B6C3F1 male mice treated with APAP was examined. Mice received TFP (10 mg/kg, oral gavage) prior to APAP (200 mg/kg IP) and at 7 and 36 h after APAP. Measures of metabolism (hepatic glutathione and APAP protein adducts) were comparable in the two groups of mice. Toxicity was decreased in the APAP/TFP mice at 2, 4, and 8 h, compared to the APAP mice. At 24 and 48 h, there were no significant differences in toxicity between the two groups. TFP lowered HIF-1α induction but also reduced the expression of proliferating cell nuclear antigen, a marker of hepatocyte regeneration. TFP can also inhibit phospholipase A{sub 2}, and cytosolic and secretory PLA{sub 2} activity levels were reduced in the APAP/TFP mice compared to the APAP mice. TFP also lowered prostaglandin E{sub 2} expression, a known mechanism of cytoprotection. In summary, the MPT inhibitor TFP delayed the onset of toxicity and lowered HIF-1α induction in APAP treated mice. TFP also reduced PGE{sub 2} expression and hepatocyte regeneration, likely through a mechanism involving PLA{sub 2}. -- Highlights: ► Trifluoperazine reduced acetaminophen toxicity and lowered HIF-1α induction. ► Trifluoperazine had no effect on the metabolism of acetaminophen. ► Trifluoperazine reduced hepatocyte regeneration. ► Trifluoperazine reduced phospholipase A{sub 2} activity and prostaglandin E{sub 2} levels.

  15. Effect of trifluoperazine on toxicity, HIF-1α induction and hepatocyte regeneration in acetaminophen toxicity in mice.

    Science.gov (United States)

    Chaudhuri, Shubhra; McCullough, Sandra S; Hennings, Leah; Brown, Aliza T; Li, Shun-Hwa; Simpson, Pippa M; Hinson, Jack A; James, Laura P

    2012-10-15

    Oxidative stress and mitochondrial permeability transition (MPT) are important mechanisms in acetaminophen (APAP) toxicity. The MPT inhibitor trifluoperazine (TFP) reduced MPT, oxidative stress, and toxicity in freshly isolated hepatocytes treated with APAP. Since hypoxia inducible factor-one alpha (HIF-1α) is induced very early in APAP toxicity, a role for oxidative stress in the induction has been postulated. In the present study, the effect of TFP on toxicity and HIF-1α induction in B6C3F1 male mice treated with APAP was examined. Mice received TFP (10mg/kg, oral gavage) prior to APAP (200mg/kg IP) and at 7 and 36h after APAP. Measures of metabolism (hepatic glutathione and APAP protein adducts) were comparable in the two groups of mice. Toxicity was decreased in the APAP/TFP mice at 2, 4, and 8h, compared to the APAP mice. At 24 and 48h, there were no significant differences in toxicity between the two groups. TFP lowered HIF-1α induction but also reduced the expression of proliferating cell nuclear antigen, a marker of hepatocyte regeneration. TFP can also inhibit phospholipase A(2), and cytosolic and secretory PLA(2) activity levels were reduced in the APAP/TFP mice compared to the APAP mice. TFP also lowered prostaglandin E(2) expression, a known mechanism of cytoprotection. In summary, the MPT inhibitor TFP delayed the onset of toxicity and lowered HIF-1α induction in APAP treated mice. TFP also reduced PGE(2) expression and hepatocyte regeneration, likely through a mechanism involving PLA(2).

  16. Damage of the mouse testis by tritiated water and 137Cs-gamma-rays.

    Science.gov (United States)

    Kashiwabara, Shoji; Kashimoto, Naoki; Sanoh, Seigo; Uesaka, Toshihiro; Katoh, Osamu; Watanabe, Hiromitsu

    2003-09-01

    Tritiated water at 23.2, 46.3 or 92.5 MBq/animal and 137Cs-gamma-rays at 9.5 Gy (equivalent 370 MBq) or lower doses were administered to 6-week old male C3H/HeNCrj and C57BL/6NCrj mice, as well as F1 Crj: B6C3F1 (C3H x C57BL) progeny. Each set of six to ten animals were autopsied 30 days after the first irradiation. Testis weights were decreased dose dependently, relative values being highest in the C3H and lowest in the C57BL case, with B6C3F1 intermediate. Vacuolization in seminiferous tubules appeared in the 23.2 MBq group and increased with the dose. Focal pyknosis and karyomegaly were found at 46.3 MBq, while primary and secondary spermatocytes and spermatids disappeared with 92.5 MBq. Only a few spermatogonia and Sertoli cells remained after exposure to 9.5 Gy 137Cs-gamma-rays. Sizes of seminiferous tubules were decreased dose dependently, with no strain differences. When male B6C3F1 mice were irradiated with Cs-gamma-rays at 0.119 (equivalent 4.63 MBq tritiated water) or 2.38 Gy (equivalent 92.5 MBq tritiated water), body weights and size of the seminiferous tubules were decreased at both doses, and the larger dose also caused reduction of testis weight and abnormal sperm. However, all changes except for the alteration in weights had disappeared 1 month after the final irradiation. It is considered that the size of seminiferous tubules may be a good parameter for radiation damage in the testis.

  17. Pre—exposure effect of low—dose 16O8+ or γ—rays on testicular endocrine of mice

    Institute of Scientific and Technical Information of China (English)

    ZhangHong; ZhengRong-Liang; 等

    1998-01-01

    The testes of the B6C3F1 hybrid strain mice were irradiated with 0.05Gy of 16O8+ ion/60Co γ-ray as the pre-exposure dose,and were then irradiated with 2 Gy of 16O8+ion/60Co γ-ray as challenging irradiation dosc at 4h after pre-exposure.The results show that irradiation of mouse testes with 2Gy of 16O8+ ion or 60Co-γ-ray significantly diminished mouse body mass,testis mass and serum testosterone.However,Pre-exposure with a low-dose (0.05Gy)significantly reduces this kind of effect.The relative biological effectiveness of 6O8+ ion was calculated with respect to 60Co γ-ray for the induction of reduction in body mass,testis mass and serum testosterone to be 1.71,1.81 and 1.42 respectively.γ

  18. Differences in the pathways for metabolism of benzene in rats and mice simulated by a physiological model.

    Science.gov (United States)

    Medinsky, M A; Sabourin, P J; Henderson, R F; Lucier, G; Birnbaum, L S

    1989-07-01

    Studies conducted by the National Toxicology Program on the chronic toxicity of benzene indicated that B6C3F1 mice were more sensitive to the carcinogenic effects of benzene than were F344 rats. A physiological model was developed to describe the uptake and metabolism of benzene in rats and mice. Our objective was to determine if differences in toxic effects could be explained by differences in pathways for benzene metabolism or by differences in total uptake of benzene. Compartments incorporated into the model included liver, fat, a poorly perfused tissue group, a richly perfused tissue group, an alveolar or lung compartment and blood. Metabolism of benzene was assumed to take place only in the liver and to proceed by four major competing pathways. These included formation of hydroquinone conjugates (HQC), formation of phenyl conjugates (PHC), ring-breakage and formation of muconic acid (MUC), and conjugation with glutathione with subsequent mercapturic acid (PMA) formation. Values for parameters such as alveolar ventilation, cardiac output, organ volumes, blood flow, partition coefficients, and metabolic rate constants were taken from the literature. Model simulations confirmed that during and after 6-hr inhalation exposures mice metabolized more benzene on a mumole per kilogram body weight basis than did rats. After oral exposure, rats metabolized more benzene than mice at doses above 50 mg/kg because of the more rapid absorption and exhalation of benzene by mice. Model simulations for PHC and PMA, generally considered to be detoxification metabolites, were similar in shape and dose-response to those for total metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

  19. Acetaminophen hepatotoxicity and HIF-1α induction in acetaminophen toxicity in mice occurs without hypoxia.

    Science.gov (United States)

    Chaudhuri, Shubhra; McCullough, Sandra S; Hennings, Leah; Letzig, Lynda; Simpson, Pippa M; Hinson, Jack A; James, Laura P

    2011-05-01

    HIF-1α is a nuclear factor important in the transcription of genes controlling angiogenesis including vascular endothelial growth factor (VEGF). Both hypoxia and oxidative stress are known mechanisms for the induction of HIF-1α. Oxidative stress and mitochondrial permeability transition (MPT) are mechanistically important in acetaminophen (APAP) toxicity in the mouse. MPT may occur as a result of oxidative stress and leads to a large increase in oxidative stress. We previously reported the induction of HIF-1α in mice with APAP toxicity and have shown that VEGF is important in hepatocyte regeneration following APAP toxicity. The following study was performed to examine the relative contribution of hypoxia versus oxidative stress to the induction of HIF-1α in APAP toxicity in the mouse. Time course studies using the hypoxia marker pimonidazole showed no staining for pimonidazole at 1 or 2h in B6C3F1 mice treated with APAP. Staining for pimonidazole was present in the midzonal to periportal regions at 4, 8, 24 and 48h and no staining was observed in centrilobular hepatocytes, the sites of the toxicity. Subsequent studies with the MPT inhibitor cyclosporine A showed that cyclosporine A (CYC; 10mg/kg) reduced HIF-1α induction in APAP treated mice at 1 and 4h and did not inhibit the metabolism of APAP (depletion of hepatic non-protein sulfhydryls and hepatic protein adduct levels). The data suggest that HIF-1α induction in the early stages of APAP toxicity is secondary to oxidative stress via a mechanism involving MPT. In addition, APAP toxicity is not mediated by a hypoxia mechanism.

  20. Respiratory tract changes in guinea pigs, rats, and mice following a single six-hour exposure to methyl isocyanate vapor

    Energy Technology Data Exchange (ETDEWEB)

    Fowler, E.H.; Dodd, D.E.

    1987-06-01

    Groups of male and female Fischer 344 rats, B6C3F1 mice, and Hartley guinea pigs were exposed once for 6 hr to mean concentrations of 10.5, 5.4, 2.4, 1.0, or 0 (control) ppm of methyl isocyanate (MIC) vapor. Rats and mice were also exposed to 20.4 ppm of MIC. The majority of deaths occurred during postexposure days 1 through 3. The 6-hr LC/sub 50/ values were 6.1 ppm for rats, 12.2 ppm for mice, and 5.4 ppm for guinea pigs. Notable clinical observations during and immediately following MIC exposure were lacrimation, perinasal/perioral wetness, respiratory difficulty (e.g., mouth breathing), decreased activity, ataxia, and hypothermia. Body weight losses were common in all species following MIC exposures of 2.4 ppm or greater. Microscopic lesions included acute necrosis of the epithelial lining throughout the respiratory tract in animals that died shortly after exposure, coupled with congestion, edema, and inflammation. A microscopic lesion that appeared unique to guinea pigs was bronchiolitis obliterans. Additional microscopic lesions observed in some animals that died or were sacrificed at the end of the study (postexposure day 14) consisted of squamous metaplasia of respiratory epithelium in the nasal cavity, which extended into the larynx, trachea, and in some cases, the bronchi. In addition, epithelial regeneration throughout the tract and submucosal fibroplasia in the trachea, bronchi, and bronchioles were observed, the latter lesion being primarily confined to rodents. Only in guinea pigs were there lesions in the 1.0 ppm group attributed to MIC exposure. In conclusion, guinea pigs were more sensitive to the MIC vapor than were rats, which were in turn more sensitive than mice.

  1. Immunochemical quantitation of 3-(cystein-S-yl)acetaminophen adducts in serum and liver proteins of acetaminophen-treated mice.

    Science.gov (United States)

    Pumford, N R; Hinson, J A; Potter, D W; Rowland, K L; Benson, R W; Roberts, D W

    1989-01-01

    Using a recently developed enzyme-linked immunosorbent assay specific for 3-(cystein-S-yl)acetaminophen adducts we have quantitated the formation of these specific adducts in liver and serum protein of B6C3F1 male mice dosed with acetaminophen. Administration of acetaminophen at doses of 50, 100, 200, 300, 400 and 500 mg/kg to mice resulted in evidence of hepatotoxicity (increase in serum levels of alanine aminotransferase and aspartate aminotransferase) at 4 hr in the 300, 400 and 500 mg/kg treatment groups only. The formation of 3-(cystein-S-yl)acetaminophen adducts in liver protein was not observed in the groups receiving 50, 100 and 200 mg/kg doses, but was observed in the groups receiving doses above 300 mg/kg of acetaminophen. Greater levels of adduct formation were observed at the higher doses. 3-(Cystein-S-yl)acetaminophen protein adducts were also observed in serum of mice receiving hepatotoxic doses of acetaminophen. After a 400 mg/kg dose of acetaminophen, 3-(cystein-S-yl)acetaminophen adducts in the liver protein reached peak levels 2 hr after dosing. By 12 hr the levels decreased to approximately 10% of the peak level. In contrast, 3-(cystein-S-yl)acetaminophen adducts in serum protein were delayed, reaching a sustained peak 6 to 12 hr after dosing. The dose-response correlation between the appearance of serum aminotransferases and 3-(cystein-S-yl)acetaminophen adducts in serum protein and the temporal correlation between the decrease in 3-(cystein-S-yl)acetaminophen adducts in liver protein and the appearance of adducts in serum protein are consistent with a hepatic origin of the adducts detected in serum protein.(ABSTRACT TRUNCATED AT 250 WORDS)

  2. Molecular stress response in the CNS of mice after systemic exposureto interferon-alpha, ionizing radiation and ketamine

    Energy Technology Data Exchange (ETDEWEB)

    Lowe, Xiu R.; Marchetti, Francesco; Lu, Xiaochen; Wyrobek, Andrew J.

    2009-03-03

    We previously showed that the expression of troponin T1 (Tnnt 1) was induced in the central nervous system (CNS) of adultmice 30 min after treatment with ketamine, a glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonist. We hypothesized that Tnnt 1 expression may be an early molecular biomarker of stress response in the CNS of mice. To further evaluate this hypothesis, we investigated the regional expression of Tnnt 1 in the mouse brain using RNA in situ hybridization 4 h after systemic exposure to interferon-a (IFN-a) and gamma ionizing radiation, both of which have be associated with wide ranges of neuropsychiatric complications. Adult B6C3F1 male mice were treated with either human IFN-a (a single i.p. injection at 1 x 105 IU/kg) or whole body gamma-radiation (10 cGy or 2 Gy). Patterns of Tnnt 1 transcript expression were compared in various CNS regions after IFN-a, radiation and ketamine treatments (previous study). Tnnt 1 expression was consistently induced in pyramidal neurons of cerebral cortex and hippocampus after all treatment regimens including 10 cGy of ionizing radiation. Regional expression of Tnnt 1 was induced in Purkinje cells of cerebellum after ionizing radiation and ketamine treatment; but not after IFN-a treatment. None of the three treatments induced Tnnt 1 expression in glial cells. The patterns of Tnnt 1 expression in pyramidal neurons of cerebral cortex andhippocampus, which are both known to play important roles in cognitive function, memory and emotion, suggest that the expression of Tnnt 1 may be an early molecular biomarker of induced CNS stress.

  3. The embryo's cystatin C and F expression functions as a protective mechanism against the maternal proteinase cathepsin S in mice.

    Science.gov (United States)

    Baston-Buest, D M; Schanz, A; Buest, S; Fischer, J C; Kruessel, J S; Hess, A P

    2010-04-01

    A successful implantation of a mammalian embryo into the maternal endometrium depends on a highly synchronized fetal-maternal dialogue involving chemokines, growth factors, and matrix-modifying enzymes. A growing body of evidence suggests an important role for proteinases playing a role in matrix degeneration and enhancing the embryo's invasive capacity and influencing the mother's immunological status in favor of the conceptus. This study focused on the expression of cathepsin S (CTSS) and its inhibitors in the murine fetal-maternal interface as well as the detection of the cellular sources of either proteinase and inhibitors. Nested RT-PCR for detection of embryonic mRNAs, immunohistochemistry of maternal and fetal tissues in B6C3F1 mice, and FACS analysis for determination of immunocompetent cell population were applied. This study shows that the cysteine proteinase CTSS is upregulated in the stroma of the implantation site, and that pregnancy induces an influx of CTSS-positive uterine natural killer cells. Compared to maternal tissues, the CTSS inhibitors cystatin F and C, but not the proteinase itself, are expressed in blastocysts. In conclusion, CTSS underlies a hormonal regulation in the maternal tissue and therewith most likely supports the embryonic implantation. The invading embryo regulates the depth of its own invasion through the expression of the cathepsin inhibitors and furthermore, interleukin-6 to activate CTSS in maternal tissues. Additionally, the observed decrease in CD3(+) cells leads to the hypothesis that cells of the cytotoxic T-cell group are down-regulated in the decidua to support the implantation and ensure the survival of the embryo.

  4. Differences in Butadiene Adduct Formation between Rats and Mice Not Due to Selective Inhibition of CYP2E1 by Butadiene Metabolites

    Science.gov (United States)

    Pianalto, Kaila M.; Hartman, Jessica H.; Boysen, Gunnar; Miller, Grover P.

    2013-01-01

    CYP2E1 metabolizes 1,3-butadiene (BD) into genotoxic and possibly carcinogenic 1,2-epoxy-3-butene (EB), 1,2:3,4-diepoxybutane (DEB), and 1,2-epoxy-3,4-butanediol (EB-diol). The dose response of DNA and protein adducts derived from BD metabolites increase linearly at low BD exposures and then saturate at higher exposures in rats, but not mice. It was hypothesized that differences in adduct formation between rodents reflect more efficient BD oxidation in mice than rats. Herein, we assessed whether BD-derived metabolites selectively inhibit rat but not mouse CYP2E1 activity using B6C3F1 mouse and Fisher 344 rat liver microsomes. Basal CYP2E1 activities toward 4-nitrophenol were similar between rodents. Through IC50 studies, EB was the strongest inhibitor (IC50 54 μM, mouse; 98 μM, rat), BD-diol considerably weaker (IC50 1200 μM, mouse; 1000 μM, rat), and DEB inhibition nonexistent (IC50 >25 mM). Kinetic studies showed that in both species EB and BD-diol inhibited 4-nitrophenol oxidation through two-site mechanisms in which inhibition constants reflected trends observed in IC50 studies. None of the reactive epoxide metabolites inactivated CYP2E1 irreversibly. Thus, there was no selective inhibition or inactivation of rat CYP2E1 by BD metabolites relative to mouse Cyp2e1, and it can be inferred that CYP2E1 activity toward BD between rodent species would similarly not be impacted by the presence of BD metabolites. Inhibition of CYP2E1 by BD metabolites is then not responsible for the reported species difference in BD metabolism, formation of BD-derived DNA and protein adducts, mutagenicity and tumorigenesis. PMID:24021170

  5. Final Commissioning of the MICE RF Module Prototype with Production Couplers

    Energy Technology Data Exchange (ETDEWEB)

    Torun, Yagmur [IIT, Chicago; Anderson, Terry [Fermilab; Backfish, Michael [Fermilab; Bowring, Daniel [Fermilab; Freemire, Ben [IIT, Chicago (main); Hart, Terrence [Mississippi U.; Kochemirovskiy, Alexey [Illinois U., Chicago; Lane, Peter [IIT, Chicago; Luo, Tianhuan [LBNL, Berkeley; Moretti, Alfred [Fermilab; Neuffer, David [Fermilab; Peterson, David [Fermilab; Popovic, Milorad [Fermilab; Yonehara, Katsuya [Fermilab

    2016-06-01

    We report operational experience from the prototype RF module for the Muon Ionization Cooling Experiment (MICE) with final production couplers at Fermilab's MuCool Test Area. This is the last step in fully qualifying the RF modules for operation in the experiment at RAL.

  6. KINETIC MODELING OF B-CHLOROPRENE METABOLISM:II. THE APPLICATION OF PHYSIOLOGICALLY BASED MODELLING FOR CANCER DOSE RESPONSE ANALYSIS

    Science.gov (United States)

    ABSTRACTbeta-Chloroprene (2-chloro-1,3-butadiene, CD) which is used in the synthesis of polychloroprene, caused significant incidences of several tumor types in B6C3F1 mice and Fischer rats, but not in Wistar rats or Syrian hamsters. This project investigates the relevance o...

  7. FORMATION OF HEMOGLOBIN AND ALBUMIN ADDUCTS OF BENZENE OXIDE IN MOUSE, RAT, AND HUMAN BLOOD

    Science.gov (United States)

    Little is known about the formation and disposition of benzene oxide (BO), the initial metabolite arising from oxidation of benzene by cytochrome P450. In this study, reactions of BO with hemoglobin (Hb) and albumin (Alb) were investigated in blood from B6C3F1 mice, F344 rats, ...

  8. Subchronic dispositional and toxicological effects of arsenate administered in drinking water to mice.

    Science.gov (United States)

    Hughes, M F; Thompson, D J

    1996-10-11

    Exposure to the drinking water contaminant arsenate is a daily occurrence and there are concerns that this exposure may lead to cancer. Although the acute dispositional effects of arsenate have been studied in detail, there is minimal information on the disposition and toxicological effects of it after continuous exposure. The objective of this study was to examine in mice the effect of a 4-wk treatment with arsenate administered in drinking water. Female B6C3F1 mice (3/cage) were housed in metabolism cages and given water and food ad libitum. Two groups (A, B) of mice were treated (4 cages/treatment/group) with distilled water (control, C) or water containing 0.025 mg/L (L) or 2.5 mg/L (H) arsenate. Group A was sacrificed on d 28 and plasma and urine samples were taken for determination of clinical chemistry parameters. Liver and kidney tissue samples were taken for histopathological analysis. The reduced nonprotein sulfhydryl (NPSH) content in several tissues was determined. Group B was gavaged with [73As]arsenate on d 28 and continued the arsenate drinking water exposure for 48 h. Excreta and tissues were collected and analyzed for 73As. Urine was further analyzed for arsenate and its metabolites. There were no effects on the mean daily amount of water and food consumed, whereas the mean daily urine volume excreted was significantly elevated by 10% in the H-treated animals compared to C and L. A dose-related hepatic vacuolar degeneration in the liver was observed, but no histological changes were evident in the kidney. Only clinical chemistry parameters in plasma were altered by the arsenate treatment. Glucose was significantly lower at the H dose compared to C and L, triglycerides were significantly greater in C than L and H, and creatinine was significantly greater in H than C. Hepatic NPSH content in the H animals was significantly lower than C and L animals, whereas no effects in lung and kidney were detected. The weights of liver, lung, and kidney, as well

  9. Assessment of trichloroethylene (TCE) exposure in murine strains genetically-prone and non-prone to develop autoimmune disease.

    Science.gov (United States)

    Keil, Deborah E; Peden-Adams, Margie M; Wallace, Stacy; Ruiz, Phillip; Gilkeson, Gary S

    2009-04-01

    There is increasing laboratory and epidemiologic evidence relating exposure to trichloroethylene (TCE) with autoimmune disease including scleroderma and lupus. New Zealand Black/New Zealand White (NZBWF1) and B6C3F1 mice were exposed to TCE (0, 1, 400 or 14,000 ppb) via drinking water for 27 or 30 weeks, respectively. NZBWF1 mice spontaneously develop autoimmune disease while B6C3F1 mice, a standard strain used in immunotoxicology testing, are not genetically prone to develop autoimmune disease. During the TCE exposure period, serum levels of total IgG, and autoantibodies (anti-ssDNA, -dsDNA, and -glomerular antigen [GA]) were monitored. At the termination of the study, renal pathology, natural killer (NK) cell activity, total IgG levels, autoantibody production, T-cell activation, and lymphocytic proliferative responses were evaluated. TCE did not alter NK cell activity, or T- and B-cell proliferation in either strain. Numbers of activated T-cells (CD4+/CD44+) were increased in the B6C3F1 mice but not in the NZBWF1 mice. Renal pathology, as indicated by renal score, was significantly increased in the B6C3F1, but not in the NZBWF1 mice. Serum levels of autoantibodies to dsDNA and ssDNA were increased at more time points in B6C3F1, as compared to the NZBWF1 mice. Anti-GA autoantibodies were increased by TCE treatment in early stages of the study in NZBWF1 mice, but by 23 weeks of age, control levels were comparable to those of TCE-exposed animals. Serum levels anti-GA autoantibodies in B6C3F1 were not affected by TCE exposure. Overall, these data suggest that TCE did not contribute to the progression of autoimmune disease in autoimmune-prone mice during the period of 11-36 weeks of age, but rather lead to increased expression of markers associated with autoimmune disease in a non-genetically prone mouse strain.

  10. Clear evidence of carcinogenic activity by a whole-leaf extract of Aloe barbadensis miller (aloe vera) in F344/N rats.

    Science.gov (United States)

    Boudreau, Mary D; Mellick, Paul W; Olson, Greg R; Felton, Robert P; Thorn, Brett T; Beland, Frederick A

    2013-01-01

    Aloe barbadensis Miller (Aloe vera) is an herbal remedy promoted to treat a variety of illnesses; however, only limited data are available on the safety of this dietary supplement. Drinking water exposure of F344/N rats and B6C3F1 mice to an Aloe vera whole-leaf extract (1, 2, and 3%) for 13 weeks resulted in goblet cell hyperplasia of the large intestine in both species. Based upon this observation, 2-year drinking water studies were conducted to assess the carcinogenic potential of an Aloe vera whole-leaf extract when administered to F344/N rats (48 per sex per group) at 0.5, 1, and 1.5%, and B6C3F1 mice (48 per sex per group) at 1, 2, and 3%. Compared with controls, survival was decreased in the 1.5% dose group of female rats. Treatment-related neoplasms and nonneoplastic lesions in both species were confined primarily to the large intestine. Incidences of adenomas and/or carcinomas of the ileo-cecal and cecal-colic junction, cecum, and ascending and transverse colon were significantly higher than controls in male and female rats in the 1 and 1.5% dose groups. There were no neoplasms of the large intestine in mice or in the 0 or 0.5% dose groups of rats. Increased incidences of mucosa hyperplasia of the large intestine were observed in F344/N rats, and increased incidences of goblet cell hyperplasia of the large intestine occurred in B6C3F1 mice. These results indicate that Aloe vera whole-leaf extract is an intestinal irritant in F344/N rats and B6C3F1 mice and a carcinogen of the large intestine in F344/N rats.

  11. Inhalation developmental toxicology studies: Teratology study of 1,3-butadiene in mice: Final report

    Energy Technology Data Exchange (ETDEWEB)

    Hackett, P.L.; Sikov, M.R.; Mast, T.J.; Brown, M.G.; Buschbom, R.L.; Clark, M.L.; Decker, J.R.; Evanoff, J.J.; Rommereim, R.L.; Rowe, S.E.; Westerberg, R.B.

    1987-11-01

    Maternal toxicity, reproductive performance and developmental toxicology were evaluated in CD-1 mice following whole-body, inhalation exposures to 0, 40, 200 and 1000 ppM of 1,3-butadiene. The female mice, which had mated with unexposed males were exposed to the chemical for 6 hours/day on 6 through 15 dg and sacrificed on 18 dg. Maternal animals were weighed prior to mating and on 0, 6, 11 and 18 dg; the mice were observed for mortality, morbidity and signs of toxicity during exposure and examined for gross tissue abnormalities at necropsy. Live fetuses were weighed and subjected to external, visceral and skeletal examinations to detect growth retardation and morphologic anomalies. Significant concentration-related decreases were detected in a number of maternal body weight measures. There was a significant concentration-related depression of fetal body weights and placental weights. Body weights of male fetuses of all exposed groups were significantly lower than values for control fetuses; weights of female fetuses were significantly depressed in the mice exposed to 200 and 1000 ppM. In the 200- and 1000-ppM exposure groups, weights of placentas of male fetuses were significantly decreased, but placental weights of female fetuses were significantly affected only in litters exposed to the highest 1,3-butadiene concentration. This exposure regimen produced significant signs of maternal toxicity at concentrations of 200 and 1000 ppM 1,3-butadiene.

  12. Inhalation developmental toxicology studies: Teratology study of isoprene in mice and rats: Final report

    Energy Technology Data Exchange (ETDEWEB)

    Mast, T.J.; Evanoff, J.J.; Stoney, K.H.; Westerberg, R.B.; Rommereim, R.L.; Weigel, R.J.

    1989-01-01

    Isoprene, a reactive, branched diene, is used in large quantities in the manufacture of polyisoprene and as a copolymer in the synthesis of butyl rubber. The potential for isoprene to cause developmental toxicity was assessed in rodents, by exposing four groups each of Sprague-Dawley rats and Swiss (CD-1) mice to 0, 280, 1400, or 7000 ppM isoprene vapors, 6 h/day, 7 day/wk. Each treatment group consisted of 10 virgin females (for comparison), and approx.30 positively mated rats or mice. Positively mated mice were exposed on days 6-17 of gestation (dg), and rats on 6-19 dg. The day of plug or sperm detection was designated as 0 dg. Body weights were obtained throughout the study period, and uterine and fetal body weights were obtained at sacrifice (rats, 20 dg; mice, 18 dg). Implants were enumerated and their status recorded. Live fetuses were sexed and examined for gross, visceral, skeletal, and soft-tissue craniofacial defects. 31 refs., 6 figs., 19 tabs.

  13. Inhalation developmental toxicology studies: Teratology study of tetrahydrofuran in mice and rats: Final report

    Energy Technology Data Exchange (ETDEWEB)

    Mast, T.J.; Evanoff, J.J.; Stoney, K.H.; Westerberg, R.B.; Rommereim, R.L.; Weigel, R.J.

    1988-08-01

    Tetrahydrofuran (THF), a four-carbon cyclic ether, is widely used as an industrial solvent. Although it has been used in large quantities for many years, few long-term toxicology studies, and no reproductive or developmental studies, have been conducted on THF. This study addresses the potential for THF to cause developmental toxicity in rodents by exposing Sprague-Dawley rats and Swiss (CD-1) mice to 0, 600, 1800, or 5000 ppm tetrahydrofuran (THF) vapors, 6 h/day, 7 dy/wk. Each treatment group consisted of 10 virgin females (for comparison), and approx.33 positively mated rats or mice. Positively mated mice were exposed on days 6--17 of gestation (dg), and rats on 6--19 dg. The day of plug or sperm detection was designated as O dg. Body weights were obtained throughout the study period, and uterine and fetal body weights were obtained at sacrifice (rats, 20 dg; mice, 18 dg). Implants were enumerated and their status recorded and live fetuses were examined for gross, visceral, skeletal, and soft-tissue craniofacial defects. 27 refs., 6 figs., 23 tabs.

  14. Inhalation developmental toxicology studies: Teratology study of acetone in mice and rats: Final report

    Energy Technology Data Exchange (ETDEWEB)

    Mast, T.J.; Evanoff, J.J.; Rommereim, R.L.; Stoney, K.H.; Weigel, R.J.; Westerberg, R.B.

    1988-11-01

    Acetone, an aliphatic ketone, is a ubiquitous industrial solvent and chemical intermediate; consequently, the opportunity for human exposure is high. The potential for acetone to cause developmental toxicity was assessed in Sprague-Dawley rats exposed to 0, 440, 2200, or 11000 ppm, and in Swiss (CD-1) mice exposed to 0, 440, 2200, and 6600 ppm acetone vapors, 6 h/day, 7 days/week. Each of the four treatment groups consisted of 10 virgin females (for comparison), and approx.32 positively mated rats or mice. Positively mated mice were exposed on days 6-17 of gestation (dg), and rats on 6-19 dg. The day of plug or sperm detection was designated as 0 dg. Body weights were obtained throughout the study period, and uterine and fetal body weights were obtained at sacrifice (rats, 20 dg; mice, 18 dg). Implants were enumerated and their status recorded. Live fetuses were sexed and examined for gross, visceral, skeletal, and soft-tissue craniofacial defects. 46 refs., 6 figs., 27 tabs.

  15. Pharmacokinetic Models for the Elimination of Drinking Water Contaminants from the Body,

    Science.gov (United States)

    1990-03-01

    for the MFO and GSH pathways in B6C3F1 mice .111-5 111-4 Log (total area under curve) for animals dosed with trichloroethylene in oil plotted against...values 8XE - Ethylene glycol monomethyl ethgr EPA = Environmental Protection Agency exp - Exponential function g - Gram GSH = Glutathione S-transferase...the laboratory are often available. The earliest PBPK models were developed for cancer I chemotherapeutic agents such as methotraxate and cisplatin

  16. Inhalation developmental toxicology studies: Teratology study of methyl ethyl ketone in mice: Final report

    Energy Technology Data Exchange (ETDEWEB)

    Mast, T.J.; Dill, J.A.; Evanoff, J.J.; Rommereim, R.L.; Weigel, R.J.; Westerberg, R.B.

    1989-02-01

    Methyl ethyl ketone (MEK) is a widely used industrial solvent which results in considerable human exposure. In order to assess the potential for MEK to cause developmental toxicity in rodents, four groups of Swiss (CD-1) mice were exposed to 0, 400, 1000 or 3000 ppM MEK vapors, 7 h/day, 7 dy/wk. Ten virgin females and approx.30 plug-positive females per group were exposed concurrently for 10 consecutive days (6--15 dg for mated mice). Body weights were obtained throughout the study period, and uterine and fetal body weights were obtained at sacrifice on 18 dg. Uterine implants were enumerated and their status recorded. Live fetuses were sexed and examined for gross, visceral, skeletal, and soft-tissue craniofacial defects. Exposure of pregnant mice to these concentrations of MEK did not result in apparent maternal toxicity, although there was a slight, treatment-correlated increase in liver to body weight ratios which was significant for the 3000-ppM group. Mild developmental toxicity was evident at 3000-ppM as a reduction in mean fetal body weight. This reduction was statistically significant for the males only, although the relative decrease in mean fetal body weight was the same for both sexes. 17 refs., 4 figs., 10 tabs.

  17. Damage of the Mouse Testis by Tritiated Water and <137>^Cs-γ-Rays

    OpenAIRE

    Kashiwabara, Shoji; Kashimoto, Naoki; Sanoh, Seigo; Uesaka, Toshihiro; Katoh, Osamu; WATANABE, HIROMITSU

    2003-01-01

    Tritiated water at 23.2, 46.3 or 92.5 MBq/animal and ^Cs-γ-rays at 9.5 Gy (equivalent 370 MBq) or lower doses were administered to 6-week old male C3H/HeNCrj and C57BL/6NCrj mice, as well as FI Crj: B6C3F1 (C3H × C57BL) progeny. Each set of six to ten animals were autopsied 30 days after the first irradiation. Testis weights were decreased dose dependently, relative values being highest in the C3H and lowest in the C57BL case, with B6C3F1 intermediate. Vacuolization in seminiferous tubules ap...

  18. Metabolism and disposition of 1-bromopropane in rats and mice following inhalation or intravenous administration.

    Science.gov (United States)

    Garner, C E; Sumner, S C J; Davis, J G; Burgess, J P; Yueh, Y; Demeter, J; Zhan, Q; Valentine, J; Jeffcoat, A R; Burka, L T; Mathews, J M

    2006-08-15

    Workplace exposure to 1-bromopropane (1-BrP) can potentially occur during its use in spray adhesives, fats, waxes, and resins. 1-BrP may be used to replace ozone depleting solvents, resulting in an increase in its annual production in the US, which currently exceeds 1 million pounds. The potential for human exposure to 1-BrP and the reports of adverse effects associated with potential occupational exposure to high levels of 1-BrP have increased the need for the development of biomarkers of exposure and an improved understanding of 1-BrP metabolism and disposition. In this study, the factors influencing the disposition and biotransformation of 1-BrP were examined in male F344 rats and B6C3F1 mice following inhalation exposure (800 ppm) or intravenous administration (5, 20, and 100 mg/kg). [1,2,3-(13)C]1-BrP and [1-(14)C]1-BrP were administered to enable characterization of urinary metabolites using NMR spectroscopy, LC-MS/MS, and HPLC coupled radiochromatography. Exhaled breath volatile organic chemicals (VOC), exhaled CO(2), urine, feces, and tissues were collected for up to 48 h post-administration for determination of radioactivity distribution. Rats and mice exhaled a majority of the administered dose as either VOC (40-72%) or (14)CO(2) (10-30%). For rats, but not mice, the percentage of the dose exhaled as VOC increased between the mid ( approximately 50%) and high ( approximately 71%) dose groups; while the percentage of the dose exhaled as (14)CO(2) decreased (19 to 10%). The molar ratio of exhaled (14)CO(2) to total released bromide, which decreased as dose increased, demonstrated that the proportion of 1-BrP metabolized via oxidation relative to pathways dependent on glutathione conjugation is inversely proportional to dose in the rat. [(14)C]1-BrP equivalents were recovered in urine (13-17%, rats; 14-23% mice), feces (1-bromopropane to 1-bromo-2-propanol and bromoacetone and following subsequent glutathione conjugation with either of these compounds. Rats

  19. Inhalation developmental toxicology studies: Teratology study of n-hexane in mice: Final report

    Energy Technology Data Exchange (ETDEWEB)

    Mast, T.J.; Decker, J.R.; Stoney, K.H.; Westerberg, R.B.; Evanoff, J.J.; Rommereim, R.L.; Weigel, R.J.

    1988-05-01

    Gestational exposure to n-hexane resulted in an increase in the number of resorbed fetuses for exposure groups relative to the control group; however, the increases were not directly correlated to exposure concentration. The differences were statistically significant for the 200-ppM with respect to total intrauterine death (early plus late resorptions), and with respect to late resorptions for the 5000-ppM group. A small, but statistically significant, reduction in female (but not male) fetal body weight relative to the control group was observed at the 5000-ppM exposure level. There were no exposure-related increases in any individual fetal malformation or variation, nor was there any increase in the incidence of combined malformations or variations. Gestational exposure of CD-1 mice to n-hexane vapors appeared to cause a degree of concentration-related developmental toxicity in the absence of overt maternal toxicity, but the test material was not found to be teratogenic. This developmental toxicity was manifested as an increase in the number of resorptions per litter for all exposure levels, and as a decrease in the uterine: extra-gestational weight gain ratio at the 5000-ppM exposure level. Because of the significant increase in the number of resorptions at the 200-ppM exposure level, a no observable effect level (NOEL) for developmental toxicity was not established for exposure of mice to 200, 1000 or 5000-ppM n-hexane vapors. 21 refs., 3 figs., 9 tabs.

  20. Final report of the safety assessment of L-Ascorbic Acid, Calcium Ascorbate, Magnesium Ascorbate, Magnesium Ascorbyl Phosphate, Sodium Ascorbate, and Sodium Ascorbyl Phosphate as used in cosmetics.

    Science.gov (United States)

    Elmore, Amy R

    2005-01-01

    observed in either mice, rats, or guinea pigs in short-term studies. Male guinea pigs fed a control basal diet and given up to 250 mg Ascorbic Acid orally for 20 weeks had similar hemoglobin, blood glucose, serum iron, liver iron, and liver glycogen levels compared to control values. Male and female F344/N rats and B6C3F(1) mice were fed diets containing up to 100,000 ppm Ascorbic Acid for 13 weeks with little toxicity. Chronic Ascorbic Acid feeding studies showed toxic effects at dosages above 25 mg/kg body weight (bw) in rats and guinea pigs. Groups of male and female rats given daily doses up to 2000 mg/kg bw Ascorbic Acid for 2 years had no macro- or microscopically detectable toxic lesions. Mice given Ascorbic Acid subcutaneous and intravenous daily doses (500 to 1000 mg/kg bw) for 7 days had no changes in appetite, weight gain, and general behavior; and histological examination of various organs showed no changes. Ascorbic Acid was a photoprotectant when applied to mice and pig skin before exposure to ultraviolet (UV) radiation. The inhibition of UV-induced suppression of contact hypersensitivity was also noted. Magnesium Ascorbyl Phosphate administration immediately after exposure in hairless mice significantly delayed skin tumor formation and hyperplasia induced by chronic exposure to UV radiation. Pregnant mice and rats were given daily oral doses of Ascorbic Acid up to 1000 mg/kg bw with no indications of adult-toxic, teratogenic, or fetotoxic effects. Ascorbic Acid and Sodium Ascorbate were not genotoxic in several bacterial and mammalian test systems, consistent with the antioxidant properties of these chemicals. In the presence of certain enzyme systems or metal ions, evidence of genotoxicity was seen. The National Toxicology Program (NTP) conducted a 2-year oral carcinogenesis bioassay of Ascorbic Acid (25,000 and 50,000 ppm) in F344/N rats and B6C3F(1) mice. Ascorbic Acid was not carcinogenic in either sex of both rats and mice. Inhibition of carcinogenesis

  1. Assessment of chimeric mice with humanized livers in new drug development: generation of pharmacokinetics, metabolism and toxicity data for selecting the final candidate compound.

    Science.gov (United States)

    Kamimura, Hidetaka; Ito, Satoshi

    2016-01-01

    1. Chimeric mice with humanized livers are expected to be a novel tool for new drug development. This review discusses four applications where these animals can be used efficiently to collect supportive data for selecting the best compound in the final stage of drug discovery. 2. The first application is selection of the final compound based on estimated pharmacokinetic parameters in humans. Since chimeric mouse livers are highly repopulated with human hepatocytes, hepatic clearance values in vivo could be used preferentially to estimate pharmacokinetic profiles for humans. 3. The second is prediction of human-specific or disproportionate metabolites. Chimeric mice reproduce human-specific metabolites of drugs under development to conform to ICH guidance M3(R2), except for compounds that were extensively eliminated by co-existing mouse hepatocytes. 4. The third is identifying metabolites with distinct pharmacokinetic profiles in humans. Slow metabolite elimination specifically in humans increases its exposure level, but if its elimination is faster in laboratory animals, the animal exposure level might not satisfy ICH guidance M3(R2). 5. Finally, two examples of reproducing acute liver toxicity in chimeric mice are introduced. Integrated pharmacokinetics, metabolism and toxicity information are expected to assist pharmaceutical scientists in selecting the best candidate compound in new drug development.

  2. Immunoblot analysis of protein containing 3-(cystein-S-yl)acetaminophen adducts in serum and subcellular liver fractions from acetaminophen-treated mice.

    Science.gov (United States)

    Pumford, N R; Hinson, J A; Benson, R W; Roberts, D W

    1990-07-01

    The hepatotoxicity of acetaminophen is believed to be mediated by the metabolic activation of acetaminophen to N-acetyl-p-benzoquinone imine which covalently binds to cysteinyl residues on proteins as 3-(cystein-S-yl)acetaminophen adducts. The formation of these adducts in hepatic protein correlates with the hepatotoxicity. In this study, the formation of 3-(cystein-S-yl)acetaminophen adducts in specific cellular proteins was investigated using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and detected using affinity-purified antisera specific for 3-(cystein-S-yl)acetaminophen adducts on immunoblots. These techniques were used to investigate the liver 10,000g supernatant and serum from B6C3F1 mice that received hepatotoxic doses of acetaminophen. More than 15 proteins containing 3-(cystein-S-yl)acetaminophen adducts were detected in the liver 10,000g supernatant. The most prominent protein containing 3-(cystein-S-yl)acetaminophen adducts in the hepatic 10,000g supernatant had a relative molecular mass of 55 kDa. Serum proteins containing 3-(cystein-S-yl)acetaminophen adducts had molecular masses similar to those found in the liver 10,000g supernatant (55, 87, and approximately 102 kDa). These data, combined with our previous findings describing the temporal relationship between the appearance of 3-(cystein-S-yl)acetaminophen adducts in protein in the serum and the decrease in the levels of 3-(cystein-S-yl)acetaminophen adducts in protein in the liver, suggested that liver adducts were released into the serum following lysis of hepatocytes. The temporal relationship between the formation of specific adducts and hepatotoxicity in mice following a hepatotoxic dose of acetaminophen was examined using immunoblots of mitochondria, microsomes, cytosol, and plasma membranes. Hepatotoxicity indicated by serum alanine aminotransferase levels was increased at 2 and 4 hr after dosing. The cytosolic fraction contained numerous proteins with 3-(cystein

  3. Extract of the seed coat of Tamarindus indica inhibits nitric oxide production by murine macrophages in vitro and in vivo.

    Science.gov (United States)

    Komutarin, T; Azadi, S; Butterworth, L; Keil, D; Chitsomboon, B; Suttajit, M; Meade, B J

    2004-04-01

    The seed coat extract of Tamarindus indica, a polyphenolic flavonoid, has been shown to have antioxidant properties. The present studies investigated the inhibitory effect of the seed coat extract of T. indica on nitric oxide production in vitro using a murine macrophage-like cell line, RAW 264.7, and in vitro and in vivo using freshly isolated B6C3F1 mouse peritoneal macrophages. In vitro exposure of RAW 264.7 cells or peritoneal macrophages to 0.2-200 microg/mL of T. indica extract significantly attenuated (as much as 68%) nitric oxide production induced by lipopolysaccharide (LPS) and interferon gamma (IFN-gamma) in a concentration-dependent manner. In vivo administration of T. indica extract (100-500 mg/kg) to B6C3F1 mice dose-dependently suppressed TPA, LPS and/or IFN-gamma induced production of nitric oxide in isolated mouse peritoneal macrophages in the absence of any effect on body weight. Exposure to T. indica extract had no effect on cell viability as assessed by the MTT assay. In B6C3F1 mice, preliminary safety studies demonstrated a decrease in body weight at only the highest dose tested (1000 mg/kg) without alterations in hematology, serum chemistry or selected organ weights or effects on NK cell activity. A significant decrease in body weight was observed in BALB/c mice exposed to concentrations of extract of 250 mg/kg or higher. Oral exposure of BALB/c mice to T. indica extract did not modulate the development of T cell-mediated sensitization to DNFB or HCA as measured by the local lymph node assay, or dermal irritation to nonanoic acid or DNFB. These studies suggest that in mice, T. indica extract at concentrations up to 500 mg/kg may modulate nitric oxide production in the absence of overt acute toxicity.

  4. A Single Neonatal Exposure to Aflatoxin B1 Induces Prolonged Genetic Damage in Two Loci of Mouse Liver

    OpenAIRE

    2012-01-01

    Aflatoxin B 1 (AFB1) is a risk factor for hepatocellular carcinoma in humans. Infant, but not adult, mice are sensitive to AFB1-induced liver carcinogenesis; a single dose during the neonatal period leads to hepatocellular carcinoma in adulthood. Earlier work defined the mutational spectrum in the gpt gene of gpt delta B6C3F1 mice 3 weeks after exposure to aflatoxin. In the present study, we examined the gpt spectrum 10 weeks postdosing and expanded the study to examine, at 3 and 10 weeks,...

  5. Dominant lethal study in CD-1 mice following inhalation exposure to 1,3-butadiene: Final technical report

    Energy Technology Data Exchange (ETDEWEB)

    Hackett, P.L.; Mast, T.J.; Brown, M.G.; Clark, M.L.; Evanoff, J.J.; Rowe, S.E.; McClanahan, B.J.; Buschbom, R.L.; Decker, J.R.; Rommereim, R.L.; Westerberg, R.B.

    1988-04-01

    The effects of whole-body inhalation exposures to 1,3-butadiene on the reproductive system was evaluated. The results of dominant lethality in CD-1 male mice that were exposed to 1,3-butadiene are described. Subsequent to exposure, males were mated with two unexposed females. Mating was continued for 8 weeks with replacement of two females each week. Gravid uteri were removed, and the total number, position and status of implantations were determined. The mice were weighed prior to exposure and at 0, 1, 2, 3, 4, 5, 6, 7, and 8 weeks after exposure and at sacrifice. The animals were observed for mortality, morbidity and signs of toxicity throughout the study. 19 refs., 5 figs., 9 tabs.

  6. Preclinical Toxicology of New Drugs

    Science.gov (United States)

    1988-07-31

    v/v) Tween 80 were conducted in Fischer 344 rats. The dose ranges encom- passed 66 mg/kg to 1400 mg/kg. G-8740-1400 Acute (LOSO) Intraperitoneal...1% (w/v) methylcellulose/O.4% (v/v) Tween 80 were conducted in Fischer 344 rats. The dose ranges encom- passed 0 mg/kg (vehicle control) to 320 mg/kg...suspended in a vehicle of 1% (w/v) methylcellulose/O.4% (v/v) Tween 80 were conducted in B6C3F1 mice. The dose range encompassed 62.5 mg/kg to 1000 mg

  7. Impact of Environmental Enrichment Devices on NTP In Vivo Studies.

    Science.gov (United States)

    Churchill, Sheba R; Morgan, Daniel L; Kissling, Grace E; Travlos, Gregory S; King-Herbert, Angela P

    2016-02-01

    The goal of this study was to determine whether the use of nesting material or polycarbonate shelters as enrichment devices would have an impact on end points commonly measured during the conduct of the National Toxicology Program (NTP) 13-week studies. The study design was consistent with the NTP 13-week toxicity studies. Harlan Sprague-Dawley (HSD) rats and their offspring and B6C3F1/N mice were assigned to control (unenriched) and enriched experimental groups. Body weight, food and water consumption, behavioral observations, fecal content, clinical pathology, gross pathology, organ weights, and histopathology were evaluated. Enriched male mice and male and female rats exhibited decreased feed intake without a subsequent decrease in body weight; this may have been the result of the nesting material reducing the effect of cold stress, thereby allowing for more efficient use of feed. There were statistical differences in some hematological parameters; however, these were not considered physiologically relevant since all values were within the normal range. Gross pathology and histopathological findings were background changes and were not considered enrichment-related. Nesting material and shelters were used frequently and consistently and allowed animals to display species-typical behavior. There was no significant impact on commonly measured end points in HSD rats and B6C3F1/N mice given enrichment devices.

  8. Effects of the PPARα Agonist and Widely Used Antihyperlipidemic Drug Gemfibrozil on Hepatic Toxicity and Lipid Metabolism

    Directory of Open Access Journals (Sweden)

    Michael L. Cunningham

    2010-01-01

    Full Text Available Gemfibrozil is a widely prescribed hypolipidemic agent in humans and a peroxisome proliferator and liver carcinogen in rats. Three-month feed studies of gemfibrozil were conducted by the National Toxicology Program (NTP in male Harlan Sprague-Dawley rats, B6C3F1 mice, and Syrian hamsters, primarily to examine mechanisms of hepatocarcinogenicity. There was morphologic evidence of peroxisome proliferation in rats and mice. Increased hepatocyte proliferation was observed in rats, primarily at the earliest time point. Increases in peroxisomal enzyme activities were greatest in rats, intermediate in mice, and least in hamsters. These studies demonstrate that rats are most responsive while hamsters are least responsive. These events are causally related to hepatotoxicity and hepatocarcinogenicity of gemfibrozil in rodents via peroxisome proliferator activated receptor-α (PPARα activation; however, there is widespread evidence that activation of PPARα in humans results in expression of genes involved in lipid metabolism, but not in hepatocellular proliferation.

  9. Human recombinant vascular endothelial growth factor reduces necrosis and enhances hepatocyte regeneration in a mouse model of acetaminophen toxicity.

    Science.gov (United States)

    Donahower, Brian C; McCullough, Sandra S; Hennings, Leah; Simpson, Pippa M; Stowe, Cindy D; Saad, Ali G; Kurten, Richard C; Hinson, Jack A; James, Laura P

    2010-07-01

    We reported previously that vascular endothelial growth factor (VEGF) was increased in acetaminophen (APAP) toxicity in mice and treatment with a VEGF receptor inhibitor reduced hepatocyte regeneration. The effect of human recombinant VEGF (hrVEGF) on APAP toxicity in the mouse was examined. In early toxicity studies, B6C3F1 mice received hrVEGF (50 microg s.c.) or vehicle 30 min before receiving APAP (200 mg/kg i.p.) and were sacrificed at 2, 4, and 8 h. Toxicity was comparable at 2 and 4 h, but reduced in the APAP/hrVEGF mice at 8 h (p toxicity and increased hepatocyte regeneration in APAP toxicity in the mouse. Attenuation of sinusoidal cell endothelial dysfunction and changes in neutrophil dynamics may be operant mechanisms in the hepatoprotection mediated by hrVEGF in APAP toxicity.

  10. Transcriptomic profiling of trichloroethylene exposure in male mouse liver

    Directory of Open Access Journals (Sweden)

    Yan Jiang

    2015-03-01

    Full Text Available Chronic Trichloroethylene (TCE exposure could induce hepatocellular carcinoma in mice, and occupational exposure in humans was suggested to be associated with liver cancer. To understand the role of non-genotoxic mechanism(s for TCE action, we examined the gene expression and DNA methylation changes in the liver of B6C3F1 mice orally administered with TCE for 5 days. As a beginning step, we profiled gene expression alterations induced by the TCE in mouse livers. Here we describe in detail the experimental methods, quality controls, and other information associated with our data deposited into Gene Expression Omnibus (GEO under GSE58819. Our data provide useful information for gene expression responses to TCE in mouse liver.

  11. Duodenal crypt health following exposure to Cr(VI): Micronucleus scoring, γ-H2AX immunostaining, and synchrotron X-ray fluorescence microscopy

    Energy Technology Data Exchange (ETDEWEB)

    Thompson, Chad M.; Wolf, Jeffrey C.; Elbekai, Reem H.; Paranjpe, Madhav G.; Seiter, Jennifer M.; Chappell, Mark A.; Tappero, Ryan V.; Suh, Mina; Proctor, Deborah M.; Bichteler, Anne; Haws, Laurie C.; Harris, Mark A.

    2015-08-01

    Lifetime exposure to high concentrations of hexavalent chromium [Cr(VI)] in drinking water results in intestinal damage and an increase in duodenal tumors in B6C3F1 mice. To assess whether these tumors could be the result of a direct mutagenic or genotoxic mode of action, we conducted a GLP-compliant 7-day drinking water study to assess crypt health along the entire length of the duodenum. Mice were exposed to water (vehicle control), 1.4, 21, or 180 ppm Cr(VI) via drinking water for 7 consecutive days. Crypt enterocytes in Swiss roll sections were scored as normal, mitotic, apoptotic, karyorrhectic, or as having micronuclei. A single oral gavage of 50 mg/kg cyclophosphamide served as a positive control for micronucleus induction. Exposure to 21 and 180 ppm Cr(VI) significantly increased the number of crypt enterocytes. Micronuclei and γ-H2AX immunostaining were not elevated in the crypts of Cr(VI)-treated mice. In contrast, treatment with cyclophosphamide significantly increased numbers of crypt micronuclei and qualitatively increased γ-H2AX immunostaining. Synchrotron-based X-ray fluorescence (XRF) microscopy revealed the presence of strong Cr fluorescence in duodenal villi, but negligible Cr fluorescence in the crypt compartment. Together, these data indicate that Cr(VI) does not adversely effect the crypt compartment where intestinal stem cells reside, and provide additional evidence that the mode of action for Cr(VI)-induced intestinal cancer in B6C3F1 mice involves chronic villous wounding resulting in compensatory crypt enterocyte hyperplasia.

  12. First Steps Towards an Understanding of a Mode ofCarcinogenic Action for Vanadium Pentoxide

    Science.gov (United States)

    Schuler, Detlef; Chevalier, Hans-Jörg; Merker, Mandy; Morgenthal, Katja; Ravanat, Jean-Luc; Sagelsdorff, Peter; Walter, Marc; Weber, Klaus; Mcgregor, Douglas

    2011-01-01

    Inhalation of vanadium pentoxide clearly increases the incidence of alveolar/bronchiolar neoplasms in male and female B6C3F1 mice at all concentrations tested (1, 2 or 4 mg/m3), whereas responses in F344/N rats was, at most, ambiguous. While vanadium pentoxide is mutagenic in vitro and possibly in vivo in mice, this does not explain the species or site specificity of the neoplastic response. A nose-only inhalation study was conducted in female B6C3F1 mice (0, 0.25, 1 and 4 mg/m3, 6 h/day for 16 days) to explore histopathological, biochemical (α-tocopherol, glutathione and F2-isoprostane) and genetic (comet assays and 9 specific DNA-oxo-adducts) changes in the lungs. No treatment related histopathology was observed at 0.25 mg/m3. At 1 and 4 mg/m3, exposure-dependent increases were observed in lung weight, alveolar histiocytosis, sub-acute alveolitis and/or granulocytic infiltration and a generally time-dependent increased cell proliferation rate of histiocytes. Glutathione was slightly increased, whereas there were no consistent changes in α-tocopherol or 8-isoprostane F2α. There was no evidence for DNA strand breakage in lung or BAL cells, but there was an increase in 8-oxodGuo DNA lesions that could have been due to vanadium pentoxide induction of the lesions or inhibition of repair of spontaneous lesions. Thus, earlier reports of histopathological changes in the lungs after inhalation of vanadium pentoxide were confirmed, but no evidence has yet emerged for a genotoxic mode of action. Evidence is weak for oxidative stress playing any role in lung carcinogenesis at the lowest effective concentrations of vanadium pentoxide. PMID:22272055

  13. Dichloroacetate Stimulates Glycogen Accumulation in Primary Hepatocytes through an Insulin-Independent Mechanism

    Energy Technology Data Exchange (ETDEWEB)

    Lingohr, Melissa K.(Washington State University); Bull, Richard J.(SELF-EMPLOYED CONSULTANTS); Kato-Weinstein, Junko (UNIVERSITY PROGRAMS); Thrall, Brian D.(BATTELLE (PACIFIC NW LAB))

    2002-01-01

    Dichloroacetate (DCA), a by-product of water chlorination, causes liver cancer in B6C3F1 mice. A hallmark response observed in mice exposed to carcinogenic doses of DCA is an accumulation of hepatic glycogen content. To distinguish whether the in vivo glycogenic effect of DCA was dependent on insulin and insulin signaling proteins, experiments were conducted in isolated hepatocytes where insulin concentrations could be controlled. In hepatocytes isolated from male B6C3F1 mice, DCA increased glycogen levels in a dose-related manner, independently of insulin. The accumulation of hepatocellular glycogen induced by DCA was not the result of decreased glycogenolysis, since DCA had no effect on the rate of glucagon-stimulated glycogen breakdown. Glycogen accumulation caused by DCA treatment was not hindered by inhibitors of extracellular-regulated protein kinase kinase (Erk1/2 kinase or MEK) or p70 kDa S6 protein kinase (p70(S6K)), but was completely blocked by the phosphatidylinositol 3-kinase (PI3K) inhibitors, LY294002 and wortmannin. Similarly, insulin-stimulated glycogen deposition was not influenced by the Erk1/2 kinase inhibitor, PD098509, or the p70(S6K) inhibitor, rapamycin. Unlike DCA-stimulated glycogen deposition, PI3K-inhibition only partially blocked the glycogenic effect of insulin. DCA did not cause phosphorylation of the downstream PI3K target protein, protein kinase B (PKB/Akt). The phosphorylation of PKB/Akt did not correlate to insulin-stimulated glycogenesis either. Similar to insulin, DCA in the medium decreased IR expression in isolated hepatocytes. The results indicate DCA increases hepatocellular glycogen accumulation through a PI3K-dependent mechanism that does not involve PKB/Akt and is, at least in part, different from the classical insulin-stimulated glycogenesis pathway. Somewhat surprisingly, insulin-stimulated glycogenesis also appears not to involve PKB/Akt in isolated murine hepatocytes.

  14. Effects of Pre-exposure of Mouse Pituitary with Low-dose 60Co γ-ray on Male Reproductive Endocrine Capacity Induced by Subsequent High-dose Irradiation

    Institute of Scientific and Technical Information of China (English)

    ZhangHong; LiWenjian; JingXiaodong; LiuBing; MinFengling; ZhouQingming; XieYi

    2003-01-01

    To investigate the effects of pre-exposure of mouse pituitary with low-dose 60Co γ-ray on male reproductive endocrine capacity induced by subsequent high-dose irradiation, the pituitary of the B6C3F1 hybrid strain male mice were irradiated with 0.05 Gy of 60Co γ-ray as the pre-exposure dose (D1), and were then irradiated with 2 Gy of 60Co γ-ray as challenging irradiation dose (D2) at 4 h after per-exposure. Pituitary gonadotroping hormones --follicle-stimulating hormone (FSH) and luterinzing hormone (LH), serum testosterone, testis weight and sperm count were measured at 35th day after irradiation.

  15. Final Report

    Energy Technology Data Exchange (ETDEWEB)

    DeTar, Carleton [P.I.

    2012-12-10

    This document constitutes the Final Report for award DE-FC02-06ER41446 as required by the Office of Science. It summarizes accomplishments and provides copies of scientific publications with significant contribution from this award.

  16. Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Gurney, Kevin R

    2015-01-12

    This document constitutes the final report under DOE grant DE-FG-08ER64649. The organization of this document is as follows: first, I will review the original scope of the proposed research. Second, I will present the current draft of a paper nearing submission to Nature Climate Change on the initial results of this funded effort. Finally, I will present the last phase of the research under this grant which has supported a Ph.D. student. To that end, I will present the graduate student’s proposed research, a portion of which is completed and reflected in the paper nearing submission. This final work phase will be completed in the next 12 months. This final workphase will likely result in 1-2 additional publications and we consider the results (as exemplified by the current paper) high quality. The continuing results will acknowledge the funding provided by DOE grant DE-FG-08ER64649.

  17. Psychopharmacological Studies in Mice.

    Science.gov (United States)

    Matsuda, Toshio

    2016-01-01

    Since 1998, when the laboratory of Medicinal Pharmacology was established in the Graduate School of Pharmaceutical Sciences, Osaka University, I have been interested in psychopharmacological research topics. During this period, we identified a number of novel regulatory mechanisms that control the prefrontal dopamine system through functional interaction between serotonin1A and dopamine D2 receptors or between serotonin1A and σ1 receptors. Our findings suggest that strategies that enhance the prefrontal dopamine system may have therapeutic potential in the treatment of psychiatric disorders. We also found that environmental factors during development strongly impact the psychological state in adulthood. Furthermore, we clarified the pharmacological profiles of the acetylcholinesterase inhibitors donepezil, galantamine, and rivastigmine, providing novel insights into their mechanisms of action. Finally, we developed the female encounter test, a novel method for evaluating motivation in mice. This simple method should help advance future psychopharmacological research. In this review, we summarize the major findings obtained from our recent studies in mice.

  18. Final Report

    DEFF Research Database (Denmark)

    Heiselberg, Per; Brohus, Henrik; Nielsen, Peter V.

    This final report for the Hybrid Ventilation Centre at Aalborg University describes the activities and research achievement in the project period from August 2001 to August 2006. The report summarises the work performed and the results achieved with reference to articles and reports published...

  19. Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Stinis, Panos [Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

    2016-08-07

    This is the final report for the work conducted at the University of Minnesota (during the period 12/01/12-09/18/14) by PI Panos Stinis as part of the "Collaboratory on Mathematics for Mesoscopic Modeling of Materials" (CM4). CM4 is a multi-institution DOE-funded project whose aim is to conduct basic and applied research in the emerging field of mesoscopic modeling of materials.

  20. Correlation of MRI findings to histology of acetaminophen toxicity in the mouse.

    Science.gov (United States)

    Brown, Aliza T; Ou, Xiawei; James, Laura P; Jambhekar, Kedar; Pandey, Tarun; McCullough, Sandra; Chaudhuri, Shubhra; Borrelli, Michael J

    2012-02-01

    Acetaminophen (APAP) toxicity is responsible for approximately half of all cases of acute liver failure in the United States. The mouse model of APAP toxicity is widely used to examine mechanisms of APAP toxicity. Noninvasive approaches would allow for serial measurements in a single animal to study the effects of experimental interventions on the development and resolution of hepatocellular necrosis. The following study examined the time course of hepatic necrosis using small animal magnetic resonance imaging (MRI) following the administration of 200 mg/kg ip APAP given to B6C3F1 male mice. Mice treated with saline served as controls (CON). Other mice received treatment with the clinical antidote N-acetylcysteine (APAP+NAC). Mouse liver pathology was characterized using T1- and T2-weighted sequences at 2, 4, 8 and 24 h following APAP administration. Standard assays for APAP toxicity [serum alanine aminotransaminase (ALT) levels and hematoxylin and eosin (H&E) staining of liver sections] were examined relative to MRI findings. Overall, T2 sequences had a greater sensitivity for necrosis and hemorrhage than T1 (FLASH) images. Liver injury severity scoring of MR images demonstrated increased scores in the APAP mice at 4, 8 and 24 h compared to the CON mice. APAP+NAC mice had MRI scores similar to the CON mice. Semiquantitative analysis of hepatic hemorrhage strongly correlated with serum ALT. Small animal MRI can be used to monitor the evolution of APAP toxicity over time and to evaluate the response to therapy.

  1. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Jarillo-Herrero, Pablo [Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)

    2017-02-07

    This is the final report of our research program on electronic transport experiments on Topological Insulator (TI) devices, funded by the DOE Office of Basic Energy Sciences. TIbased electronic devices are attractive as platforms for spintronic applications, and for detection of emergent properties such as Majorana excitations , electron-hole condensates , and the topological magneto-electric effect . Most theoretical proposals envision geometries consisting of a planar TI device integrated with materials of distinctly different physical phases (such as ferromagnets and superconductors). Experimental realization of physics tied to the surface states is a challenge due to the ubiquitous presence of bulk carriers in most TI compounds as well as degradation during device fabrication.

  2. Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Webb, Robert C. [Texas A& M University; Kamon, Teruki [Texas A& M University; Toback, David [Texas A& M University; Safonov, Alexei [Texas A& M University; Dutta, Bhaskar [Texas A& M University; Dimitri, Nanopoulos [Texas A& M University; Pope, Christopher [Texas A& M University; White, James [Texas A& M University

    2013-11-18

    Overview The High Energy Physics Group at Texas A&M University is submitting this final report for our grant number DE-FG02-95ER40917. This grant has supported our wide range of research activities for over a decade. The reports contained here summarize the latest work done by our research team. Task A (Collider Physics Program): CMS & CDF Profs. T. Kamon, A. Safonov, and D. Toback co-lead the Texas A&M (TAMU) collider program focusing on CDF and CMS experiments. Task D: Particle Physics Theory Our particle physics theory task is the combined effort of Profs. B. Dutta, D. Nanopoulos, and C. Pope. Task E (Underground Physics): LUX & NEXT Profs. R. Webb and J. White(deceased) lead the Xenon-based underground research program consisting of two main thrusts: the first, participation in the LUX two-phase xenon dark matter search experiment and the second, detector R&D primarily aimed at developing future detectors for underground physics (e.g. NEXT and LZ).

  3. Pion contamination in the MICE muon beam

    Science.gov (United States)

    Adams, D.; Alekou, A.; Apollonio, M.; Asfandiyarov, R.; Barber, G.; Barclay, P.; de Bari, A.; Bayes, R.; Bayliss, V.; Bertoni, R.; Blackmore, V. J.; Blondel, A.; Blot, S.; Bogomilov, M.; Bonesini, M.; Booth, C. N.; Bowring, D.; Boyd, S.; Brashaw, T. W.; Bravar, U.; Bross, A. D.; Capponi, M.; Carlisle, T.; Cecchet, G.; Charnley, C.; Chignoli, F.; Cline, D.; Cobb, J. H.; Colling, G.; Collomb, N.; Coney, L.; Cooke, P.; Courthold, M.; Cremaldi, L. M.; DeMello, A.; Dick, A.; Dobbs, A.; Dornan, P.; Drews, M.; Drielsma, F.; Filthaut, F.; Fitzpatrick, T.; Franchini, P.; Francis, V.; Fry, L.; Gallagher, A.; Gamet, R.; Gardener, R.; Gourlay, S.; Grant, A.; Greis, J. R.; Griffiths, S.; Hanlet, P.; Hansen, O. M.; Hanson, G. G.; Hart, T. L.; Hartnett, T.; Hayler, T.; Heidt, C.; Hills, M.; Hodgson, P.; Hunt, C.; Iaciofano, A.; Ishimoto, S.; Kafka, G.; Kaplan, D. M.; Karadzhov, Y.; Kim, Y. K.; Kuno, Y.; Kyberd, P.; Lagrange, J.-B.; Langlands, J.; Lau, W.; Leonova, M.; Li, D.; Lintern, A.; Littlefield, M.; Long, K.; Luo, T.; Macwaters, C.; Martlew, B.; Martyniak, J.; Mazza, R.; Middleton, S.; Moretti, A.; Moss, A.; Muir, A.; Mullacrane, I.; Nebrensky, J. J.; Neuffer, D.; Nichols, A.; Nicholson, R.; Nugent, J. C.; Oates, A.; Onel, Y.; Orestano, D.; Overton, E.; Owens, P.; Palladino, V.; Pasternak, J.; Pastore, F.; Pidcott, C.; Popovic, M.; Preece, R.; Prestemon, S.; Rajaram, D.; Ramberger, S.; Rayner, M. A.; Ricciardi, S.; Roberts, T. J.; Robinson, M.; Rogers, C.; Ronald, K.; Rubinov, P.; Rucinski, P.; Sakamato, H.; Sanders, D. A.; Santos, E.; Savidge, T.; Smith, P. J.; Snopok, P.; Soler, F. J. P.; Speirs, D.; Stanley, T.; Stokes, G.; Summers, D. J.; Tarrant, J.; Taylor, I.; Tortora, L.; Torun, Y.; Tsenov, R.; Tunnell, C. D.; Uchida, M. A.; Vankova-Kirilova, G.; Virostek, S.; Vretenar, M.; Warburton, P.; Watson, S.; White, C.; Whyte, C. G.; Wilson, A.; Winter, M.; Yang, X.; Young, A.; Zisman, M.

    2016-03-01

    The international Muon Ionization Cooling Experiment (MICE) will perform a systematic investigation of ionization cooling with muon beams of momentum between 140 and 240 MeV/c at the Rutherford Appleton Laboratory ISIS facility. The measurement of ionization cooling in MICE relies on the selection of a pure sample of muons that traverse the experiment. To make this selection, the MICE Muon Beam is designed to deliver a beam of muons with less than ~1% contamination. To make the final muon selection, MICE employs a particle-identification (PID) system upstream and downstream of the cooling cell. The PID system includes time-of-flight hodoscopes, threshold-Cherenkov counters and calorimetry. The upper limit for the pion contamination measured in this paper is fπ < 1.4% at 90% C.L., including systematic uncertainties. Therefore, the MICE Muon Beam is able to meet the stringent pion-contamination requirements of the study of ionization cooling.

  4. Pion contamination in the MICE muon beam

    CERN Document Server

    Bogomilov, M.; Vankova-Kirilova, G.; Bertoni, R.; Bonesini, M.; Chignoli, F.; Mazza, R.; Palladino, V.; de Bari, A.; Cecchet, G.; Capponi, M.; Iaciofano, A.; Orestano, D.; Pastore, F.; Tortora, L.; Kuno, Y.; Sakamoto, H.; Ishimoto, S.; Japan, Ibaraki; Filthaut, F.; Hansen, O.M.; Ramberger, S.; Vretenar, M.; Asfandiyarov, R.; Blondel, A.; Drielsma, F.; Karadzhov, Y.; Charnley, G.; Collomb, N.; Gallagher, A.; Grant, A.; Griffiths, S.; Hartnett, T.; Martlew, B.; Moss, A.; Muir, A.; Mullacrane, I.; Oates, A.; Owens, P.; Stokes, G.; Warburton, P.; White, C.; Adams, D.; Barclay, P.; Bayliss, V.; Bradshaw, T.W.; Courthold, M.; Francis, V.; Fry, L.; Hayler, T.; Hills, M.; Lintern, A.; Macwaters, C.; Nichols, A.; Preece, R.; Ricciardi, S.; Rogers, C.; Stanley, T.; Tarrant, J.; Watson, S.; Wilson, A.; Bayes, R.; Nugent, J.C.; Soler, F.J.P.; Cooke, P.; Gamet, R.; Alekou, A.; Apollonio, M.; Barber, G.; Colling, D.; Dobbs, A.; Dornan, P.; Hunt, C.; Lagrange, J-B.; Long, K.; Martyniak, J.; Middleton, S.; Pasternak, J.; Santos, E.; Savidge, T.; Uchida, M.A.; Blackmore, V.J.; Carlisle, T.; Cobb, J.H.; Lau, W.; Rayner, M.A.; Tunnell, C.D.; Booth, C.N.; Hodgson, P.; Langlands, J.; Nicholson, R.; Overton, E.; Robinson, M.; Smith, P.J.; Dick, A.; Ronald, K.; Speirs, D.; Whyte, C.G.; Young, A.; Boyd, S.; Franchini, P.; Greis, J.R.; Pidcott, C.; Taylor, I.; Gardener, R.; Kyberd, P.; Littlefield, M.; Nebrensky, J.J.; Bross, A.D.; Fitzpatrick, T.; Leonova, M.; Moretti, A.; Neuffer, D.; Popovic, M.; Rubinov, P.; Rucinski, R.; Roberts, T.J.; Bowring, D.; DeMello, A.; Gourlay, S.; Li, D.; Prestemon, S.; Virostek, S.; Zisman, M.; Drews, M.; Hanlet, P.; Kafka, G.; Kaplan, D.M.; Rajaram, D.; Snopok, P.; Torun, Y.; Winter, M.; Blot, S.; Kim, Y.K.; Bravar, U.; Onel, Y.; Cremaldi, L.M.; Hart, T.L.; Luo, T.; Sanders, D.A.; Summers, D.J.; Cline, D.; Yang, X.; Coney, L.; Hanson, G.G.; Heidt, C.

    2016-01-01

    The international Muon Ionization Cooling Experiment (MICE) will perform a systematic investigation of ionization cooling with muon beams of momentum between 140 and 240\\,MeV/c at the Rutherford Appleton Laboratory ISIS facility. The measurement of ionization cooling in MICE relies on the selection of a pure sample of muons that traverse the experiment. To make this selection, the MICE Muon Beam is designed to deliver a beam of muons with less than $\\sim$1\\% contamination. To make the final muon selection, MICE employs a particle-identification (PID) system upstream and downstream of the cooling cell. The PID system includes time-of-flight hodoscopes, threshold-Cherenkov counters and calorimetry. The upper limit for the pion contamination measured in this paper is $f_\\pi < 1.4\\%$ at 90\\% C.L., including systematic uncertainties. Therefore, the MICE Muon Beam is able to meet the stringent pion-contamination requirements of the study of ionization cooling.

  5. Toxicity and carcinogenicity studies of Ginkgo biloba extract in rat and mouse: liver, thyroid, and nose are targets.

    Science.gov (United States)

    Rider, Cynthia V; Nyska, Abraham; Cora, Michelle C; Kissling, Grace E; Smith, Cynthia; Travlos, Gregory S; Hejtmancik, Milton R; Fomby, Laurene M; Colleton, Curtis A; Ryan, Michael J; Kooistra, Linda; Morrison, James P; Chan, Po C

    2014-07-01

    Ginkgo biloba extract (GBE) is a popular herbal supplement that is used to improve circulation and brain function. In spite of widespread human exposure to relatively high doses over potentially long periods of time, there is a paucity of data from animal studies regarding the toxicity and carcinogenicity associated with GBE. In order to fill this knowledge gap, 3-month and 2-year toxicity and carcinogenicity studies with GBE administered by oral gavage to B6C3F1/N mice and F344/N rats were performed as part of the National Toxicology Program's Dietary Supplements and Herbal Medicines Initiative. The targets of GBE treatment were the liver, thyroid, and nose. These targets were consistent across exposure period, sex, and species, albeit with varying degrees of effect observed among studies. Key findings included a notably high incidence of hepatoblastomas in male and female mice and evidence of carcinogenic potential in the thyroid gland of both mice and rats. Various nonneoplastic lesions were observed beyond control levels in the liver, thyroid gland, and nose of rats and mice administered GBE. Although these results cannot be directly extrapolated to humans, the findings fill an important data gap in assessing risk associated with GBE use.

  6. Development of kidney tumors in the male F344/N rat after treatment with dimethyl methylphosphonate.

    Science.gov (United States)

    Dunnick, J K; Eustis, S L; Haseman, J K

    1988-07-01

    Dimethyl methylphosphonate (DMMP), a chemical that has been used as a flame retardant and as a nerve gas simulant to mimic the physical but not biologic properties of nerve gases, was administered by gavage in corn oil for up to 2 years at doses of 0, 500, or 1000 mg/kg/day to male and female F344/N rats and at doses of 0, 1000, or 2000 mg/kg/day to male and female B6C3F1 mice. Survival in dosed male rats was reduced, due in part to kidney toxicity, and lesions in the kidney included increased severity of spontaneous nephropathy, calcification, hyperplasia of the tubular and transitional epithelium, tubular cell adenocarcinomas, and transitional cell papillomas and carcinomas. Survival in female rats was similar among groups; survival in mice was reduced and this reduced survival decreased the sensitivity for detecting a carcinogenic response. There were no dose-related neoplastic responses in female rats or male or female mice. The spectrum of kidney lesions seen in the male rat given DMMP is similar to that seen after the long-term administration of a variety of other chemicals including unleaded gasoline, hydrocarbon solvents, and 1,4-dichlorobenzene.

  7. Indocyanine green clearance varies as a function of N-acetylcysteine treatment in a murine model of acetaminophen toxicity.

    Science.gov (United States)

    Milesi-Hallé, Alessandra; Abdel-Rahman, Susan M; Brown, Aliza; McCullough, Sandra S; Letzig, Lynda; Hinson, Jack A; James, Laura P

    2011-02-01

    Standard assays to assess acetaminophen (APAP) toxicity in animal models include determination of ALT (alanine aminotransferase) levels and examination of histopathology of liver sections. However, these assays do not reflect the functional capacity of the injured liver. To examine a functional marker of liver injury, the pharmacokinetics of indocyanine green (ICG) were examined in mice treated with APAP, saline, or APAP followed by N-acetylcysteine (NAC) treatment.Male B6C3F1 mice were administered APAP (200 mg/kg IP) or saline. Two additional groups of mice received APAP followed by NAC at 1 or 4 h after APAP. At 24 h, mice were injected with ICG (10 mg/kg IV) and serial blood samples (0, 2, 10, 30, 50 and 75 min) were obtained for determination of serum ICG concentrations and ALT. Mouse livers were removed for measurement of APAP protein adducts and examination of histopathology. Toxicity (ALT values and histology) was significantly increased above saline treated mice in the APAP and APAP/NAC 4 h mice. Mice treated with APAP/NAC 1 h had complete protection from toxicity. APAP protein adducts were increased in all APAP treated groups and were highest in the APAP/NAC 1 h group. Pharmacokinetic analysis of ICG demonstrated that the total body clearance (Cl(T)) of ICG was significantly decreased and the mean residence time (MRT) was significantly increased in the APAP mice compared to the saline mice. Mice treated with NAC at 1 h had Cl(T) and MRT values similar to those of saline treated mice. Conversely, mice that received NAC at 4 h had a similar ICG pharmacokinetic profile to that of the APAP only mice. Prompt treatment with NAC prevented loss of functional activity while late treatment with NAC offered no improvement in ICG clearance at 24 h. ICG clearance in mice with APAP toxicity can be utilized in future studies testing the effects of novel treatments for APAP toxicity.

  8. The effect of propylene glycol on the P450-dependent metabolism of acetaminophen and other chemicals in subcellular fractions of mouse liver

    Energy Technology Data Exchange (ETDEWEB)

    Snawder, J.E.; Benson, R.W.; Leakey, J.E.A.; Roberts, D.W. (National Center for Toxicological Research, Jefferson, AR (United States))

    1993-01-01

    Propylene glycol (PG) decreases the hepatotoxicity of acetominophen (APAP). To elucidate the mechanism for this response, the authors measured the effect of PG on the in vitro metabolism of APAP by subcellular liver fractions from 6-10 week-old male B6C3F1 mice. The fractions were assayed for their ability to bioactivate APAP to N-acetyl-p-benzoquinone imine, which was trapped as APAP-glutathione conjugates or APAP-protein adducts, and for dimethyl-nitrosamine-N-demethylase (DMN), 4-nitrophenol hydroxylase (4-NPOH), and phenacetin-O-deethylase (PAD) activities. Activity in the crude mitochondrial-rich (10,000 [times] g pellet) fraction was low and PG had no effect. PG inhibited DMN and 4-NPOH, indicators of IIE1-dependent activity, and the formation of APAP-glutathione conjugates and APAP-protein adducts in both heavy (15,000 [times] g pellet) and light (100,000 [times] g pellet) microsomes. PAD, a measure of IA2-dependent activity, was not inhibited. These data demonstrate that PG selectively inhibits IIE1 activity, including the bioactivation of APAP, and implicates this as the mechanism for PG-mediated protection of APAP hepatotoxicity in mice. 27 refs., 1 fig., 1 tab.

  9. Toxicologic Assessment of a Commercial Decolorized Whole Leaf Aloe Vera Juice, Lily of the Desert Filtered Whole Leaf Juice with Aloesorb

    Directory of Open Access Journals (Sweden)

    Inder Sehgal

    2013-01-01

    Full Text Available Aloe vera, a common ingredient in cosmetics, is increasingly being consumed as a beverage supplement. Although consumer interest in aloe likely stems from its association with several health benefits, a concern has also been raised by a National Toxicology Program Report that a nondecolorized whole leaf aloe vera extract taken internally by rats was associated with intestinal mucosal hyperplasia and ultimately malignancy. We tested a decolorized whole leaf (DCWL aloe vera, treated with activated charcoal to remove the latex portion of the plant, for genotoxicity in bacteria, acute/subacute toxicity in B6C3F1 mice, and subchronic toxicity in F344 rats. We found this DCWL aloe vera juice to be nongenotoxic in histidine reversion and DNA repair assays. Following acute administration, mice exhibited no adverse signs at 3- or 14-day evaluation periods. When fed to male and female F344 rats over 13 weeks, DCWL aloe led to no toxicity as assessed by behavior, stools, weight gain, feed consumption, organ weights, and hematologic or clinical chemistry profiles. These rats had intestinal mucosal morphologies—examined grossly and microscopically—that were similar to controls. Our studies show that oral administration of this DCWL aloe juice has a different toxicology profile than that of the untreated aloe juice at exposures up to 13 weeks.

  10. Gene expression studies demonstrate that the K-ras/Erk MAP kinase signal transduction pathway and other novel pathways contribute to the pathogenesis of cumene-induced lung tumors.

    Science.gov (United States)

    Wakamatsu, Nobuko; Collins, Jennifer B; Parker, Joel S; Tessema, Mathewos; Clayton, Natasha P; Ton, Thai-Vu T; Hong, Hue-Hua L; Belinsky, Steven; Devereux, Theodora R; Sills, Robert C; Lahousse, Stephanie A

    2008-07-01

    National Toxicology Program (NTP) inhalation studies demonstrated that cumene significantly increased the incidence of alveolar/bronchiolar adenomas and carcinomas in B6C3F1 mice. Cumene or isopropylbenzene is a component of crude oil used primarily in the production of phenol and acetone. The authors performed global gene expression analysis to distinguish patterns of gene regulation between cumene-induced tumors and normal lung tissue and to look for patterns based on the presence or absence of K-ras and p53 mutations in the tumors. Principal component analysis segregated the carcinomas into groups with and without K-ras mutations, but failed to separate the tumors based on p53 mutation status. Expression of genes associated with the Erk MAP kinase signaling pathway was significantly altered in carcinomas with K-ras mutations compared to tumors without K-ras mutations or normal lung. Gene expression analysis also suggested that cumene-induced carcinomas with K-ras mutations have greater malignant potential than those without mutations. In addition, significance analysis of function and expression (SAFE) demonstrated expression changes of genes regulated by histone modification in carcinomas with K-ras mutations. The gene expression analysis suggested the formation of alveolar/bronchiolar carcinomas in cumene-exposed mice typically involves mutation of K-ras, which results in increased Erk MAP kinase signaling and modification of histones.

  11. Dermal Exposure to Cumene Hydroperoxide: Assessing Its Toxic Relevance and Oxidant Potential.

    Science.gov (United States)

    Rider, Cynthia V; Chan, Po; Herbert, Ron A; Kissling, Grace E; Fomby, Laurene M; Hejtmancik, Milton R; Witt, Kristine L; Waidyanatha, Suramya; Travlos, Greg S; Kadiiska, Maria B

    2016-07-01

    Cumene hydroperoxide (CHP) is a high production volume chemical that is used to generate phenol and acetone. Dermal exposure to CHP was hypothesized to result in systemic tissue toxicity, production of free radicals, and consequent decrease in plasma antioxidant levels. To evaluate the hypothesis and characterize the toxicity of CHP, male and female B6C3F1/N mice and F344/N rats were exposed to varying doses of CHP applied topically for 14 or 90 days. No significant changes in survival or body weight of mice and rats were observed following 14 days of exposure. However, 90 days of CHP exposure at the high dose (12 mg/kg) triggered a significant decrease (-15%) in the body weight of the male rat group only. Irritation of the skin was observed at the site of application and was characterized by inflammation and epidermal hyperplasia. In treated animals, histology of liver tissue, free radical generation, and antioxidant levels in blood plasma were not significantly changed as compared to the corresponding controls. Consistent with the lack of systemic damage, no increase in micronucleated erythrocytes was seen in peripheral blood. In conclusion, topical CHP application caused skin damage only at the application site and did not cause systemic tissue impairment.

  12. Toxicologic assessment of a commercial decolorized whole leaf aloe vera juice, lily of the desert filtered whole leaf juice with aloesorb.

    Science.gov (United States)

    Sehgal, Inder; Winters, Wallace D; Scott, Michael; David, Andrew; Gillis, Glenn; Stoufflet, Thaya; Nair, Anand; Kousoulas, Konstantine

    2013-01-01

    Aloe vera, a common ingredient in cosmetics, is increasingly being consumed as a beverage supplement. Although consumer interest in aloe likely stems from its association with several health benefits, a concern has also been raised by a National Toxicology Program Report that a nondecolorized whole leaf aloe vera extract taken internally by rats was associated with intestinal mucosal hyperplasia and ultimately malignancy. We tested a decolorized whole leaf (DCWL) aloe vera, treated with activated charcoal to remove the latex portion of the plant, for genotoxicity in bacteria, acute/subacute toxicity in B6C3F1 mice, and subchronic toxicity in F344 rats. We found this DCWL aloe vera juice to be nongenotoxic in histidine reversion and DNA repair assays. Following acute administration, mice exhibited no adverse signs at 3- or 14-day evaluation periods. When fed to male and female F344 rats over 13 weeks, DCWL aloe led to no toxicity as assessed by behavior, stools, weight gain, feed consumption, organ weights, and hematologic or clinical chemistry profiles. These rats had intestinal mucosal morphologies-examined grossly and microscopically-that were similar to controls. Our studies show that oral administration of this DCWL aloe juice has a different toxicology profile than that of the untreated aloe juice at exposures up to 13 weeks.

  13. Improved mutagen testing systems in mice. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Roderick, T.H.

    1992-12-31

    Our laboratory was the first to induce and ascertain a mammalian chromosomal inversion; we did this by searching for a high frequency of first meiotic anaphase bridges in testes of males whose fathers received post-spermatogonial radiation or mutagenesis from chromosomal breaking chemical mutagens. One test in was examined in each mouse, and those showing a high frequency were then mated to determine if the high frequency were passed on as a dominant and whether linkage analysis suggested the presence of an inversion. A very high incidence (exceeding 20% bridges in first meiotic anaphase bridges) was found in about 1 in 150 males examined and this frequency was generally found to be passed on to the offspring an predicted. Later cytological banding techniques were developed elsewhere and we used them to show visually the inverted orders of the inverted chromosomal segments. Since that time we have induced inversions covering most of the mouse genome.

  14. Effects of heavy ion to the primary culture of mouse brain cells

    Science.gov (United States)

    Nojima, Kumie; Nakadai, Taeko; Kohno, Yukio; Vazquez, Marcelo E.; Yasuda, Nakahiro; Nagaoka, Shunji

    2004-01-01

    To investigate effects of low dose heavy particle radiation to CNS system, we adopted mouse neonatal brain cells in culture being exposed to heavy ions by HIMAC at NIRS and NSRL at BNL. The applied dose varied from 0.05 Gy up to 2.0 Gy. The subsequent biological effects were evaluated by an induction of apoptosis and neuron survival focusing on the dependencies of the animal strains, SCID, B6, B6C3F1, C3H, used for brain cell culture, SCID was the most sensitive and C3H the least sensitive to particle radiation as evaluated by 10% apoptotic criterion. The LET dependency was compared with using SCID and B6 cells exposing to different ions (H, C, Ne, Si, Ar, and Fe). Although no detectable LET dependency was observed in the high LET (55-200 keV/micrometers) and low dose (<0.5 Gy) regions. The survivability profiles of the neurons were different in the mouse strains and ions. In this report, a result of memory and learning function to adult mice after whole-body and brain local irradiation at carbon ion and iron ion.

  15. Effects of Pre-exposure Mouse Pituitary with Low-dose 60Co γ-ray on Growth Hormone (GH) and Body Mass Induced by Subsequent High-dose Irradiation

    Institute of Scientific and Technical Information of China (English)

    ZhangHong; LiWenjian; JingXiaodong; LiuBing; MinFengling; ZhouQingming; XieYi

    2003-01-01

    The pituitary of the B6C3F1 hybrid strain mice were irradiated with 0.05 Gy of 60Co γ-ray as the pre-exposure dose (D1), and were then irradiated with 2 Gy of 60Co γ-ray as challenging irradiation dose (D2) at 4h after per-exposure. Body weight and serum growth hormone (GH) were measured at 35th day after irradiation. The results showed that irradiation of mouse testes with 2 Gy of 60Co γ-ray significantly diminished mousebody weight and level of serum GH (Table). Pre-exposure with a low-dose (0.05 Gy) of 60Co γ-ray significantly alleviated reductions of mouse body weight and level of serum GH induced by subsequent a high-dose (2 Gy) irradiation (Table). The data suggested that low-dose ionizing irradiation can induce adaptive responses to the harmful effects of pituitary by subsequent high-dose exposure.

  16. LPS-inducible factor(s) from activated macrophages mediates cytolysis of Naegleria fowleri amoebae

    Energy Technology Data Exchange (ETDEWEB)

    Cleary, S.F.; Marciano-Cabral, F.

    1986-03-01

    Soluble cytolytic factors of macrophage origin have previously been described with respect to their tumoricidal activity. The purpose of this study was to investigate the mechanism and possible factor(s) responsible for cytolysis of the amoeba Naegleria fowleri by activated peritoneal macrophages from B6C3F1 mice. Macrophages or conditioned medium (CM) from macrophage cultures were incubated with /sup 3/H-Uridine labeled amoebae. Percent specific release of label served as an index of cytolysis. Bacille Calmette-Guerin (BCG) and Corynebacterium parvum macrophages demonstrated significant cytolysis of amoebae at 24 h with an effector to target ratio of 10:1. Treatment of macrophages with inhibitors of RNA or protein synthesis blocked amoebicidal activity. Interposition of a 1 ..mu..m pore membrane between macrophages and amoebae inhibited killing. Inhibition in the presence of the membrane was overcome by stimulating the macrophages with LPS. CM from SPS-stimulated, but not unstimulated, cultures of activated macrophages was cytotoxic for amoebae. The activity was heat sensitive and was recovered from ammonium sulfate precipitation of the CM. Results indicate that amoebicidal activity is mediated by a protein(s) of macrophage origin induced by target cell contact or stimulation with LPS.

  17. Evaluation of 4-methylimidazole, in the Ames/Salmonella test using induced rodent liver and lung S9.

    Science.gov (United States)

    Beevers, Carol; Adamson, Richard H

    2016-01-01

    4-methylimidazole (4-MeI) is formed by the interaction of ammonia with reducing sugars and low levels have been identified as a by-product in coffee, soy sauce, wine, dark beers, soft drinks, and caramel colors. The 4-MeI has been reported to induce alveolar/bronchiolar tumors in mice but not rats. Its mechanism of action is unlikely to be due to genotoxicity as 4-MeI does not induce mutation in Salmonella typhimurium and does not induce micronuclei in rodent peripheral erythrocytes or bone marrow cells. However, the question of whether genetically reactive intermediates could be formed via lung-specific metabolism has not previously been addressed. The 4-MeI was tested for its ability to induce mutation in five standard Ames strains of S. typhimurium using induced rat (F344/N) and mouse (B6C3F1) liver and lung S9 as a source of exogenous metabolism. The chemicals were tested in an OECD 471-compliant bacterial reverse mutation assay, using both plate-incorporation and pre-incubation methodologies, together with 10% S-9 metabolic activation. No induction of mutation (as measured by an increase in revertant colonies) was observed and it was concluded that 4-MeI was not mutagenic in S. typhimurium using either rodent liver or lung S9 for exogenous metabolism.

  18. The toxicity and pathology of selected dietary herbal medicines.

    Science.gov (United States)

    Dunnick, June K; Nyska, Abraham

    2013-02-01

    Toxicity studies were conducted by the National Toxicology Program (NTP) to provide information on the potential for toxicity from long-term use of commonly used herbal medicines. Here, we review the findings from these NTP toxicology/carcinogenesis 2-year rodent studies of 7 commonly used herbs. In these studies, the individual herb or herbal product was administered to F344/N rats and B6C3F1 mice by oral administration for up to 2 years. The spectrum of carcinogenic responses ranged from no or equivocal evidence for carcinogenic activity (ginseng, milk thistle, and turmeric oleoresin) to a liver tumor response (ginkgo, goldenseal, kava), thyroid tumor response (ginkgo), or an intestinal tumor response (Aloe vera whole leaf nondecolorized extract). Different mechanisms may be involved in the occurrence of liver (ginkgo, goldenseal, and kava kava) and gastrointestinal toxicity (turmeric oleoresin and Aloe vera whole leaf nondecolorized extract), while the toxic lesion is the same. The results from these hazard identification toxicity/carcinogenesis studies along with those from ongoing National Institute of Health clinical trials of herbal medicines provide more complete information on the risks and benefits from herbal medicine use in the general population.

  19. MICE IN CHINA

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    @@ The MICE (Meetings, Incentives, Conventions, and Exhibitions) industry has exploded worldwide over the past decade. The benefits brought by meetings, incentives, conventions, and exhibitions are also benefiting other sectors involved in MICE events, including hotels, travel, and retail. Industry analysts estimate that the income from the global MICE industry will soon exceed USD 220 billion, and is expected to increase by 8-10% each year.

  20. A Family of Mice

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    @@ 一、故事内容 There is a family of mice in my house. They are father mouse, mother mouse and baby mouse. Baby mouse likes dancing. He is very cute. Father mouse likes watching TV. He likes the sports on TV best. These three mice are clever.

  1. Of mice and men

    CERN Multimedia

    1973-01-01

    At the end of March , sixty mice were irradiated at the synchro-cyclotron in the course of an experimental programme studying radiation effects on mice and plants (Vicia faba bean roots) being carried out by the CERN Health Physics Group.

  2. Loss of ovarian function in the VCD mouse-model of menopause leads to insulin resistance and a rapid progression into the metabolic syndrome.

    Science.gov (United States)

    Romero-Aleshire, Melissa J; Diamond-Stanic, Maggie K; Hasty, Alyssa H; Hoyer, Patricia B; Brooks, Heddwen L

    2009-09-01

    Factors comprising the metabolic syndrome occur with increased incidence in postmenopausal women. To investigate the effects of ovarian failure on the progression of the metabolic syndrome, female B(6)C(3)F(1) mice were treated with 4-vinylcyclohexene diepoxide (VCD) and fed a high-fat (HF) diet for 16 wk. VCD destroys preantral follicles, causing early ovarian failure and is a well-characterized model for the gradual onset of menopause. After 12 wk on a HF diet, VCD-treated mice had developed an impaired glucose tolerance, whereas cycling controls were unaffected [12 wk AUC HF mice 13,455 +/- 643 vs. HF/VCD 17,378 +/- 1140 mg/dl/min, P diet, VCD-treated mice had significantly higher fasting insulin levels (HF 5.4 +/- 1.3 vs. HF/VCD 10.1 +/- 1.4 ng/ml, P diet (HF 56.2 +/- 16.7 vs. HF/VCD 113.1 +/- 19.6 mg/dl x microU/ml, P diet gained more weight than mice on a standard diet, and weight gain in HF/VCD mice was significantly increased compared with HF cycling controls. Interestingly, even without a HF diet, progression into VCD-induced menopause caused a significant increase in cholesterol and free fatty acids. Furthermore, in mice fed a standard diet (6% fat), insulin resistance developed 4 mo after VCD-induced ovarian failure. Insulin resistance following ovarian failure (menopause) was prevented by estrogen replacement. Studies here demonstrate that ovarian failure (menopause) accelerates progression into the metabolic syndrome and that estrogen replacement prevents the onset of insulin resistance in VCD-treated mice. Thus, the VCD model of menopause provides a physiologically relevant means of studying how sex hormones influence the progression of the metabolic syndrome.

  3. Final Technical Report

    Energy Technology Data Exchange (ETDEWEB)

    Schuur, Edward [Northern Arizona Univ., Flagstaff, AZ (United States); Luo, Yiqi [Univ. of Oklahoma, Norman, OK (United States)

    2016-12-01

    This final grant report is a continuation of the final grant report submitted for DE-SC0006982 as the Principle Investigator (Schuur) relocated from the University of Florida to Northern Arizona University. This report summarizes the original project goals, as well as includes new project activities that were completed in the final period of the project.

  4. Final Focus Test Stand final report

    CERN Document Server

    Jeremie, A; Burrows, P

    2013-01-01

    Future Linear colliders will need particle beam sizes in the nanometre range. The beam also needs to be stable all along the beam line and especially at the Final Focus section. A dedicated Final Focus test stand has been used for this study and is comprised of several sub-parts. First there is the Stabilisation/Isolation system with sensors and actuators stabilizing down to sub-nanometre level. Then the Magnet itself needs to comply with very specific design constraints. In addition to the mechanical items, the beam can be stabilized acting on the trajectory directly and Beam-based controls have been developed and tested on different accelerator facilities.

  5. The design, construction and performance of the MICE target

    CERN Document Server

    Booth, C N; Howlett, L; Nicholson, R; Overton, E; Robinson, M; Smith, P J; Apollonio, M; Barber, G; Dobbs, A; Leaver, J; Long, K R; Shepherd, B; Adams, D; Capocci, E; McCarron, E; Tarrant, J

    2012-01-01

    The pion-production target that serves the MICE Muon Beam consists of a titanium cylinder that is dipped into the halo of the ISIS proton beam. The design and construction of the MICE target system are described along with the quality-assurance procedures, electromagnetic drive and control systems, the readout electronics, and the data-acquisition system. The performance of the target is presented together with the particle rates delivered to the MICE Muon Beam. Finally, the beam loss in ISIS generated by the operation of the target is evaluated as a function of the particle rate, and the operating parameters of the target are derived.

  6. Cassini's Grand Finale: The Final Orbits

    Science.gov (United States)

    Spilker, Linda; Edgington, Scott

    2016-04-01

    The Cassini-Huygens mission, a joint collaboration between NASA, ESA and the Italian Space Agency, is approaching its last year of operations after nearly 12 years in orbit around Saturn. Cassini will send back its final bits of unique data on September 15th, 2017 as it plunges into Saturn's atmosphere, vaporizing and satisfying planetary protection requirements. Before that time Cassini will continue its legacy of exploration and discovery with 12 close flybys of Titan in 2016 and 2017 that will return new science data as well as sculpt the inclinations and periods of the final orbits. Even though all of our close icy satellite flybys, including those of Enceladus, are now completed, numerous Voyager-class flybys (summer solstice approaches. In November 2016 Cassini will transition to a series of orbits with peripases just outside Saturn's F ring. These 20 orbits will include close flybys of some tiny ring moons and excellent views of the F ring and outer A ring. The 126th and final close flyby of Titan will propel Cassini across Saturn's main rings and into its final orbits. Cassini's Grand Finale, starting in April 2017, is comprised of 22 orbits at an inclination of 63 degrees. Cassini will repeatedly dive between the innermost rings and the upper atmosphere of the planet providing insights into fundamental questions unattainable during the rest of the mission. Cassini will be the first spacecraft to explore this region. These close orbits provide the highest resolution observations of both the rings and Saturn, and direct in situ sampling of the ring particles, composition, plasma, Saturn's exosphere and the innermost radiation belts. Saturn's gravitational field will be measured to unprecedented accuracy, providing information on the interior structure of the planet, winds in the outer layers of Saturn's atmosphere, and the mass distribution in the rings. Probing the magnetic field will give insight into the nature of the magnetic dynamo, telling us: why the

  7. The neuronal nitric oxide synthase inhibitor NANT blocks acetaminophen toxicity and protein nitration in freshly isolated hepatocytes.

    Science.gov (United States)

    Banerjee, Sudip; Melnyk, Stepan B; Krager, Kimberly J; Aykin-Burns, Nukhet; Letzig, Lynda G; James, Laura P; Hinson, Jack A

    2015-12-01

    3-Nitrotyrosine (3NT) in liver proteins of mice treated with hepatotoxic doses of acetaminophen (APAP) has been postulated to be causative in toxicity. Nitration is by a reactive nitrogen species formed from nitric oxide (NO). The source of the NO is unclear. iNOS knockout mice were previously found to be equally susceptible to APAP toxicity as wildtype mice and iNOS inhibitors did not decrease toxicity in mice or in hepatocytes. In this work we examined the potential role of nNOS in APAP toxicity in hepatocytes using the specific nNOS inhibitor NANT (10 µM)(N-[(4S)-4-amino-5-[(2-aminoethyl)amino]pentyl]-N'-nitroguanidinetris (trifluoroacetate)). Primary hepatocytes (1 million/ml) from male B6C3F1 mice were incubated with APAP (1mM). Cells were removed and assayed spectrofluorometrically for reactive nitrogen and oxygen species using diaminofluorescein (DAF) and Mitosox red, respectively. Cytotoxicity was determined by LDH release into media. Glutathione (GSH, GSSG), 3NT, GSNO, acetaminophen-cysteine adducts, NAD, and NADH were measured by HPLC. APAP significantly increased cytotoxicity at 1.5-3.0 h. The increase was blocked by NANT. NANT did not alter APAP mediated GSH depletion or acetaminophen-cysteine adducts in proteins which indicated that NANT did not inhibit metabolism. APAP significantly increased spectroflurometric evidence of reactive nitrogen and oxygen formation at 0.5 and 1.0 h, respectively, and increased 3NT and GSNO at 1.5-3.0 h. These increases were blocked by NANT. APAP dramatically increased NADH from 0.5-3.0 h and this increase was blocked by NANT. Also, APAP decreased the Oxygen Consumption Rate (OCR), decreased ATP production, and caused a loss of mitochondrial membrane potential, which were all blocked by NANT.

  8. Preclinical toxicology studies with the new dopamine agonist pergolide. Acute, subchronic, and chronic evaluations.

    Science.gov (United States)

    Francis, P C; Carlson, K H; Owen, N V; Adams, E R

    1994-03-01

    Pergolide (LY127809, CAS 66104-23-2), a dopamine agonist for the treatment of Parkinson's disease, was evaluated for toxicity in acute, subchronic, and chronic studies. Acute toxicity tests using oral, intravenous and intraperitoneal routes were conducted in rats, mice, rabbits, and dogs. The acute oral median lethal doses (MLD) ranged from 8.4 to 33.6 mg/kg in Wistar and Fischer 344 rats, and from 54.0 to 87.2 mg/kg in ICR mice. Oral doses of 20 and 25 mg/kg produced no mortality in rabbits or dogs, respectively. The MLD by the iv route ranged from 0.59 to 0.87 mg/kg for Fischer 344 rats and from 11.6 to 37.1 mg/kg for ICR mice. The predominant signs of toxicity in the acute studies included hyperactivity, poor grooming, ptosis, aggressive behavior, increased gnawing activity, tremors, convulsions, and emesis. In the subchronic and chronic studies, Fischer 344 rats, B6C3F1 mice, and beagle dogs were administered pergolide either by gavage or in the diet for up to 1 year. Daily doses in these studies ranged up to 20 mg/kg for rats, 45 mg/kg for mice, and 5 mg/kg for dogs. The predominant treatment-related effects seen in these studies were attributable to the pharmacologic activity of pergolide. These consisted primarily of CNS-mediated clinical signs in rats and dogs, weight loss or decreased weight gain, emesis in dogs, and inhibition of lysis of corpora lutea with a corresponding increase in the weight of the uterus and ovaries. Pergolide treatment was not associated with any specific target organ toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

  9. Aurora final report

    Energy Technology Data Exchange (ETDEWEB)

    Robert, Dross; Amedeo, Conti

    2013-12-06

    Final Technical report detailing the work done by Nuvera and its partners to fulfill the goals of the program "Transport Studies Enabling Efficiency Optimization of Cost-Competitive Fuel Cell Stacks" (a.k.a. AURORA)

  10. Final focus test beam

    Energy Technology Data Exchange (ETDEWEB)

    1991-03-01

    This report discusses the following: the Final Focus Test Beam Project; optical design; magnets; instrumentation; magnetic measurement and BPM calibration; mechanical alignment and stabilization; vacuum system; power supplies; control system; radiation shielding and personnel protection; infrastructure; and administration.

  11. Final focus nomenclature

    Energy Technology Data Exchange (ETDEWEB)

    Erickson, R.

    1986-08-08

    The formal names and common names for all devices in the final focus system of the SLC are listed. The formal names consist of a device type designator, microprocessor designator, and a four-digit unit number. (LEW)

  12. Transacsys PLC - Final Results

    CERN Multimedia

    2002-01-01

    Final results from Transacsys PLC. A subsidary of this company was set up to develop the CERN EDH system into a commercial product but incurred too much financial loss so the project was cancelled (1/2 page).

  13. WMO Marine Final Reports

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Final reports of the World Meteorological Organization (WMO) Commission for Marine Meteorology, Commission for Synoptic Meteorology, and Commission for Basic...

  14. Peripheral surgical wounding and age-dependent neuroinflammation in mice.

    Directory of Open Access Journals (Sweden)

    Zhipeng Xu

    Full Text Available Post-operative cognitive dysfunction is associated with morbidity and mortality. However, its neuropathogenesis remains largely to be determined. Neuroinflammation and accumulation of β-amyloid (Aβ have been reported to contribute to cognitive dysfunction in humans and cognitive impairment in animals. Our recent studies have established a pre-clinical model in mice, and have found that the peripheral surgical wounding without the influence of general anesthesia induces an age-dependent Aβ accumulation and cognitive impairment in mice. We therefore set out to assess the effects of peripheral surgical wounding, in the absence of general anesthesia, on neuroinflammation in mice with different ages. Abdominal surgery under local anesthesia was established in 9 and 18 month-old mice. The levels of tumor necrosis factor-α (TNF-α, interleukin-6 (IL-6, Iba1 positive cells (the marker of microglia activation, CD33, and cognitive function in mice were determined. The peripheral surgical wounding increased the levels of TNF-α, IL-6, and Iba1 positive cells in the hippocampus of both 9 and 18 month-old mice, and age potentiated these effects. The peripheral surgical wounding increased the levels of CD33 in the hippocampus of 18, but not 9, month-old mice. Finally, anti-inflammatory drug ibuprofen ameliorated the peripheral surgical wounding-induced cognitive impairment in 18 month-old mice. These data suggested that the peripheral surgical wounding could induce an age-dependent neuroinflammation and elevation of CD33 levels in the hippocampus of mice, which could lead to cognitive impairment in aged mice. Pending further studies, anti-inflammatory therapies may reduce the risk of postoperative cognitive dysfunction in elderly patients.

  15. Data breaches. Final rule.

    Science.gov (United States)

    2008-04-11

    This document adopts, without change, the interim final rule that was published in the Federal Register on June 22, 2007, addressing data breaches of sensitive personal information that is processed or maintained by the Department of Veterans Affairs (VA). This final rule implements certain provisions of the Veterans Benefits, Health Care, and Information Technology Act of 2006. The regulations prescribe the mechanisms for taking action in response to a data breach of sensitive personal information.

  16. CLIC Final Focus Studies

    CERN Document Server

    Tomás, R; Schulte, Daniel; Zimmermann, Frank

    2006-01-01

    The CLIC final focus system has been designed based on the local compensation scheme proposed by P. Raimondi and A. Seryi. However, there exist important chromatic aberrations that deteriorate the performance of the system. This paper studies the optimization of the final focus based on the computation of the higher orders of the map using MAD-X and PTC. The use of octupole tail folding to reduce the size of the halo in the locations with aperture limitations is also discussed.

  17. MICE Particle Identification System

    CERN Document Server

    Bogomilov, M

    2010-01-01

    The Muon Ionization Cooling Experiment, MICE, at the ISIS accelerator lo- cated at the Rutherford Appleton Laboratory, UK, will be the first experiment to study muon cooling at high precision. Demonstration of muon ionization cooling is an essential step towards the construction of a neutrino factory or a muon collider. Muons are produced by pion decay in a superconducting solenoid and reach MICE with a range of emittances and momenta. The purity of the muon beam is ensured by a system of particle detectors we will briefly describe here.

  18. Nod2 mediates susceptibility to Yersinia pseudotuberculosis in mice.

    Directory of Open Access Journals (Sweden)

    Ulrich Meinzer

    Full Text Available Nucleotide oligomerisation domain 2 (NOD2 is a component of the innate immunity known to be involved in the homeostasis of Peyer patches (PPs in mice. However, little is known about its role during gut infection in vivo. Yersinia pseudotuberculosis is an enteropathogen causing gastroenteritis, adenolymphitis and septicaemia which is able to invade its host through PPs. We investigated the role of Nod2 during Y. pseudotuberculosis infection. Death was delayed in Nod2 deleted and Crohn's disease associated Nod2 mutated mice orogastrically inoculated with Y. pseudotuberculosis. In PPs, the local immune response was characterized by a higher KC level and a more intense infiltration by neutrophils and macrophages. The apoptotic and bacterial cell counts were decreased. Finally, Nod2 deleted mice had a lower systemic bacterial dissemination and less damage of the haematopoeitic organs. This resistance phenotype was lost in case of intraperitoneal infection. We concluded that Nod2 contributes to the susceptibility to Y. pseudotuberculosis in mice.

  19. Mechanistic Investigation of Toxaphene Induced Mouse Liver Tumors.

    Science.gov (United States)

    Wang, Zemin; Neal, Barbara H; Lamb, James C; Klaunig, James E

    2015-10-01

    Chronic exposure to toxaphene resulted in an increase in liver tumors in B6C3F1 mice. This study was performed to investigate the mode of action of toxaphene induced mouse liver tumors. Following an initial 14 day dietary dose range-finding study in male mice, a mechanistic study (0, 3, 32, and 320 ppm toxaphene in diet for 7, 14, and 28 days of treatment) was performed to examine the potential mechanisms of toxaphene induced mouse liver tumors. Toxaphene induced a significant increase in expression of constitutive androstane receptor (CAR) target genes (Cyp2b10, Cyp3a11) at 32 and 320 ppm toxaphene. aryl hydrocarbon receptor (AhR) target genes (Cyp1a1 and Cyp1a2) were slightly increased in expression at the highest toxaphene dose (320 ppm). No increase in peroxisome proliferator-activated receptor alpha activity or related genes was seen following toxaphene treatment. Lipid peroxidation was seen following treatment with 320 ppm toxaphene. These changes correlated with increases in hepatic DNA synthesis. To confirm the role of CAR in this mode of action, CAR knockout mice (CAR(-/-)) treated with toxaphene confirmed that the induction of CAR responsive genes seen in wild-type mice was abolished following treatment with toxaphene for 14 days. These findings, taken together with previously reported studies, support the mode of action of toxaphene induced mouse liver tumors is through a nongenotoxic mechanism involving primarily a CAR-mediated processes that results in an increase in cell proliferation in the liver, promotes the clonal expansion of preneoplastic lesions leading to adenoma formation.

  20. Acylcarnitine Profiles in Acetaminophen Toxicity in the Mouse: Comparison to Toxicity, Metabolism and Hepatocyte Regeneration

    Directory of Open Access Journals (Sweden)

    Jack Hinson

    2013-08-01

    Full Text Available High doses of acetaminophen (APAP result in hepatotoxicity that involves metabolic activation of the parent compound, covalent binding of the reactive intermediate N-acetyl-p-benzoquinone imine (NAPQI to liver proteins, and depletion of hepatic glutathione. Impaired fatty acid β-oxidation has been implicated in previous studies of APAP-induced hepatotoxicity. To better understand relationships between toxicity and fatty acid β-oxidation in the liver in APAP toxicity, metabolomic assays for long chain acylcarnitines were examined in relationship to established markers of liver toxicity, oxidative metabolism, and liver regeneration in a time course study in mice. Male B6C3F1 mice were treated with APAP (200 mg/kg IP or saline and sacrificed at 1, 2, 4, 8, 24 or 48 h after APAP. At 1 h, hepatic glutathione was depleted and APAP protein adducts were markedly increased. Alanine aminotransferase (ALT levels were elevated at 4 and 8 h, while proliferating cell nuclear antigen (PCNA expression, indicative of hepatocyte regeneration, was apparent at 24 h and 48 h. Elevations of palmitoyl, oleoyl and myristoyl carnitine were apparent by 2–4 h, concurrent with the onset of Oil Red O staining in liver sections. By 8 h, acylcarnitine levels were below baseline levels and remained low at 24 and 48 h. A partial least squares (PLS model suggested a direct association of acylcarnitine accumulation in serum to APAP protein adduct and hepatic glutathione levels in mice. Overall, the kinetics of serum acylcarnitines in APAP toxicity in mice followed a biphasic pattern involving early elevation after the metabolism phases of toxicity and later depletion of acylcarnitines.

  1. AGEMAP: a gene expression database for aging in mice.

    Directory of Open Access Journals (Sweden)

    Jacob M Zahn

    2007-11-01

    Full Text Available We present the AGEMAP (Atlas of Gene Expression in Mouse Aging Project gene expression database, which is a resource that catalogs changes in gene expression as a function of age in mice. The AGEMAP database includes expression changes for 8,932 genes in 16 tissues as a function of age. We found great heterogeneity in the amount of transcriptional changes with age in different tissues. Some tissues displayed large transcriptional differences in old mice, suggesting that these tissues may contribute strongly to organismal decline. Other tissues showed few or no changes in expression with age, indicating strong levels of homeostasis throughout life. Based on the pattern of age-related transcriptional changes, we found that tissues could be classified into one of three aging processes: (1 a pattern common to neural tissues, (2 a pattern for vascular tissues, and (3 a pattern for steroid-responsive tissues. We observed that different tissues age in a coordinated fashion in individual mice, such that certain mice exhibit rapid aging, whereas others exhibit slow aging for multiple tissues. Finally, we compared the transcriptional profiles for aging in mice to those from humans, flies, and worms. We found that genes involved in the electron transport chain show common age regulation in all four species, indicating that these genes may be exceptionally good markers of aging. However, we saw no overall correlation of age regulation between mice and humans, suggesting that aging processes in mice and humans may be fundamentally different.

  2. Colorful Kindergarten Mice

    Science.gov (United States)

    Bobick, Bryna; Wheeler, Elizabeth

    2008-01-01

    Developing kindergarten lessons can be very challenging, especially at the beginning of the school year when many students are just learning to cut paper and hold crayons. The author's favorite beginning unit of the year is "mice paintings," a practical introduction to drawing, color theory, and painting. This unit also incorporates children's…

  3. Bone marrow transplantation. [Mice, gamma radiation

    Energy Technology Data Exchange (ETDEWEB)

    Storb, R.; Santos, G.W.

    1979-03-01

    Bone marrow transplantation has been increasingly used to treat patients with severe combined immunodeficiency diseases, severe aplastic anemia, and malignant hematologic diseases, especially leukemia. At the Workshop a number of problems were discussed, e.g., conditioning regimens aimed at overcoming the problem of marrow graft rejection and reducing the incidence of recurrent leukemia, prevention of graft-versus-host disease (GVHD), possible mechanisms involved in stable graft-host tolerance, graft-versus-leukemia effect in mice, and finally, the possible use of autologous marrow transplantation.

  4. Mice Drawer System

    Science.gov (United States)

    Cancedda, Ranieri

    2008-01-01

    The Mice Drawer System (MDS) is an Italian Space Agency (ASI) facility which is able to support mice onboard the International Space Station during long-duration exploration missions (from 100 to 150-days) by living space, food, water, ventilation and lighting. Mice can be accommodated either individually (maximum 6) or in groups (4 pairs). MDS is integrated in the Space Shuttle middeck during transportation (uploading and downloading) to the ISS and in an EXPRESS Rack in Destiny, the US Laboratory during experiment execution. Osteoporosis is a debilitating disease that afflicts millions of people worldwide. One of the physiological changes experienced by astronauts during space flight is the accelerated loss of bone mass due to the lack of gravitational loading on the skeleton. This bone loss experienced by astronauts is similar to osteoporosis in the elderly population. MDS will help investigate the effects of unloading on transgenic (foreign gene that has been inserted into its genome to exhibit a particular trait) mice with the Osteoblast Stimulating Factor-1, OSF-1, a growth and differentiation factor, and to study the genetic mechanisms underlying the bone mass pathophysiology. MDS will test the hypothesis that mice with an increased bone density are likely to be more protected from osteoporosis, when the increased bone mass is a direct effect of a gene involved in skeletogenesis (skeleton formation). Osteoporosis is a debilitating disease that afflicts millions worldwide. One of the physiological changes experienced by astronauts during space flight is the accelerated loss of bone mass due to the lack of gravitational loading on the skeleton, a loss that is similar to osteoporosis in the elderly population on Earth. Osteoblast Stimulating Factor-1 (OSF-1), also known as pleiotrophin (PTN) or Heparin-Binding Growth- Associated Molecule (HB-GAM) belongs to a family of secreted heparin binding proteins..OSF-1 is an extracellular matrix-associated growth and

  5. Final Technical Report

    Energy Technology Data Exchange (ETDEWEB)

    Gilbert, Chris [Altamont Environmental, Inc.

    2014-11-13

    The project, Capital Investment to Fund Equipment Purchases and Facility Modifications to Create a Sustainable Future for EnergyXchange served to replace landfill gas energy with alternative energy resources, primarily solar and wood waste. This is the final project closeout report.

  6. CAFE Project : final report

    NARCIS (Netherlands)

    Weber, A.; Carter, R.; Stanford, C.J.; Weber, A.

    2003-01-01

    [MAS E-0302] This is the final public report of the CAFE project (ESPRIT 7023). CAFE developed a secure conditional access architecture and implemented a multi-currency electronic purse system based on smart cards and infrared wallets. The electronic purse was tested in user trials at the European C

  7. Neuroglobin over expressing mice

    DEFF Research Database (Denmark)

    Raida, Zindy; Hundahl, Christian Ansgar; Nyengaard, Jens R

    2013-01-01

    BACKGROUND: Stroke is a major cause of death and severe disability, but effective treatments are limited. Neuroglobin, a neuronal heme-globin, has been advocated as a novel pharmacological target in combating stroke and neurodegenerative disorders based on cytoprotective properties. Using...... thoroughly validated antibodies and oligos, we give a detailed brain anatomical characterization of transgenic mice over expressing Neuroglobin. Moreover, using permanent middle artery occlusion the effect of elevated levels of Neuroglobin on ischemic damage was studied. Lastly, the impact of mouse strain...... genetic background on ischemic damage was investigated. PRINCIPAL FINDINGS: A four to five fold increase in Neuroglobin mRNA and protein expression was seen in the brain of transgenic mice. A β-actin promoter was used to drive Neuroglobin over expression, but immunohistochemistry and in situ hybridization...

  8. The MICE PID Instrumentation

    CERN Document Server

    Bonesini, M

    2008-01-01

    The international Muon Ionization Cooling Experiment (MICE) will carry out a systematic investigation of ionization cooling of a muon beam. As the emittance measurement will be done on a particle-by-particle basis, sophisticated beam instrumentation is needed to measure particle coordinates and timing vs RF. A PID system based on three time-of-flight stations, two Aerogel Cerenkov detectors and a KLOE-like calorimeter has been constructed in order to keep beam contamination ($e, \\pi$) well below 1%. The MICE time-of-flight system will measure timing with a resolution better than 70 ps per plane, in a harsh environment due to high particle rates, fringe magnetic fields and electron backgrounds from RF dark current.

  9. Final Technical Report

    Energy Technology Data Exchange (ETDEWEB)

    Maxwell, Mike, J., P.E.

    2012-08-30

    The STI product is the Final Technical Report from ReliOn, Inc. for contract award DE-EE0000487: Recovery Act PEM Fuel Cell Systems Providing Emergency Reserve and Backup Power. The program covered the turnkey deployment of 431 ReliOn fuel cell systems at 189 individual sites for AT&T and PG&E with ReliOn functioning as the primary equipment supplier and the project manager. The Final Technical Report provides an executive level summary, a comparison of the actual accomplishments vs. the goals and objectives of the project, as well as a summary of the project activity from the contract award date of August 1, 2009 through the contract expiration date of December 31, 2011. Two photos are included in the body of the report which show hydrogen storage and bulk hydrogen refueling technologies developed as a result of this program.

  10. Geolocation Technologies Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Magnoli, D E

    2003-06-02

    This paper is the final report for LL998 In Situ Sensing Subtask 7 (Geo-location) undertaken for NNSA NA-22 enabling technologies R&D for Counterproliferation Detection. A few state-of-the-art resolution parameters are presented for accelerometers, indoor and outdoor GPS (Global Positioning Satellite) systems, and INSs (Inertial Navigation Systems). New technologies are described, including one which has demonstrated the ability to track within a building to a resolution of under a foot.

  11. CMS Is Finally Completed

    CERN Multimedia

    2008-01-01

    Yet another step in the completion of the Large Hadron Collider was taken yesterday morning, as the final element of the Compact Muon Solenoid was lowered nearly 100 meters bellow ground. After more than eight years of work at the world's most powerful particle accelerator, scientists hope that they will be able to start initial experiments with the LHC until the end of this year.

  12. Catarse e Final Feliz

    Directory of Open Access Journals (Sweden)

    Myriam Ávila

    2001-12-01

    Full Text Available Resumo: É a certeza de que nada mais – ou nada importante – pode acontecer após o final de um conto que permite o acontecimento da catarse. Se na maioria das narrativas existe algum tipo de dénouement, em algumas delas isso acontece de maneira especialmente satisfatória e afirmativa. O conto de fadas é uma dessas formas narrativas onde o efeito catártico é extremo e preenche objetivos específicos, de acordo com Bruno Bettelheim. Hollywood mimetizou essa forma como estratégia de sedução, iniciando a tradição do final feliz no cinema. A partir do conto de fadas Cinderela, em diferentes versões, juntamente com a animação homônima da Disney e ainda duas versões do filme Sabrina, será traçada aqui uma relação entre a catarse e o final feliz nos contos de fada, bem como seu uso pela indústria cultural. Palavras-chave: catarse, contos de fada, Hollywood

  13. Schedulability Analysis for Java Finalizers

    DEFF Research Database (Denmark)

    Bøgholm, Thomas; Hansen, Rene Rydhof; Ravn, Anders P.;

    2010-01-01

    Java finalizers perform clean-up and finalisation of objects at garbage collection time. In real-time Java profiles the use of finalizers is either discouraged (RTSJ, Ravenscar Java) or even disallowed (JSR-302), mainly because of the unpredictability of finalizers and in particular their impact ...... programs. Finally, we extend the SARTS tool for automated schedulability analysis of Java bytecode programs to handle finalizers in a fully automated way.......Java finalizers perform clean-up and finalisation of objects at garbage collection time. In real-time Java profiles the use of finalizers is either discouraged (RTSJ, Ravenscar Java) or even disallowed (JSR-302), mainly because of the unpredictability of finalizers and in particular their impact...... on the schedulability analysis. In this paper we show that a controlled scoped memory model results in a structured and predictable execution of finalizers, more reminiscent of C++ destructors than Java finalizers. Furthermore, we incorporate finalizers into a (conservative) schedulability analysis for Predictable Java...

  14. Extracellular signal-regulated kinases 1/2 and Akt contribute to triclosan-stimulated proliferation of JB6 Cl 41-5a cells.

    Science.gov (United States)

    Wu, Yuanfeng; Beland, Frederick A; Chen, Si; Fang, Jia-Long

    2015-08-01

    Triclosan is a broad spectrum anti-bacterial agent widely used in many personal care products, household items, medical devices, and clinical settings. Human exposure to triclosan is mainly through oral and dermal routes. In previous studies, we found that sub-chronic dermal exposure of B6C3F1 mice to triclosan induced epidermal hyperplasia and focal necrosis; however, the mechanisms for these responses remain elusive. In this study, using mouse epidermis-derived JB6 Cl 41-5a cells, we found that triclosan stimulated cell growth in a concentration- and time-dependent manner. Enhanced cell proliferation was demonstrated by a substantial increase in the percentage of BrdU-positive cells, an elevation in the protein levels of cyclin D1 and cyclin A, and a reduction in the protein level of p27(Kip1). Western blotting analysis revealed that triclosan induced the activation of extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinases (JNK), p38, and Akt. Pre-treatment of the cells with PD184352, an inhibitor of the upstream kinase MEK1/2, or with wortmannin, an inhibitor of phosphoinositide 3-kinase, blocked triclosan-mediated phosphorylation of ERK1/2 and Akt, respectively, and substantially suppressed triclosan-stimulated cell proliferation, whereas the JNK inhibitor SP600125 or the p38 inhibitor SB203580 had little to no effect on triclosan-stimulated cell proliferation. The phosphorylation activation of ERK1/2 and Akt was further confirmed on the skin of mice dermally administered triclosan. These data suggest that the activation of ERK1/2 and Akt is involved in triclosan-stimulated proliferation of JB6 Cl 41-5a cells.

  15. A water-soluble extract from cultured medium of Ganoderma lucidum (Reishi) mycelia attenuates the small intestinal injury induced by anti-cancer drugs.

    Science.gov (United States)

    Kashimoto, Naoki; Ishii, Satomi; Myojin, Yuki; Ushijima, Mitsuyasu; Hayama, Minoru; Watanabe, Hiromitsu

    2010-01-01

    The present study investigated whether a water-soluble extract from the culture medium of Ganoderma lucidum (Reishi) mycelia (MAK) is able to protect the small intestine against damage induced by anti-cancer drugs. Six-week-old male B6C3F1/Crlj mice were fed a basal diet (MF) alone or with various doses of MAK or Agarics blazei Murrill (AGA) beginning one week before treatment with the anti-cancer drugs. Mice were sacrificed 3.5 days after injection of the anti-cancer drug, the small intestine was removed and tissue specimens were examined for the regeneration of small intestinal crypts. In experiment 1, the number of regenerative crypts after the administration of 5-fluorouracil (5FU) intravenously (250 mg/kg) or intraperitoneally (250 or 500 mg/kg) was compared after treatment with MAK or AGA. MAK protected against 5FU-induced small intestinal injury whereas AGA did not. In experiment 2, we investigated the protective effect of MAK against small intestinal injury induced by the anti-cancer drugs: UFT (tegafur with uracil; 1,000 mg/kg, orally), cisplatin (CDDP; 12.5 and 25 mg/kg, intraperitoneally), cyclophosphamide (CPA; 250 mg/kg, orally) and gefitinib (Iressa; 2,000 and 4,000 mg/kg, orally). UFT and CDDP decreased the number of regenerative crypts, but treatment with MAK attenuated the extent of UFT- or CDDP-induced small intestinal injury. CPA or Iressa plus MAK up-regulated crypt regeneration. The present results indicate that MAK ameliorates the small intestinal injury caused by several anti-cancer drugs, suggesting that MAK is a potential preventive agent against this common adverse effect of chemotherapy.

  16. Hepatic transcriptomic alterations for N,N-dimethyl-p-toluidine (DMPT) and p-toluidine after 5-day exposure in rats.

    Science.gov (United States)

    Dunnick, June K; Shockley, Keith R; Morgan, Daniel L; Brix, Amy; Travlos, Gregory S; Gerrish, Kevin; Michael Sanders, J; Ton, T V; Pandiri, Arun R

    2017-04-01

    N,N-dimethyl-p-toluidine (DMPT), an accelerant for methyl methacrylate monomers in medical devices, was a liver carcinogen in male and female F344/N rats and B6C3F1 mice in a 2-year oral exposure study. p-Toluidine, a structurally related chemical, was a liver carcinogen in mice but not in rats in an 18-month feed exposure study. In this current study, liver transcriptomic data were used to characterize mechanisms in DMPT and p-toluidine liver toxicity and for conducting benchmark dose (BMD) analysis. Male F344/N rats were exposed orally to DMPT or p-toluidine (0, 1, 6, 20, 60 or 120 mg/kg/day) for 5 days. The liver was examined for lesions and transcriptomic alterations. Both chemicals caused mild hepatic toxicity at 60 and 120 mg/kg and dose-related transcriptomic alterations in the liver. There were 511 liver transcripts differentially expressed for DMPT and 354 for p-toluidine at 120 mg/kg/day (false discovery rate threshold of 5 %). The liver transcriptomic alterations were characteristic of an anti-oxidative damage response (activation of the Nrf2 pathway) and hepatic toxicity. The top cellular processes in gene ontology (GO) categories altered in livers exposed to DMPT or p-toluidine were used for BMD calculations. The lower confidence bound benchmark doses for these chemicals were 2 mg/kg/day for DMPT and 7 mg/kg/day for p-toluidine. These studies show the promise of using 5-day target organ transcriptomic data to identify chemical-induced molecular changes that can serve as markers for preliminary toxicity risk assessment.

  17. Species and sex-dependent toxicokinetics of 1-bromopropane: the role of hepatic cytochrome P450 oxidation and glutathione (GSH).

    Science.gov (United States)

    Garner, C Edwin; Yu, X

    2014-07-01

    1. The objectives of the current studies were to evaluate the factors influencing the toxicokinetics of 1-bromopropane (1-BP) in rodents after intravenous (IV) and inhalation exposure. 2. F-344 rats were administered 1-BP via IV bolus injection at 5 and 20 mg/kg and blood concentration determined versus time. F-344 rats and B6C3F1 mice were also exposed to starting inhalation concentrations 70, 240, 800 and 2700 ppm 1-BP in a closed gas uptake system and chamber 1-BP levels were monitored for 6 h. Plasma bromide concentrations were determined to estimate total metabolized dose. Rats were pretreated with chemical inhibitors of cytochrome P450 and glutathione (GSH) synthesis, prior to exposure to 1-BP at 800 ppm within inhalation chambers. 3. Systemic clearance of 1-BP in rat was rapid and decreased with increasing dose. As inhalation chamber concentration of 1-BP increased, the terminal elimination rates decreased. Half-life of 1-BP in rats following inhibition of P450 (9.6 h) or depletion of GSH (4.1 h) increased relative to controls (2.0 h) at 800 ppm. The percentage of 1-BP metabolized decreased with increasing inhalation exposure. Hepatic levels of GSH were significantly lowered regardless of the exposure level in both rats and mice. Chamber concentration-time curves were fit to a two compartment model which was used to estimate metabolic rate constants. 4. These data suggest that in rat, 1-BP clearance is saturable and that elimination is highly dependent on both P450 and GSH-dependent metabolism. This investigation in rodents may provide an understanding of interspecies differences in toxicokinetics and eventually aid translation of animal studies to human risk assessment.

  18. Experimental Granulomatous Pulmonary Nocardiosis in BALB/C Mice

    Science.gov (United States)

    Mifuji Lira, Roque M.; Limón Flores, Alberto Yairh; Salinas Carmona, Mario César

    2016-01-01

    Pulmonary nocardiosis is a granulomatous disease with high mortality that affects both immunosuppressed and immunocompetent patients. The mechanisms leading to the establishment and progression of the infection are currently unknown. An animal model to study these mechanisms is sorely needed. We report the first in vivo model of granulomatous pulmonary nocardiosis that closely resembles human pathology. BALB/c mice infected intranasally with two different doses of GFP-expressing Nocardia brasiliensis ATCC700358 (NbGFP), develop weight loss and pulmonary granulomas. Mice infected with 109 CFUs progressed towards death within a week while mice infected with 108 CFUs died after five to six months. Histological examination of the lungs revealed that both the higher and lower doses of NbGFP induced granulomas with NbGFP clearly identifiable at the center of the lesions. Mice exposed to 108 CFUs and subsequently to 109 CFUs were not protected against disease severity but had less granulomas suggesting some degree of protection. Attempts to identify a cellular target for the infection were unsuccessful but we found that bacterial microcolonies in the suspension used to infect mice were responsible for the establishment of the disease. Small microcolonies of NbGFP, incompatible with nocardial doubling times starting from unicellular organisms, were identified in the lung as early as six hours after infection. Mice infected with highly purified unicellular preparations of NbGFP did not develop granulomas despite showing weight loss. Finally, intranasal delivery of nocardial microcolonies was enough for mice to develop granulomas with minimal weight loss. Taken together these results show that Nocardia brasiliensis microcolonies are both necessary and sufficient for the development of granulomatous pulmonary nocardiosis in mice. PMID:27303806

  19. Experimental Granulomatous Pulmonary Nocardiosis in BALB/C Mice.

    Directory of Open Access Journals (Sweden)

    Roque M Mifuji Lira

    Full Text Available Pulmonary nocardiosis is a granulomatous disease with high mortality that affects both immunosuppressed and immunocompetent patients. The mechanisms leading to the establishment and progression of the infection are currently unknown. An animal model to study these mechanisms is sorely needed. We report the first in vivo model of granulomatous pulmonary nocardiosis that closely resembles human pathology. BALB/c mice infected intranasally with two different doses of GFP-expressing Nocardia brasiliensis ATCC700358 (NbGFP, develop weight loss and pulmonary granulomas. Mice infected with 109 CFUs progressed towards death within a week while mice infected with 108 CFUs died after five to six months. Histological examination of the lungs revealed that both the higher and lower doses of NbGFP induced granulomas with NbGFP clearly identifiable at the center of the lesions. Mice exposed to 108 CFUs and subsequently to 109 CFUs were not protected against disease severity but had less granulomas suggesting some degree of protection. Attempts to identify a cellular target for the infection were unsuccessful but we found that bacterial microcolonies in the suspension used to infect mice were responsible for the establishment of the disease. Small microcolonies of NbGFP, incompatible with nocardial doubling times starting from unicellular organisms, were identified in the lung as early as six hours after infection. Mice infected with highly purified unicellular preparations of NbGFP did not develop granulomas despite showing weight loss. Finally, intranasal delivery of nocardial microcolonies was enough for mice to develop granulomas with minimal weight loss. Taken together these results show that Nocardia brasiliensis microcolonies are both necessary and sufficient for the development of granulomatous pulmonary nocardiosis in mice.

  20. Glucocorticoid-like effects of antihepatocarcinogen Rotenone are mediated via enhanced serum corticosterone levels: Molecular Fitting and Receptor Activation Studies

    Directory of Open Access Journals (Sweden)

    Youssef Jihan

    2003-02-01

    Full Text Available Abstract Background Recent studies suggest that rotenone alters cell signal transduction pathways in a manner similar to glucocorticoids. Histological and biochemical markers of glucocorticoid effects in vivo, evaluated in our laboratories, provide further evidence for similarities in the activity of glucocorticoids and rotenone. The purpose of this study was to investigate the mechanism by which rotenone produces glucocorticoid-like effects. Methods Male B6C3F1 mice were treated for 7 days with rotenone (600 ppm in diet, the glucocorticoid antagonist RU486 (2 mg/kg/day, ip, corticosterone (2 mg/kg/day, ip, or both rotenone and RU 486. Control mice received drug-free diet and the vehicle (corn oil, ip. Following preservation in 10% neutral buffered formalin, tissues were embedded in paraffin. Sections were stained with hematoxylin, eosin, and were examined by light microscopy. Tissue sections were processed for in situ enzymatic end labeling of 3'-hydroxy-DNA strand breaks, a measure of apoptosis. Corticosterone was quantified in sera, using a solid phase radioimmunoassay kit. Cells (cell line 1470.2 derived from C127 mouse mammary adenocarcinoma cells were transiently transfected with 5 μg of pLTRLuc and 1 μg of β-Galactosidase expression vectors using a BTX square-wave pulser at 155 V, 4 pulses (40 ms each. Cells were then treated with dexamethasone, rotenone, or a mixture of both for 6 hr, harvested and assayed for luciferase and β-Galactosidase activity. Using Root Mean Square (RMS fit analysis (Alchemy™, Tripose, Inc., St Louis, MO, we assessed possible structural similarities between rotenone and corticosterone, dehydrocorticosterone, glucocorticoid antagonists ZK 98.299, and RU 486. RMS fit was calculated by selecting three atoms in each of the molecules, followed by calculating the distance between these atoms. An RMS value of zero between two molecules indicates identical molecular characteristics. A positive value suggests

  1. MPD in Telomerase Null Mice

    Science.gov (United States)

    2007-09-01

    telomere dysfunctional mice will further fuel the genomic instability generated from progressive Figure 5 5FU treated telomere dysfunction bone...marrow has increased megakaryocytic colonies. Equal number of bone marrow cells from the 5FU treated mice of the various indicated cohorts are...We treated the cohorts of the G4 mTerc mutant mice with telomere dysfunction and normal G0 controls with 5FU at (50mg/kg body weight) once every

  2. Prometheus Project final report

    Science.gov (United States)

    Taylor, Randall

    2005-01-01

    This Final Report serves as an executive summary of the Prometheus Project's activities and deliverables from November 2002 through September 2005. It focuses on the challenges from a technical and management perspective, what was different and innovative about this project, and identifies the major options, decisions, and accomplishments of the Project team as a whole. However, the details of the activities performed by DOE NR and its contractors will be documented separately in accordance with closeout requirements of the DOE NR and consistent with agreements between NASA and NR.

  3. Service dogs. Final rule.

    Science.gov (United States)

    2012-09-05

    The Department of Veterans Affairs (VA) amends its regulations concerning veterans in need of service dogs. Under this final rule, VA will provide to veterans with visual, hearing, or mobility impairments benefits to support the use of a service dog as part of the management of such impairments. The benefits include assistance with veterinary care, travel benefits associated with obtaining and training a dog, and the provision, maintenance, and replacement of hardware required for the dog to perform the tasks necessary to assist such veterans.

  4. Final Technical Report

    Energy Technology Data Exchange (ETDEWEB)

    Sobecky, Patricia A; Taillefert, Martial

    2013-03-29

    This final technical report describes results and findings from a research project to examine the role of microbial phosphohydrolase enzymes in naturally occurring subsurface microorganisms for the purpose of promoting the immobilization of the radionuclide uranium through the production of insoluble uranium phosphate minerals. The research project investigated the microbial mechanisms and the physical and chemical processes promoting uranium biomineralization and sequestration in oxygenated subsurface soils. Uranium biomineralization under aerobic conditions can provide a secondary biobarrier strategy to immobilize radionuclides should the metal precipitates formed by microbial dissimilatory mechanisms remobilize due to a change in redox state.

  5. The PHENIX final texts

    Energy Technology Data Exchange (ETDEWEB)

    Vasile, A.; Fontaine, B.; Vanier, M.; Gauthe, P.; Pascal, V.; Prulhiere, G.; Jaecki, P.; Martin, L. [CEA Cadarache, 13 - Saint Paul lez Durance (France); Tenchine, D. [CEA Grenoble, 38 (France); Sauvage, J.F. [Electricite de France (EDF/SEPTEN), 69 - Villeurbanne (France); Dupraz, R.; Woaye Hune, A. [AREVA NP, 75 - Paris (France)

    2010-11-15

    The 250 MWe (140 MWe since 1993) PHENIX sodium cooled fast reactor was shut down on March 6, 2009. Before decommissioning, a final set of tests was performed during May 2009 - January 2010. These tests covered core physics, fuel behaviour and thermal-hydraulics areas. Detailed analysis of the tests results is ongoing. It will be used for the extension of the validation of ERANOS and DARWIN codes for core physics, TRIO{sub U} and CATHARE for thermal-hydraulics and GERMINAL for fuel behaviour. In addition, the program included 2 tests related to the comprehension of the four negative reactivity transients (AURN) experienced during the reactor operation in 1989 and 1990 and not yet fully explained. This was also a great opportunity to involve young engineers in the different processes like the design of the tests, their carrying out and the analysis of the results. The standard instrumentation of the reactor was completed by specifically designed devices. (authors)

  6. Final Progress Report

    Energy Technology Data Exchange (ETDEWEB)

    Josef Michl

    2011-10-31

    In this project we have established guidelines for the design on organic chromophores suitable for producing high triplet yields via singlet fission. We have proven their utility by identifying a chromophore of a structural class that had never been examined for singlet fission before, 1,3-diphenylisobenzofuran, and demonstrating in two independent ways that a thin layer of this material produces a triplet yield of 200% within experimental error. We have also designed a second chromophore of a very different type, again of a structural class that had not been examined for singlet fission before, and found that in a thin layer it produces a 70% triplet yield. Finally, we have enhanced the theoretical understanding of the quantum mechanical nature of the singlet fission process.

  7. DEWPOINT. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Riddle, R.A.

    1994-09-01

    The DEWPOINT (Directed Energy POwer INTegration) program was aimed at providing the large amounts of electric power required for a laser or accelerator based in space, or on an aircraft or satellite platform. This is our final report on our efforts as a part of this program which was cancelled before completion. This report summarizes the entire scope of effort funded by this program. It also includes some related information on cryogenically cooled microchannel heatsinks which was funded internally by LLNL. Specifically, the DEWPOINT program was to provide the electrical power for the proposed Neutral Particle Beam weapon system of the Strategic Defense Initiative. The Neutral Particle Beam called for a space-based accelerator driven by radio frequency power sources. The radio frequency solid-state power amplifiers generate waste heat which must be dissipated.

  8. AIPM Final Report

    Energy Technology Data Exchange (ETDEWEB)

    John Mookken

    2006-06-30

    The final AIPM project report consists of six sections. Each section includes information on the original AIPM project and extension work on the high temperature design. The first section (1) provides an overview of the program and highlights the significant targets to meet at the end of the program. The next section (2) summarizes the significant technical accomplishments by the SEMIKRON AIPM team during the course of the project. Greater technical details are provided in a collection of all the quarterly reports which can be found in the appendix. Section three (3) presents some the more significant technical data collected from technology demonstrators. Section four (4) analyzes the manufacturing cost or economic aspects of producing 100,000 units/yr. Section five (5) describes the commercialization efforts of the AIPM technology into the automotive market. The last section (6) recommends follow on work that will build on the efforts and achievements of the AIPM program.

  9. FINAL/ SCIENTIFIC TECHNICAL REPORT

    Energy Technology Data Exchange (ETDEWEB)

    McDonald, Henry; Singh, Suminderpal

    2006-08-28

    The overall objective of the Chattanooga fuel cell demonstrations project was to develop and demonstrate a prototype 5-kW grid-parallel, solid oxide fuel cell (SOFC) system that co-produces hydrogen, based on Ion America’s technology. The commercial viability of the 5kW SOFC system was tested by transporting, installing and commissioning the SOFC system at the Alternative Energy Laboratory at the University of Tennessee – Chattanooga. The system also demonstrated the efficiency and the reliability of the system running on natural gas. This project successfully contributed to the achievement of DOE technology validation milestones from the Technology Validation section of the Hydrogen, Fuel Cells and Infrastructure Technologies Program Multi-Year Research, Development and Demonstration Plan. Results of the project can be found in the final technical report.

  10. Final technical report

    DEFF Research Database (Denmark)

    Juhl, Thomas Winther; Nielsen, Jakob Skov

    This project entails research with the goal to extend laser cutting of steel based metals to thickness above 20 mm and laser powers in the 10 kW range, with adequate accuracy and economically viable cutting speeds. The technical approach is to develop mirror based cutting heads with truly coaxial....... Phase 2: Development of mirror based test cutting heads. Phase 3: Test and evaluation of the cutting heads on high power CO2 laser sources in the 6-12 kW power range. The test phase concentrates on cutting steels, applied in the heavy industry. In the first part of the project fundamental studies have...... gas jet chamber and laser beam path from the final focusing mirror. The project consists of three phases: Phase 1: Fundamental studies of cutting front mechanisms, beam propagation, nozzle design and chemical reactions in the cut kerf with special emphasize on high laser powers and thick sections...

  11. Final Technical Report

    Energy Technology Data Exchange (ETDEWEB)

    John Tanis

    2005-11-25

    This document comprises the final technical report for atomic collisions research supported by DOE grant No. DE-FG02-87ER13778 from September 1, 2001 through August 31, 2004. The research involved the experimental investigation of excitation and charge-changing processes occurring in ion-atom and ion-molecule collisions. Major emphases of the study were: (1) interference effects resulting from coherent electron emission in H2, (2) production of doubly vacant K-shell (hollow ion) states due to electron correlation, and (3) formation of long-lived metastable states in electron transfer processes. During the period of the grant, this research resulted in 23 publications, 12 invited presentations, and 39 contributed presentations at national and international meetings and other institutions. Brief summaries of the completed research are presented below.

  12. Humoral and cellular immune responses induced in mice by purified iridoid mixture that inhibits penetration of Schistosoma mansoni cercariae upon topical treatment of mice tails.

    Science.gov (United States)

    Bahgat, Mahmoud; Shalaby, Nagwa M M; Ruppel, Andreas; Maghraby, Amany S

    2005-08-01

    When tested for possible blocking effect on the cercarial, serine proteinase, elastase (CE) activity, an iridoid mixture extracted from leaves of Citharexylum quadrangular abolished 31% of the enzyme activity at final concentration 15 microg. When formulated in jojoba oil and applied to mice tails followed by infection with Schistosoma mansoni cercariae, the iridoid mixture blocked cercarial penetration and caused significant reducetion (94%; P < 0.05) in worm burden in treated mice in comparison to controls. Also, immunomodulatory effects of iridoid mixture, iridoid-treated S. mansoni worm homogenate on mice were studied by measuring IgG and IgM levels against E. coli lysates (ECL), solube S. mansoni worm antigenic preparation (SWAP) and cancer bladder homogenates (CBH) as antigens by ELISA. Cellular immune responses were studied by calculating mean percent of CD4+, CD8(+)-T, B-mesenteric lymph node cells (MLNC) and CD4+, CD8(+)-T thymocytes by direct immunofluorescence staining in treated mice as compared to untreated homogenate given mice or untreated mice. Injecting mice with serial dilutions of iridoid mixture resulted in fluctuation, peaks and troughs, in both IgG and IgM responses against the above mentioned antigens. 1st and 2nd immunizations with iridoid mixture treated homogenate resulted in significantly elevated (P < 0.05). IgM and IgG levels against the 3 used antigens in comparison with sera from control mice. Immunized mice with homogenate treated with iridoid mixture showed a significant increase (P < 0.05) in CD4+T thymocytes, a non significant increase in CD8+T thymocytes, a significant increase (P < 0.05) in CD4+T lymphocytes (MLNC) and a non significant increase in CD8+ T- and B-lymphocytes (MLNC) compared with mice immunized with untreated homogenate or non-injected normal mice.

  13. Final Technical Report

    Energy Technology Data Exchange (ETDEWEB)

    Aristos Aristidou Natureworks); Robert Kean (NatureWorks); Tom Schechinger (IronHorse Farms, Mat); Stuart Birrell (Iowa State); Jill Euken (Wallace Foundation & Iowa State)

    2007-10-01

    The two main objectives of this project were: 1) to develop and test technologies to harvest, transport, store, and separate corn stover to supply a clean raw material to the bioproducts industry, and 2) engineer fermentation systems to meet performance targets for lactic acid and ethanol manufacturers. Significant progress was made in testing methods to harvest corn stover in a “single pass” harvest mode (collect corn grain and stover at the same time). This is technically feasible on small scale, but additional equipment refinements will be needed to facilitate cost effective harvest on a larger scale. Transportation models were developed, which indicate that at a corn stover yield of 2.8 tons/acre and purchase price of $35/ton stover, it would be unprofitable to transport stover more than about 25 miles; thus suggesting the development of many regional collection centers. Therefore, collection centers should be located within about 30 miles of the farm, to keep transportation costs to an acceptable level. These collection centers could then potentially do some preprocessing (to fractionate or increase bulk density) and/or ship the biomass by rail or barge to the final customers. Wet storage of stover via ensilage was tested, but no clear economic advantages were evident. Wet storage eliminates fire risk, but increases the complexity of component separation and may result in a small loss of carbohydrate content (fermentation potential). A study of possible supplier-producer relationships, concluded that a “quasi-vertical” integration model would be best suited for new bioproducts industries based on stover. In this model, the relationship would involve a multiyear supply contract (processor with purchase guarantees, producer group with supply guarantees). Price will likely be fixed or calculated based on some formula (possibly a cost plus). Initial quality requirements will be specified (but subject to refinement).Producers would invest in harvest

  14. Schedulability Analysis for Java Finalizers

    DEFF Research Database (Denmark)

    Bøgholm, Thomas; Hansen, Rene Rydhof; Søndergaard, Hans

    2010-01-01

    Java finalizers perform clean-up and finalisation of objects at garbage collection time. In real-time Java profiles the use of finalizers is either discouraged (RTSJ, Ravenscar Java) or even disallowed (JSR-302), mainly because of the unpredictability of finalizers and in particular their impact...... on the schedulability analysis. In this paper we show that a controlled scoped memory model results in a structured and predictable execution of finalizers, more reminiscent of C++ destructors than Java finalizers. Furthermore, we incorporate finalizers into a (conservative) schedulability analysis for Predictable Java...... programs. Finally, we extend the SARTS tool for automated schedulability analysis of Java bytecode programs to handle finalizers in a fully automated way....

  15. Resilience in Aging Mice.

    Science.gov (United States)

    Kirkland, James L; Stout, Michael B; Sierra, Felipe

    2016-11-01

    Recently discovered interventions that target fundamental aging mechanisms have been shown to increase life span in mice and other species, and in some cases, these same manipulations have been shown to enhance health span and alleviate multiple age-related diseases and conditions. Aging is generally associated with decreases in resilience, the capacity to respond to or recover from clinically relevant stresses such as surgery, infections, or vascular events. We hypothesize that the age-related increase in susceptibility to those diseases and conditions is driven by or associated with the decrease in resilience. Thus, a test for resilience at middle age or even earlier could represent a surrogate approach to test the hypothesis that an intervention delays the process of aging itself. For this, animal models to test resilience accurately and predictably are needed. In addition, interventions that increase resilience might lead to treatments aimed at enhancing recovery following acute illnesses, or preventing poor outcomes from medical interventions in older, prefrail subjects. At a meeting of basic researchers and clinicians engaged in research on mechanisms of aging and care of the elderly, the merits and drawbacks of investigating effects of interventions on resilience in mice were considered. Available and potential stressors for assessing physiological resilience as well as the notion of developing a limited battery of such stressors and how to rank them were discussed. Relevant ranking parameters included value in assessing general health (as opposed to focusing on a single physiological system), ease of use, cost, reproducibility, clinical relevance, and feasibility of being repeated in the same animal longitudinally. During the discussions it became clear that, while this is an important area, very little is known or established. Much more research is needed in the near future to develop appropriate tests of resilience in animal models within an aging context

  16. Final Project Report

    Energy Technology Data Exchange (ETDEWEB)

    Hood, Elizabeth E

    2017-03-27

    The purpose of this project was to develop technology that would facilitate production of sugars from agricultural residues to enable biofuels and biobased product manufacturing. Our primary technology is to use genetic engineering to put bacterial and fungal cellulase genes into corn kernels, using the grain as the production system for the enzymes. At the beginning of this DoE funded program, we were producing two cellulases—E1 endocellulase from a bacterium found in a hot spring at Yellowstone National Park, and CBH I exocellulase from a wood rot fungus. Our team developed several new regulatory sequences (promoters) that increased enzyme protein accumulation in two kernel compartments (embryo and endosperm). We were also able to capitalize on the diverse genetics of corn to increase protein accumulation. High oil germplasm in particular was instrumental in this increase. A second task in the program was to produce enzymes and proteins that enhanced the activity of the E1 and CBH I enzymes. Our team produced CBH II, from the same wood rot fungus at a level that enabled highly enhanced deconstruction activity of E1 and CBH I in a synergistic manner. We analyzed an additional protein, expansin from cucumber that was expressed in the maize grain expression system. This protein had been previously shown to enhance cellulase activity (D. Cosgrove, Penn State University), and required a large-scale production platform. Our team showed that the corn production system allows industrial amounts of active expansin to be harvested from the grain. One of the challenges of any new production system is to maximize recovery of active ingredient from the raw materials at a cost compatible with its final use. Our team showed that low pH extraction of grain solubilized the enzymes without contamination of native corn protein and active product could be concentrated through ultrafiltration. The final outcomes of this project were the following: 3 cellulase enzymes and the

  17. Health effects from exposure to atmospheric mineral dust near Las Vegas, NV, USA

    Directory of Open Access Journals (Sweden)

    Deborah E. Keil

    2016-01-01

    Full Text Available Desert areas are usually characterized by a continuous deposition of fine airborne particles. Over time, this process results in the accumulation of silt and clay on desert surfaces. We evaluated health effects associated with regional atmospheric dust, or geogenic dust, deposited on surfaces in the Nellis Dunes Recreation Area (NDRA in Clark County, Nevada, a popular off-road vehicle (ORV recreational site frequented daily by riders, families, and day campers. Because of atmospheric mixing and the mostly regional origin of the accumulated particles, the re-suspended airborne dust is composed of a complex mixture of minerals and metals including aluminum, vanadium, chromium, manganese, iron, cobalt, copper, zinc, arsenic, strontium, cesium, lead, uranium, and others. Geogenic dust with a median diameter of 4.1 μm was administered via oropharyngeal aspiration to female B6C3F1 mice at doses of 0.01 to 100 mg dust/kg body weight, four times, a week apart, for 28-days. Immuno- and neurotoxicological outcomes 24 h following the last exposure were evaluated. Antigen-specific IgM responses were dose-responsively suppressed at 0.1, 1.0, 10 and 100 mg/kg/day. Splenic and thymic lymphocytic subpopulations and natural killer cell activity also were significantly reduced. Antibodies against MBP, NF-68, and GFAP were not affected, while brain CD3+ T cells were decreased in number. A lowest observed adverse effect level (LOAEL of 0.1 mg/kg/day and a no observed adverse effect level (NOAEL of 0.01 mg/kg/day were derived based on the antigen-specific IgM responses.

  18. Immunochemical quantitation of 3-(cystein-S-yl)acetaminophen protein adducts in subcellular liver fractions following a hepatotoxic dose of acetaminophen.

    Science.gov (United States)

    Pumford, N R; Roberts, D W; Benson, R W; Hinson, J A

    1990-08-01

    The hepatotoxicity of acetaminophen correlates with the formation of 3-(cystein-S-yl)acetaminophen protein adducts. Using a sensitive and specific immunochemical assay, we quantitated the formation of these protein adducts in liver fractions and serum after administration of a hepatotoxic dose of acetaminophen (400 mg/kg) to B6C3F1 mice. Adducts in the cytosolic fraction increased to 3.6 nmol/mg protein at 2 hr and then decreased to 1.1 nmol/mg protein by 8 hr. Concomitant with the decrease in adducts in the cytosol, 3-(cystein-S-yl)acetaminophen protein adducts appeared in serum and their levels paralleled increases in serum alanine aminotransferase. Microsomal protein adducts peaked at 1 hr (0.7 nmol/mg protein) and subsequently decreased to 0.2 nmol/mg at 8 hr. The 4000 g pellet (nuclei, plasma membranes, and cell debris) had the highest level of adducts (3.5 nmol/mg protein), which remained constant from 1 to 8 hr. Evaluation of fractions purified from a 960 g pellet indicated that the highest concentration of 3-(cystein-S-yl)acetaminophen protein adducts was located in plasma membranes and mitochondria; peak levels were 10.3 and 5.1 nmol/mg respectively. 3-(Cystein-S-yl)acetaminophen protein adducts were detected in nuclei only after enzymatic hydrolysis of the proteins. The localization of high levels of 3-(cystein-S-yl)acetaminophen protein adducts in plasma membranes and mitochondria may play a critical role in acetaminophen toxicity.

  19. Combined exposure to X-irradiation followed by N-ethyl-N-nitrosourea treatment alters the frequency and spectrum of Ikaros point mutations in murine T-cell lymphoma

    Energy Technology Data Exchange (ETDEWEB)

    Kakinuma, Shizuko, E-mail: skakinum@nirs.go.jp [Radiobiology for Children' s Health Research Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555 (Japan); Nishimura, Mayumi; Amasaki, Yoshiko; Takada, Mayumi; Yamauchi, Kazumi; Sudo, Satomi; Shang, Yi [Radiobiology for Children' s Health Research Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555 (Japan); Doi, Kazutaka; Yoshinaga, Shinji [Regulatory Sciences Research Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555 (Japan); Shimada, Yoshiya [Radiobiology for Children' s Health Research Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555 (Japan)

    2012-09-01

    Ionizing radiation is a well-known carcinogen, but its potency may be influenced by other environmental carcinogens, which is of practical importance in the assessment of risk. Data are scarce, however, on the combined effect of radiation with other environmental carcinogens and the underlying mechanisms involved. We studied the mode and mechanism of the carcinogenic effect of radiation in combination with N-ethyl-N-nitrosourea (ENU) using doses approximately equal to the corresponding thresholds. B6C3F1 mice exposed to fractionated X-irradiation (Kaplan's method) followed by ENU developed T-cell lymphomas in a dose-dependent manner. Radiation doses above an apparent threshold acted synergistically with ENU to promote lymphoma development, whereas radiation doses below that threshold antagonized lymphoma development. Ikaros, which regulates the commitment and differentiation of lymphoid lineage cells, is a critical tumor suppressor gene frequently altered in both human and mouse lymphomas and shows distinct mutation spectra between X-ray- and ENU-induced lymphomas. In the synergistically induced lymphomas, we observed a low frequency of LOH and an inordinate increase of Ikaros base substitutions characteristic of ENU-indcued point mutations, G:C to A:T at non-CpG, A:T to G:C, G:C to T:A and A:T to T:A. This suggests that radiation doses above an apparent threshold activate the ENU mutagenic pathway. This is the first report on the carcinogenic mechanism elicited by combined exposure to carcinogens below and above threshold doses based on the mutation spectrum of the causative gene. These findings constitute a basis for assessing human cancer risk following exposure to multiple carcinogens.

  20. The Phenix final tests

    Energy Technology Data Exchange (ETDEWEB)

    Vasile, A.; Fontaine, B.; Vanier, M.; Gauthe, P.; Pascal, V.; Prulhiere, G.; Jaecki, P. [CEA Cadarache, BP 1, 13108 St Paul Lez Durance (France); Tenchine, D. [CEA Grenoble (France); Martin, L. [Centrale Phenix - CEA Marcoule (France); Sauvage, J.F. [EDF / SEPTEN - 12 av. Dutrievoz 69628 Villeurbanne (France); Dupraz, R.; Woaye-Hune, A. [AREVA NP - 10 rue Juliette Recamier 69456 LYON Cedex (France)

    2010-07-01

    The 250 MWe (140 MWe since 1993) Phenix sodium cooled fast reactor was shut down on March 6, 2009. Before decommissioning, a final set of tests were performed during the May 2009 - January 2010 period covering core physics, fuel behaviour and thermal-hydraulics areas. Detailed analysis of the tests results is ongoing. It will be used for the extension of the validation of ERANOS and DARWIN codes for core physics, TRIO-U and CATHARE for Thermal-hydraulics and GERMINAL for fuel behaviour. In addition, the program included two tests related to the comprehension of the four negative reactivity transients (AURN in French acronym) experienced during the reactor operation in '89 and '90 and not yet fully explained. This was also a great opportunity to involve young engineers in the different processes like the design of the tests, their carrying out, and the analysis of the results. The standard instrumentation of the reactor was completed by specifically designed devises. (authors)

  1. Omega, the final multiplier

    Science.gov (United States)

    Buckley, T. N.

    2008-12-01

    The application of optimisation theory to vegetation processes has rarely extended beyond the context of diurnal to intra-annual gas exchange of individual leaves and crowns. One reason is that the Lagrange multipliers in the leaf-scale solutions, which are marginal products for allocatable photosynthetic resource inputs (water and nitrogen), are mysterious in origin, and their numerical values are difficult to measure -- let alone to predict or interpret in concrete physiological or ecological terms. These difficulties disappear, however, when the optimisation paradigm itself is extended to encompass carbon allocation and growth at the lifespan scale. The trajectories of leaf (and canopy) level marginal products are then implicit in the trajectory of plant and stand structure predicted by optimal carbon allocation. Furthermore, because the input and product are the same resource -- carbon -- in the whole plant optimisation, the product in one time step defines the input constraint, and hence implicitly the marginal product for carbon, in the next time step. This effectively converts the problem from a constrained optimisation of a definite integral, in which the multipliers are undetermined, to an unconstrained maximisation of a state, in which the multipliers are all implicit. This talk will explore how the marginal products for photosynthetic inputs as well as the marginal product for carbon -- i.e., the 'final multiplier,' omega -- are predicted to vary over time and in relation to environmental change during tree growth.

  2. Final Technical Report

    Energy Technology Data Exchange (ETDEWEB)

    Velasco, Mayda [Northwestern University

    2013-11-01

    This work is focused on the design and construction of novel beam diagnostic and instrumentation for charged particle accelerators required for the next generation of linear colliders. Our main interest is in non-invasive techniques. The Northwestern group of Velasco has been a member of the CLIC Test Facility 3 (CTF3) collaboration since 2003, and the beam instrumentation work is developed mostly at this facility1. This 4 kW electron beam facility has a 25-170 MeV electron LINAC. CTF3 performed a set of dedicated measurements to finalize the development of our RF-Pickup bunch length detectors. The RF-pickup based on mixers was fully commissioned in 2009 and the RF-pickup based on diodes was finished in time for the 2010-11 data taking. The analysis of all the data taken in by the summer of 2010 was finish in time and presented at the main conference of the year, LINAC 2010 in Japan.

  3. Tiger LDRD final report

    Energy Technology Data Exchange (ETDEWEB)

    Steich, D J; Brugger, S T; Kallman, J S; White, D A

    2000-02-01

    This final report describes our efforts on the Three-Dimensional Massively Parallel CEM Technologies LDRD project (97-ERD-009). Significant need exists for more advanced time domain computational electromagnetics modeling. Bookkeeping details and modifying inflexible software constitute a vast majority of the effort required to address such needs. The required effort escalates rapidly as problem complexity increases. For example, hybrid meshes requiring hybrid numerics on massively parallel platforms (MPPs). This project attempts to alleviate the above limitations by investigating flexible abstractions for these numerical algorithms on MPPs using object-oriented methods, providing a programming environment insulating physics from bookkeeping. The three major design iterations during the project, known as TIGER-I to TIGER-III, are discussed. Each version of TIGER is briefly discussed along with lessons learned during the development and implementation. An Application Programming Interface (API) of the object-oriented interface for Tiger-III is included in three appendices. The three appendices contain the Utilities, Entity-Attribute, and Mesh libraries developed during the project. The API libraries represent a snapshot of our latest attempt at insulated the physics from the bookkeeping.

  4. AIMES Final Technical Report

    Energy Technology Data Exchange (ETDEWEB)

    Katz, Daniel S [Univ. of Illinois, Urbana-Champaign, IL (United States). National Center for Supercomputing Applications (NCSA); Jha, Shantenu [Rutgers Univ., New Brunswick, NJ (United States); Weissman, Jon [Univ. of Minnesota, Minneapolis, MN (United States); Turilli, Matteo [Rutgers Univ., New Brunswick, NJ (United States)

    2017-01-31

    This is the final technical report for the AIMES project. Many important advances in science and engineering are due to large-scale distributed computing. Notwithstanding this reliance, we are still learning how to design and deploy large-scale production Distributed Computing Infrastructures (DCI). This is evidenced by missing design principles for DCI, and an absence of generally acceptable and usable distributed computing abstractions. The AIMES project was conceived against this backdrop, following on the heels of a comprehensive survey of scientific distributed applications. AIMES laid the foundations to address the tripartite challenge of dynamic resource management, integrating information, and portable and interoperable distributed applications. Four abstractions were defined and implemented: skeleton, resource bundle, pilot, and execution strategy. The four abstractions were implemented into software modules and then aggregated into the AIMES middleware. This middleware successfully integrates information across the application layer (skeletons) and resource layer (Bundles), derives a suitable execution strategy for the given skeleton and enacts its execution by means of pilots on one or more resources, depending on the application requirements, and resource availabilities and capabilities.

  5. Final Technical Report

    Energy Technology Data Exchange (ETDEWEB)

    Alexander Fridman

    2005-06-01

    This DOE project DE-FC36-04GO14052 ''Plasma Pilot Plant Test for Treating VOC Emissions from Wood Products Plants'' was conducted by Drexel University in cooperation with Georgia-Pacific (G-P) and Kurchatov Institute (KI). The objective of this project was to test the Plasma Pilot Plant capabilities in wood industry. The final goal of the project was to replace the current state-of-the-art, regenerative thermal oxidation (RTO) technology by Low-Temperature Plasma Technology (LTPT) in paper and wood industry for Volatile Organic Components (VOC) destruction in High Volume Low Concentration (HVLC) vent emissions. MetPro Corporation joined the team as an industrial partner from the environmental control business and a potential leader for commercialization. Concurrent Technology Corporation (CTC) has a separate contract with DOE for this technology evaluation. They prepared questionnaires for comparison of this technology and RTO, and made this comparison. These data are presented in this report along with the description of the technology itself. Experiments with the pilot plant were performed with average plasma power up to 3.6 kW. Different design of the laboratory and pilot plant pulsed coronas, as well as different analytical methods revealed many new peculiarities of the VOC abatement process. The work reported herein describes the experimental results for the VOCs removal efficiency with respect to energy consumption, residence time, water effect and initial concentration.

  6. Final Technical Report

    Energy Technology Data Exchange (ETDEWEB)

    Held, Isaac [Princeton Univ., NJ (United States); Balaji, V. [Princeton Univ., NJ (United States); Fueglistaler, Stephan [Princeton Univ., NJ (United States)

    2016-09-19

    We have constructed and analyzed a series of idealized models of tropical convection interacting with large-scale circulations, with 25-50km resolution and with 1-2km cloud resolving resolution to set the stage for rigorous tests of convection closure schemes in high resolution global climate models. Much of the focus has been on the climatology of tropical cyclogenesis in rotating systems and the related problem of the spontaneous aggregation of convection in non-rotating systems. The PI (Held) will be delivering the honorary Bjerknes lecture at the Fall 2016 AGU meeting in December on this work. We have also provided new analyses of long-standing issues related to the interaction between convection and the large-scale circulation: Kelvin waves in the upper troposphere and lower stratosphere, water vapor transport into the stratosphere, and upper tropospheric temperature trends. The results of these analyses help to improve our understanding of processes, and provide tests for future high resolution global modeling. Our final goal of testing new convections schemes in next-generation global atmospheric models at GFDL has been left for future work due to the complexity of the idealized model results meant as tests for these models uncovered in this work and to computational resource limitations. 11 papers have been published with support from this grant, 2 are in review, and another major summary paper is in preparation.

  7. Final Technical Report

    Energy Technology Data Exchange (ETDEWEB)

    Dmitriy Y. Anistratov; Marvin L. Adams; Todd S. Palmer; Kord S. Smith; Kevin Clarno; Hikaru Hiruta; Razvan Nes

    2003-08-04

    OAK B202 Final Technical Report. The present generation of reactor analysis methods uses few-group nodal diffusion approximations to calculate full-core eigenvalues and power distributions. The cross sections, diffusion coefficients, and discontinuity factors (collectively called ''group constants'') in the nodal diffusion equations are parameterized as functions of many variables, ranging from the obvious (temperature, boron concentration, etc.) to the more obscure (spectral index, moderator temperature history, etc.). These group constants, and their variations as functions of the many variables, are calculated by assembly-level transport codes. The current methodology has two main weaknesses that this project addressed. The first weakness is the diffusion approximation in the full-core calculation; this can be significantly inaccurate at interfaces between different assemblies. This project used the nodal diffusion framework to implement nodal quasidiffusion equations, which can capture transport effects to an arbitrary degree of accuracy. The second weakness is in the parameterization of the group constants; current models do not always perform well, especially at interfaces between unlike assemblies. The project developed a theoretical foundation for parameterization and homogenization models and used that theory to devise improved models. The new models were extended to tabulate information that the nodal quasidiffusion equations can use to capture transport effects in full-core calculations.

  8. MTX final report

    Energy Technology Data Exchange (ETDEWEB)

    Hooper, E.B. [ed.; Allen, S.L.; Brown, M.D.; Byers, J.A.; Casper, T.A.; Cohen, B.I.; Cohen, R.H.; Fenstermacher, M.E.; Foote, J.H.; Hoshino, K. [and others

    1994-01-01

    The MTX experiment was proposed in 1986 to apply high frequency microwaves generated by a free-electron laser (FEL) to electron cyclotron resonance heating (ECRH) in a high field, high density tokamak. As the absorption of microwaves at the electron cyclotron resonance requires high frequencies, the opportunity of applying a free-electron laser has appeal as the device is not limited to frequencies in the microwave or long millimeter wavelength regions, in contrast to many other sources. In addition, the FEL is inherently a high power source of microwaves, which would permit single units of 10 MW or more, optimum for reactors. Finally, it was recognized early in the study of the application of the FEL based on the induction linear accelerator, that the nonlinear effects associated with the intense pulses of microwaves naturally generated would offer several unique opportunities to apply ECRH to current drive, MHD control, and other plasma effects. It was consequently decided to adapt the induction accelerator based FEL to heating and controlling the tokamak, and to conduct experiments on the associated physics. To this end, the Alcator C tokamak was moved from the Massachusetts Institute of Technology (MIT) to the Lawrence Livermore National Laboratory where it was installed in Building 431 and operated from March, 1989, until the conclusion of the experiment in October, 1992. The FEL, based on the ETA-11 accelerator and IMP wiggler was brought into operation by the LLNL Electron Beam Group and power injected into the tokamak during an experimental run in the Fall, 1989. Following an upgrade by the MTX group, a second experimental run was made lasting from the Winter, 1992 through the end of the experiment. Significant contributions to the ECRH experiments were made by the Japan Atomic Energy Research Institute (JAERI).

  9. p53 suppresses tetraploid development in mice.

    Science.gov (United States)

    Horii, Takuro; Yamamoto, Masamichi; Morita, Sumiyo; Kimura, Mika; Nagao, Yasumitsu; Hatada, Izuho

    2015-03-10

    Mammalian tetraploid embryos die in early development because of defects in the epiblast. Experiments with diploid/tetraploid chimeric mice, obtained via the aggregation of embryonic stem cells, clarified that while tetraploid cells are excluded from epiblast derivatives, diploid embryos with tetraploid extraembryonic tissues can develop to term. Today, this method, known as tetraploid complementation, is usually used for rescuing extraembryonic defects or for obtaining completely embryonic stem (ES) cell-derived pups. However, it is still unknown why defects occur in the epiblast during mammalian development. Here, we demonstrated that downregulation of p53, a tumour suppressor protein, rescued tetraploid development in the mammalian epiblast. Tetraploidy in differentiating epiblast cells triggered p53-dependent cell-cycle arrest and apoptosis, suggesting the activation of a tetraploidy checkpoint during early development. Finally, we found that p53 downregulation rescued tetraploid embryos later in gestation.

  10. ASEDRA Evaluation Final Report.

    Energy Technology Data Exchange (ETDEWEB)

    Mitchell, Dean J; Detwiler, Dr. Rebecca; Sjoden, Dr, Glenn E.

    2008-09-01

    The performance of the Advanced Synthetically Enhanced Detector Resolution Algorithm (ASEDRA) was evaluated by performing a blind test of 29 sets of gamma-ray spectra that were provided by DNDO. ASEDRA is a post-processing algorithm developed at the Florida Institute of Nuclear Detection and Security at the University of Florida (UF/FINDS) that extracts char-acteristic peaks in gamma-ray spectra. The QuickID algorithm, also developed at UF/FINDS, was then used to identify nuclides based on the characteristic peaks generated by ASEDRA that are inferred from the spectra. The ASEDRA/QuickID analysis results were evaluated with respect to the performance of the DHSIsotopeID algorithm, which is a mature analysis tool that is part of the Gamma Detector Response and Analysis Software (GADRAS). Data that were used for the blind test were intended to be challenging, and the radiation sources included thick shields around the radioactive materials as well as cargo containing naturally occurring radio-active materials, which masked emission from special nuclear materials and industrial isotopes. Evaluation of the analysis results with respect to the ground truth information (which was provided after the analyses were finalized) showed that neither ASEDRA/QuickID nor GADRAS could identify all of the radiation sources correctly. Overall, the purpose of this effort was primarily to evaluate ASEDRA, and GADRAS was used as a standard against which ASEDRA was compared. Although GADRAS was somewhat more accurate on average, the performance of ASEDRA exceeded that of GADRAS for some of the unknowns. The fact that GADRAS also failed to identify many of the radiation sources attests to the difficulty of analyzing the blind-test data that were used as a basis for the evaluation. This evaluation identified strengths and weaknesses of the two analysis approaches. The importance of good calibration data was also clear because the performance of both analysis methods was impeded by the

  11. Final Technical Report

    Energy Technology Data Exchange (ETDEWEB)

    Bohdan W. Oppenheim; Rudolf Marloth

    2007-10-26

    Executive Summary The document contains Final Technical Report on the Industrial Assessment Center Program at Loyola Marymount University in Los Angeles, covering the contract period of 9/1/2002 to 11/30/2006, under the contract DE-FC36-02GO 12073. The Report describes six required program tasks, as follows: TASK 1 is a summary of the assessments performed over the life of the award: 77 assessments were performed, 595 AR were recommended, covering a very broad range of manufacturing plants. TASK 2 is a description of the efforts to promote and increase the adoption of assessment recommendations and employ innovative methods to assist in accomplishing these goals. The LMU IAC has been very successful in accomplishing the program goals, including implemented savings of $5,141,895 in energy, $10,045,411 in productivity and $30,719 in waste, for a total of $15,218,025. This represents 44% of the recommended savings of $34,896,392. TASK 3 is a description of the efforts promoting the IAC Program and enhancing recruitment efforts for new clients and expanded geographic coverage. LMU IAC has been very successful recruiting new clients covering Southern California. Every year, the intended number of clients was recruited. TASK 4 describes the educational opportunities, training, and other related activities for IAC students. A total of 38 students graduated from the program, including 2-3 graduate students every semester, and the remainder undergraduate students, mostly from the Mechanical Engineering Department. The students received formal weekly training in energy (75%) and productivity (25). All students underwent extensive safety training. All students praised the IAC experience very highly. TASK 5 describes the coordination and integration of the Center activities with other Center and IAC Program activities, and DOE programs. LMU IAC worked closely with MIT, and SDSU IAC and SFSU IAC, and enthusiastically supported the SEN activities. TASK 6 describes other tasks

  12. Inborn anemias in mice

    Energy Technology Data Exchange (ETDEWEB)

    Bernstein, S.E.; Barker, J.E.; Russell, E.S.

    1981-06-01

    hereditary anemias of mice have been the chief objects of investigation. At present under study are four macrocytic anemias, five hemolytic anemias, nonhemolytic microcytic anemia, transitory siderocytic anemia, sex-linked iron-transport anemia, an ..cap alpha..-thalassemia, and a new target-cell anemia. Each of these blood dyscrasias is caused by the action of a unique mutant gene, which determines the structure of different intracellular molecules, and thus controls a different metabolic process. Thus our wide range of different hereditary anemias has considerable potential for uncovering many different aspects of hemopoietic homeostatic mechanisms in the mouse. Each anemia is studied through: (a) characterization of peripheral blood values, (b) determinations of radiosensitivity under a variety of conditions, (c) measurements of iron metabolism and heme synthesis, (d) histological and biochemical study of blood-forming tissue, (e) functional tests of the stem cell component, (f) examination of responses to erythroid stimuli, and (g) transplantation of tissue between individuals of differently affected genotypes.

  13. Transgenic mice in developmental toxicology

    Energy Technology Data Exchange (ETDEWEB)

    Woychik, R.P.

    1992-01-01

    Advances in molecular biology and embryology are being utilized for the generation of transgenic mice, animals that contain specific additions, deletions, or modifications of genes or sequences in their DNA. Mouse embryonic stem cells and homologous recombination procedures have made it possible to target specific DNA structural alterations to highly localized region in the host chromosomes. The majority of the DNA structural rearrangements in transgenic mice can be passed through the germ line and used to establish new genetic traits in the carrier animals. Since the use of transgenic mice is having such an enormous impact on so many areas of mammalian biological research, including developmental toxicology, the objective of this review is to briefly describe the fundamental methodologies for generating transgenic mice and to describe one particular application that has direct relevance to the field of genetic toxicology.

  14. Transgenic mice in developmental toxicology

    Energy Technology Data Exchange (ETDEWEB)

    Woychik, R.P.

    1992-12-31

    Advances in molecular biology and embryology are being utilized for the generation of transgenic mice, animals that contain specific additions, deletions, or modifications of genes or sequences in their DNA. Mouse embryonic stem cells and homologous recombination procedures have made it possible to target specific DNA structural alterations to highly localized region in the host chromosomes. The majority of the DNA structural rearrangements in transgenic mice can be passed through the germ line and used to establish new genetic traits in the carrier animals. Since the use of transgenic mice is having such an enormous impact on so many areas of mammalian biological research, including developmental toxicology, the objective of this review is to briefly describe the fundamental methodologies for generating transgenic mice and to describe one particular application that has direct relevance to the field of genetic toxicology.

  15. Mice, men and MHC supertypes

    DEFF Research Database (Denmark)

    Lundegaard, Claus

    2010-01-01

    vaccine formulations. Toxoplasma gondii, an intracellular parasite, causes severe neurologic and ocular disease in congenitally infected and immunocompromised individuals. No protective vaccine exists against human toxoplasmosis. However, studies with mice have revealed immunodominant cytotoxic T...

  16. Owls and larks in mice

    Directory of Open Access Journals (Sweden)

    Martina ePfeffer

    2015-05-01

    Full Text Available Humans come in different chronotypes and, particularly, the late chronotype (the so-called owl has been shown to be associated with a number of health risks. Recent studies indicate that laboratory mice also display various chronotypes. In mice as well as in humans, the chronotype shows correlations with the period length and rhythm stability. In addition, some mouse models for human diseases show alterations in their chronotypic behavior which are comparable to those humans. Thus, analysis of the behavior of mice is a powerful tool to unravel the molecular and genetic background of the chronotype and the prevalence of risks and diseases that are associated with it. In this review, we summarize the correlation of chronotype with free-running period length and rhythm stability in the most commonly used inbred mouse strains, in mice with a compromised molecular clockwork and in a mouse model for neurodegeneration.

  17. Final Performance Progress Report

    Energy Technology Data Exchange (ETDEWEB)

    Houldin, Joseph [Delaware Valley Industrial Resource Center, Philadelphia, PA (United States); Saboor, Veronica [Delaware Valley Industrial Resource Center, Philadelphia, PA (United States)

    2016-03-30

    about assessing a company’s technical assets, broadening our view of the business to go beyond what they make or what NAICS code they have…to better understand their capacity, capability, and expertise, and to learn more about THEIR customers. Knowing more about the markets they serve can often provide insight into their level of technical knowledge and sophistication. Finally, in the spirit of realizing the intent of the Accelerator we strove to align and integrate the work and activities supported by the five funding agencies to leverage each effort. To that end, we include in the Integrated Work Plan a graphic that illustrates that integration. What follows is our summary report of the project, aggregated from prior reports.

  18. Dietary resveratrol prevents the development of food allergy in mice.

    Directory of Open Access Journals (Sweden)

    Yui Okada

    Full Text Available BACKGROUND: Resveratrol is a bioactive polyphenol enriched in red wine that exhibits many beneficial health effects via multiple mechanisms. However, it is unclear whether resveratrol is beneficial for the prevention of food allergy. This study investigated whether resveratrol inhibited the development of food allergy by using a mouse model of the disease. METHODOLOGY/PRINCIPAL FINDINGS: Mice fed standard diet or standard diet plus resveratrol were sensitized by intragastric administration of ovalbumin (OVA and mucosal adjuvant cholera toxin (CT. Several manifestations of food allergy were then compared between the mice. The effects of resveratrol on T cells or dendritic cells were also examined by using splenocytes from OVA-specific T cell-receptor (TCR transgenic DO11.10 mice or mouse bone marrow-derived dendritic cells (BMDCs in vitro. We found that mice fed resveratrol showed reduced OVA-specific serum IgE production, anaphylactic reaction, and OVA-induced IL-13 and IFN-ã production from the mesenteric lymph nodes (MLNs and spleens in comparison to the control mice, following oral sensitization with OVA plus CT. In addition, resveratrol inhibited OVA plus CT-induced IL-4, IL-13, and IFN-ã production in splenocytes from DO11.10 mice associated with inhibition of GATA-3 and T-bet expression. Furthermore, resveratrol suppressed the OVA plus CT-induced CD25 expression and IL-2 production in DO11.10 mice-splenocytes in association with decreases in CD80 and CD86 expression levels. Finally, resveratrol suppressed CT-induced cAMP elevation in association with decreases in CD80 and CD86 expression levels in BMDCs. CONCLUSIONS/SIGNIFICANCE: Ingestion of resveratrol prevented the development of a food allergy model in mice. Given the in vitro findings, resveratrol might do so by inhibiting DC maturation and subsequent early T cell activation and differentiation via downregulation of CT-induced cAMP activation in mice. These results suggest that

  19. Toxaphene-induced mouse liver tumorigenesis is mediated by the constitutive androstane receptor.

    Science.gov (United States)

    Wang, Zemin; Li, Xilin; Wu, Qiangen; Lamb, James C; Klaunig, James E

    2017-02-20

    Toxaphene was shown to increase liver tumor incidence in B6C3F1 mice following chronic dietary exposure. Preliminary evidence supported a role for the constitutive androstane receptor (CAR) in the mode of action of toxaphene-induced mouse liver tumors. However, these results could not rule out a role for the pregnane X receptor (PXR) in liver tumor formation. To define further the nuclear receptors involved in this study, we utilized CAR, PXR and PXR/CAR knockout mice (CAR(-/-) , PXR(-/-) and PXR(-/-) /CAR(-/-) ) along with the wild-type C57BL/6. In this study CAR-responsive genes Cyp3a11 and Cyp2b10 were induced in the liver of C57BL/6 (wild-type) mice by toxaphene (30-570-fold) (at the carcinogenic dose 320 ppm) and phenobarbital (positive control) (16-420-fold) following 14 days' dietary treatment. In contrast, in CAR(-/-) mice, no induction of these genes was seen following treatment with either chemical. Cyp3a11 and Cyp2b10 were also induced in PXR(-/-) mice with toxaphene and phenobarbital but were not changed in treated PXR(-/-) /CAR(-/-) mice. Similarly, induction of liver pentoxyresorufin-O-deethylase (CAR activation) activity by toxaphene and phenobarbital was absent in CAR(-/-) and PXR(-/-) /CAR(-/-) mice treated with phenobarbital or toxaphene. Ethoxyresorufin-O-deethylase (EROD, represents aryl hydrocarbon receptor activation) activity in CAR(-/-) mice treated with toxaphene or phenobarbital was increased compared with untreated control, but lower overall in activity in comparison to the wild-type mouse. Liver EROD activity was also induced by both phenobarbital and toxaphene in the PXR(-/-) mice but not in the PXR(-/-) /CAR(-/-) mice. Toxaphene treatment increased 7-benzyloxyquinoline activity (a marker for PXR activation) in a similar pattern to that seen with pentoxyresorufin-O-deethylase. These observations indicate that EROD and PXR activation are evidence, as expected, of secondary overlap to primary CAR receptor activation. Together, these

  20. Aqueous Extract of Black Maca (Lepidium meyenii on Memory Impairment Induced by Ovariectomy in Mice

    Directory of Open Access Journals (Sweden)

    Julio Rubio

    2011-01-01

    Full Text Available The present study aims to test two different doses of aqueous extract of black maca on learning and memory in ovariectomized (OVX mice and their relation with malonalehyde (MDA, acetylcholinesterase (Ache and monoamine oxidase (MAO brain levels. Female mice were divided into five groups: (i naive (control, (ii sham, (iii OVX mice and OVX mice treated with (iv 0.50 g kg−1 and (v 2.00 g kg−1 black maca. Mice were orally treated with distilled water or black maca during 35 days starting 7 days after surgery. Memory and learning were assessed using the water Morris maze (from day 23–27 and the step-down avoidance test (days 34 and 35. At the end of each treatment, mice were sacrificed by decapitation and brains were dissected out for MDA, Ache and MAO determinations. Black maca (0.5 and 2.0 g/kg increased step-down latency when compared to OVX control mice. Black maca decreased MDA and Ache levels in OVX mice; whereas, no differences were observed in MAO levels. Finally, black maca improved experimental memory impairment induced by ovariectomy, due in part, by its antioxidant and Ache inhibitory activities.

  1. Salivary gland hypofunction in tyrosylprotein sulfotransferase-2 knockout mice is due to primary hypothyroidism.

    Directory of Open Access Journals (Sweden)

    Andrew D Westmuckett

    Full Text Available BACKGROUND: Protein-tyrosine sulfation is a post-translational modification of an unknown number of secreted and membrane proteins mediated by two known Golgi tyrosylprotein sulfotransferases (TPST-1 and TPST-2. We reported that Tpst2-/- mice have mild-moderate primary hypothyroidism, whereas Tpst1-/- mice are euthyroid. While using magnetic resonance imaging (MRI to look at the thyroid gland we noticed that the salivary glands in Tpst2-/- mice appeared smaller than in wild type mice. This prompted a detailed analysis to compare salivary gland structure and function in wild type, Tpst1-/-, and Tpst2 -/- mice. METHODOLOGY/PRINCIPAL FINDINGS: Quantitative MRI imaging documented that salivary glands in Tpst2-/- females were (≈ 30% smaller than wild type or Tpst1-/- mice and that the granular convoluted tubules in Tpst2-/- submandibular glands were less prominent and were almost completely devoid of exocrine secretory granules compared to glands from wild type or Tpst1-/- mice. In addition, pilocarpine-induced salivary flow and salivary α-amylase activity in Tpst2-/- mice of both sexes was substantially lower than in wild type and Tpst1-/- mice. Anti-sulfotyrosine Western blots of salivary gland extracts and saliva showed no differences between wild type, Tpst1-/-, and Tpst2-/- mice, suggesting that the salivary gland hypofunction is due to factor(s extrinsic to the salivary glands. Finally, we found that all indicators of hypothyroidism (serum T4, body weight and salivary gland hypofunction (salivary flow, salivary α-amylase activity, histological changes were restored to normal or near normal by thyroid hormone supplementation. CONCLUSIONS/SIGNIFICANCE: Our findings conclusively demonstrate that low body weight and salivary gland hypofunction in Tpst2-/- mice is due solely to primary hypothyroidism.

  2. Decreased motivation to eat in mu-opioid receptor-deficient mice.

    Science.gov (United States)

    Papaleo, Francesco; Kieffer, Brigitte L; Tabarin, Antoine; Contarino, Angelo

    2007-06-01

    Altered motivational processes might participate to the physiopathology of eating-related disorders. The endogenous opioid system is thought to mediate the hedonic properties of food intake. To assess the role for the micro-opioid receptor (MOR) pathway in the motivational properties of food intake, in the present study we tested wild-type and MOR-deficient mice (MOR-/-) in a nose-poke operant paradigm for chow or sucrose pellets. To avoid confounding factors linked to food restriction/deprivation experience, mice were always provided with food ad libitum. Although less MOR-/- than wild-type mice initiated operant behaviour, under a fixed ratio-1 (FR-1) reinforcement schedule the two genotypes showed similar patterns of food-driven nose-poking, indicating preserved cognitive abilities in MOR-deficient mice. However, during FR-3 and progressive ratio (PR) reinforcement experiments, MOR-/- mice showed lower levels of nose-poking for either chow or sucrose pellets than wild-type mice, indicating a crucial role for the MOR pathway in the motivational properties of food intake. Moreover, under the PR reinforcement schedule mice nose-poking for sucrose pellets showed higher genotype-independent breakpoint levels than mice working for chow pellets, indicating that the MOR pathway is not essential for hedonic processing of palatable food intake. Finally, MOR-/- mice did not differ from wild-type mice in the rate of operant responding extinction, further supporting the notion of unaltered cognitive abilities in the MOR-deficient mice. The present findings strongly indicate that the MOR pathway mediates the motivational properties of food intake, but it is not essential for hedonic processing of ingestive behaviour.

  3. Automatic visual tracking and social behaviour analysis with multiple mice.

    Directory of Open Access Journals (Sweden)

    Luca Giancardo

    Full Text Available Social interactions are made of complex behavioural actions that might be found in all mammalians, including humans and rodents. Recently, mouse models are increasingly being used in preclinical research to understand the biological basis of social-related pathologies or abnormalities. However, reliable and flexible automatic systems able to precisely quantify social behavioural interactions of multiple mice are still missing. Here, we present a system built on two components. A module able to accurately track the position of multiple interacting mice from videos, regardless of their fur colour or light settings, and a module that automatically characterise social and non-social behaviours. The behavioural analysis is obtained by deriving a new set of specialised spatio-temporal features from the tracker output. These features are further employed by a learning-by-example classifier, which predicts for each frame and for each mouse in the cage one of the behaviours learnt from the examples given by the experimenters. The system is validated on an extensive set of experimental trials involving multiple mice in an open arena. In a first evaluation we compare the classifier output with the independent evaluation of two human graders, obtaining comparable results. Then, we show the applicability of our technique to multiple mice settings, using up to four interacting mice. The system is also compared with a solution recently proposed in the literature that, similarly to us, addresses the problem with a learning-by-examples approach. Finally, we further validated our automatic system to differentiate between C57B/6J (a commonly used reference inbred strain and BTBR T+tf/J (a mouse model for autism spectrum disorders. Overall, these data demonstrate the validity and effectiveness of this new machine learning system in the detection of social and non-social behaviours in multiple (>2 interacting mice, and its versatility to deal with different

  4. Palatable meal anticipation in mice.

    Directory of Open Access Journals (Sweden)

    Cynthia T Hsu

    Full Text Available The ability to sense time and anticipate events is a critical skill in nature. Most efforts to understand the neural and molecular mechanisms of anticipatory behavior in rodents rely on daily restricted food access, which induces a robust increase of locomotor activity in anticipation of daily meal time. Interestingly, rats also show increased activity in anticipation of a daily palatable meal even when they have an ample food supply, suggesting a role for brain reward systems in anticipatory behavior, and providing an alternate model by which to study the neurobiology of anticipation in species, such as mice, that are less well adapted to "stuff and starve" feeding schedules. To extend this model to mice, and exploit molecular genetic resources available for that species, we tested the ability of wild-type mice to anticipate a daily palatable meal. We observed that mice with free access to regular chow and limited access to highly palatable snacks of chocolate or "Fruit Crunchies" avidly consumed the snack but did not show anticipatory locomotor activity as measured by running wheels or video-based behavioral analysis. However, male mice receiving a snack of high fat chow did show increased food bin entry prior to access time and a modest increase in activity in the two hours preceding the scheduled meal. Interestingly, female mice did not show anticipation of a daily high fat meal but did show increased activity at scheduled mealtime when that meal was withdrawn. These results indicate that anticipation of a scheduled food reward in mice is behavior, diet, and gender specific.

  5. Linkage disequilibrium in wild mice.

    Directory of Open Access Journals (Sweden)

    Cathy C Laurie

    2007-08-01

    Full Text Available Crosses between laboratory strains of mice provide a powerful way of detecting quantitative trait loci for complex traits related to human disease. Hundreds of these loci have been detected, but only a small number of the underlying causative genes have been identified. The main difficulty is the extensive linkage disequilibrium (LD in intercross progeny and the slow process of fine-scale mapping by traditional methods. Recently, new approaches have been introduced, such as association studies with inbred lines and multigenerational crosses. These approaches are very useful for interval reduction, but generally do not provide single-gene resolution because of strong LD extending over one to several megabases. Here, we investigate the genetic structure of a natural population of mice in Arizona to determine its suitability for fine-scale LD mapping and association studies. There are three main findings: (1 Arizona mice have a high level of genetic variation, which includes a large fraction of the sequence variation present in classical strains of laboratory mice; (2 they show clear evidence of local inbreeding but appear to lack stable population structure across the study area; and (3 LD decays with distance at a rate similar to human populations, which is considerably more rapid than in laboratory populations of mice. Strong associations in Arizona mice are limited primarily to markers less than 100 kb apart, which provides the possibility of fine-scale association mapping at the level of one or a few genes. Although other considerations, such as sample size requirements and marker discovery, are serious issues in the implementation of association studies, the genetic variation and LD results indicate that wild mice could provide a useful tool for identifying genes that cause variation in complex traits.

  6. TARGET 2 and Settlement Finality

    Directory of Open Access Journals (Sweden)

    Ivan MANGATCHEV

    2011-03-01

    Full Text Available This article examines how TARGET 2 as system implements the idea of settlement finality regulated by Directive 98/26 EC of the European parliament and of the Council of 19 May 1998 on settlement finality in payment and securities settlement systems (Settlement Finality Directive and Directive 2009/44/EC of the European parliament and of the Council of 6 May 2009 amending Directive 98/26/EC on settlement finality in payment and securities settlement systems and Directive 2002/47/EC on financial collateral arrangements as regards linked systems and credit claims (Directive 2009/44/EC. As the title of the arti and finality of the settlement in this system.

  7. Social defeat in adolescent mice increases vulnerability to alcohol consumption.

    Science.gov (United States)

    Rodriguez-Arias, Marta; Navarrete, Francisco; Blanco-Gandia, Maria Carmen; Arenas, Maria Carmen; Bartoll-Andrés, Adrián; Aguilar, Maria A; Rubio, Gabriel; Miñarro, José; Manzanares, Jorge

    2016-01-01

    This study employs an oral operant conditioning paradigm to evaluate the effects of repeated social defeat during adolescence on the reinforcing and motivational actions of ethanol in adult OF1 mice. Social interaction, emotional and cognitive behavioral aspects were also analyzed, and real-time polymerase chain reaction (PCR) experiments were performed to study gene expression changes in the mesocorticolimbic and hypothalamus-hypophysis-adrenal (HHA) axis. Social defeat did not alter anxiety-like behavior in the elevated plus maze or cognitive performance in the passive avoidance and Hebb-Williams tests. A social interaction test revealed depression-like symptoms and social subordination behavior in defeated OF1 mice. Interestingly, social defeat in adolescence significantly increased the number of effective responses, ethanol consumption values and motivation to drink. Finally, real-time PCR analyses revealed that social defeat significantly increased tyrosine hydroxylase and corticotropin-releasing hormone in the ventral tegmental area and paraventricular nucleus, respectively. In contrast, mu-opioid receptor gene expression was decreased in the nucleus accumbens of socially defeated mice. In summary, these findings suggest that exposure to social defeat during adolescence increases vulnerability to the rewarding effects of ethanol without affecting emotional or cognitive performance. The gene expression alterations we have observed in the mesocorticolimbic and HHA axis systems of defeated mice could be related with their increased ethanol consumption. These results endorse future research into pharmacological strategies that modulate these systems for the treatment of social stress-related alcohol consumption problems.

  8. Toxoplasma gondii: sexual transmission in mice

    OpenAIRE

    Asgari, Qasem; Keshavarz Valian, Hossein; REZAEIAN, Mostafa; SHOJAEE, Saeedeh; Mehrabani, Davood

    2013-01-01

    This study was performed to evaluate sexual transmission of Toxoplasma gondii in mice. RH strain tachyzoites were intraperitoneally inoculated into 10 Balb/C male mice and after 48 h, their semen were collected from epididymis and examined by giemsa staining and PCR. Twenty Balb/C female mice mated with four infected male mice four times and any mating time was 48 h whilst 20 female control mice mated with four uninfected male mice for 8 days. Female mate choice was assessed using a three-cha...

  9. Liquid Hydrogen Absorber for MICE

    Energy Technology Data Exchange (ETDEWEB)

    Ishimoto, S.; Suzuki, S.; Yoshida, M.; Green, Michael A.; Kuno, Y.; Lau, Wing

    2010-05-30

    Liquid hydrogen absorbers for the Muon Ionization Cooling Experiment (MICE) have been developed, and the first absorber has been tested at KEK. In the preliminary test at KEK we have successfully filled the absorber with {approx}2 liters of liquid hydrogen. The measured hydrogen condensation speed was 2.5 liters/day at 1.0 bar. No hydrogen leakage to vacuum was found between 300 K and 20 K. The MICE experiment includes three AFC (absorber focusing coil) modules, each containing a 21 liter liquid hydrogen absorber made of aluminum. The AFC module has safety windows to separate its vacuum from that of neighboring modules. Liquid hydrogen is supplied from a cryocooler with cooling power 1.5 W at 4.2 K. The first absorber will be assembled in the AFC module and installed in MICE at RAL.

  10. Progress of the MICE experiment

    CERN Document Server

    Bonesini, M

    2015-01-01

    The international Muon Ionization Cooling Experiment (MICE) will perform a systematic investigation of ionization cooling of a muon beam. The demonstration is based on a simplified version of a neutrino factory cooling channel. As the emittance measurement will be done on a particle-by-particle basis, sophisticated beam instrumentation has been developed to measure particle coordinates and timing vs RF. The muon beamline has been characterized and a preliminary measure of the beam emittance, using a particle-by-particle method with only the TOF detector system, has been performed (MICE STEP I). Data taking for the study of the properties that determine the cooling performance (MICE Step IV) has just started in 2015, while the demonstration of ionization cooling with re-acceleration is foreseen for 2017.

  11. Final focus system for TLC

    Energy Technology Data Exchange (ETDEWEB)

    Oide, K.

    1988-11-01

    A limit of the chromaticity correction for the final focus system of a TeV Linear Collider (TLC) is investigated. As the result, it becomes possible to increase the aperture of the final doublet with a small increase of the horizontal US function. The new optics design uses a final doublet of 0.5 mm half-aperture and 1.4 T pole-tip field. The length of the system is reduced from 400 m to 200 m by several optics changes. Tolerances for various machine errors with this optics are also studied. 5 refs., 7 figs., 2 tabs.

  12. Attenuated pain response of obese mice (B6.Cg-lep(ob)) is affected by aging and leptin but not sex.

    Science.gov (United States)

    Rodgers, Helen M; Liban, Suadi; Wilson, Linda M

    2014-01-17

    Genetically obese mice (B6.Cg-lep(ob)) manifest decreased responses to noxious thermal stimuli (hotplate test) suggesting endogenous analgesia (Roy et al., 1981). To examine further the analgesic response of these mice, we conducted 4 experiments. Experiment 1 assessed the response of ob/ob mice to tail flick, another noxious thermal test. Tail-flick testing was performed on B6.Cg-lep(ob) mice (n=14) and B6.Cg-lep(OB/?) (n=12) across a range of temperatures. Ob/ob mice exhibited longer latencies than control mice at all temperatures tested. In Experiment 2, potential sex differences were examined. Tail-flick latencies in male and female ob/ob mice (n=6/group) did not differ. The final 2 experiments examined factors that could modulate endogenous analgesia. Experiment 3 assessed the effects of aging in ob/ob mice (n=10/group). Older mice displayed longer tail-flick latencies than did younger mice. Experiment 4 examined the effect of leptin administration in the leptin-deficient ob/ob mice. Two groups (n=10/group) of ob/ob mice received osmotic pump implants filled with either leptin or vehicle, and were tail-flick tested at days 7 and 14 post-implantation. Ob/ob mice receiving leptin showed shorter latencies than did vehicle-receiving ob/ob mice. Taken together, these results support earlier reports of heightened analgesia in ob/ob mice and suggest that aging further reduces the already impaired pain response. Furthermore, leptin deficiency partially contributes to decreased pain sensation of ob/ob mice.

  13. Reduced metastasis of transgenic mammary cancer in urokinase-deficient mice

    DEFF Research Database (Denmark)

    Almholt, Kasper; Lund, L.R.; Rygaard, Jørgen;

    2005-01-01

    A prominent phenotype of plasmin deficiency in mice is reduced metastasis in the MMTV-PymT transgenic breast cancer model. Proteolytically active plasmin is generated from inactive plasminogen by one of 2 activators, uPA or tPA. We now find that uPA deficiency alone significantly reduces metastasis...... >7-fold in the MMTV-PymT model. We studied a cohort of 55 MMTV-PymT transgenic mice, either uPA-deficient or wild-type controls. Tumor incidence, latency, growth rate and final primary tumor burden were not significantly affected by uPA deficiency. In contrast, average lung metastasis volume...... phenotype. By comparison, spontaneous phenotypes are modest in uPA-deficient mice, probably because they still have active tPA. We show that metastasis is strongly and selectively decreased in uPA-deficient mice, suggesting that uPA-directed antimetastatic therapy would be efficacious and have limited side...

  14. Final disposal of radioactive waste

    OpenAIRE

    Freiesleben H.

    2013-01-01

    In this paper the origin and properties of radioactive waste as well as its classification scheme (low-level waste – LLW, intermediate-level waste – ILW, high-level waste – HLW) are presented. The various options for conditioning of waste of different levels of radioactivity are reviewed. The composition, radiotoxicity and reprocessing of spent fuel and their effect on storage and options for final disposal are discussed. The current situation of final waste disposal in a selected number of c...

  15. Intestine-targeted DGAT1 inhibition improves obesity and insulin resistance without skin aberrations in mice.

    Directory of Open Access Journals (Sweden)

    Naoto Tsuda

    Full Text Available OBJECTIVE: Diacylglycerol O-acyltransferase 1 (DGAT1 catalyzes the final committed step in triglyceride biosynthesis. DGAT1 null mice are known to be resistant to diet-induced obesity, and more insulin sensitive relative to the wild-type; however, the mice exhibit abnormalities in the skin. This work determined whether the intestine-targeted DGAT1 inhibitor could improve obesity and insulin resistance without skin aberrations in mice. DESIGN AND METHODS: We synthesized 2 DGAT1 inhibitors: Compound A, described in the patent application from the Japan Tobacco, and Compound B (A-922500, reported by Abbott Laboratories. Both compounds were evaluated for inhibitory activities against DGAT1 enzymes and effects on the skin in mice in vivo. Compound B was further investigated for effects on obesity and insulin resistance in diet-induced-obese (DIO mice. RESULTS: The 2 compounds comparably inhibited the DGAT1 enzyme activity and the cellular triglyceride synthesis in vitro, while they showed different distribution patterns in mice in vivo. Compound A, which distributed systemically, caused skin aberrations, while Compound B, which preferentially distributed to the intestine, improved obesity and insulin resistance without skin aberrations in DIO mice. CONCLUSIONS: Our results suggest that the intestine is the key tissue in which DGAT1 plays a role in promoting obesity and insulin resistance.

  16. An ethanolic extract of black cohosh causes hematological changes but not estrogenic effects in female rodents

    Energy Technology Data Exchange (ETDEWEB)

    Mercado-Feliciano, Minerva; Cora, Michelle C.; Witt, Kristine L. [National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, 111 Alexander Drive, Research Triangle Park, NC (United States); Granville, Courtney A.; Hejtmancik, Milton R.; Fomby, Laurene; Knostman, Katherine A.; Ryan, Michael J. [Battelle Memorial Institute, Columbus, OH (United States); Newbold, Retha; Smith, Cynthia; Foster, Paul M.; Vallant, Molly K. [National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, 111 Alexander Drive, Research Triangle Park, NC (United States); Stout, Matthew D., E-mail: StoutM@niehs.nih.gov [National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, 111 Alexander Drive, Research Triangle Park, NC (United States)

    2012-09-01

    Black cohosh rhizome (Actaea racemosa) is used as a remedy for pain and gynecological ailments; modern preparations are commonly sold as ethanolic extracts available as dietary supplements. Black cohosh was nominated to the National Toxicology Program (NTP) for toxicity testing due to its widespread use and lack of safety data. Several commercially available black cohosh extracts (BCE) were characterized by the NTP, and one with chemical composition closest to formulations available to consumers was used for all studies. Female B6C3F1/N mice and Wistar Han rats were given 0, 15 (rats only), 62.5 (mice only), 125, 250, 500, or 1000 mg/kg/day BCE by gavage for 90 days starting at weaning. BCE induced dose-dependent hematological changes consistent with a non-regenerative macrocytic anemia and increased frequencies of peripheral micronucleated red blood cells (RBC) in both species. Effects were more severe in mice, which had decreased RBC counts in all treatment groups and increased micronucleated RBC at doses above 125 mg/kg. Dose-dependent thymus and liver toxicity was observed in rats but not mice. No biologically significant effects were observed in other organs. Puberty was delayed 2.9 days at the highest treatment dose in rats; a similar magnitude delay in mice occurred in the 125 and 250 mg/kg groups but not at the higher doses. An additional uterotrophic assay conducted in mice exposed for 3 days to 0.001, 0.01, 0.1, 1, 10, 100 and 500 mg/kg found no estrogenic or anti-estrogenic activity. These are the first studies to observe adverse effects of BCE in rodents. -- Highlights: ► Mice and rats were dosed with black cohosh extract for 90 days starting at weaning. ► Hematological changes were consistent with a non-regenerative macrocytic anemia. ► Peripheral micronucleated red blood cell frequencies increased. ► Puberty was delayed 2.9 days in rats. ► No estrogenic/anti-estrogenic activity was seen in the uterotrophic assay.

  17. Inhalation toxicity and carcinogenicity studies of cobalt sulfate.

    Science.gov (United States)

    Bucher, J R; Hailey, J R; Roycroft, J R; Haseman, J K; Sills, R C; Grumbein, S L; Mellick, P W; Chou, B J

    1999-05-01

    Cobalt sulfate is a water-soluble cobalt salt with a variety of industrial and agricultural uses. Several cobalt compounds have induced sarcomas at injection sites in animals, and reports have suggested that exposure to cobalt-containing materials may cause lung cancer in humans. The present studies were done because no adequate rodent carcinogenicity studies had been performed with a soluble cobalt salt using a route relevant to occupational exposures. Groups of 50 male and 50 female F344/N rats and B6C3F1 mice were exposed to aerosols containing 0, 0.3, 1.0, or 3.0 mg/m3 cobalt sulfate hexahydrate, 6 h/day, 5 days/week, for 104 weeks. Survival and body weights of exposed rats and mice were generally unaffected by the exposures. In rats, proteinosis, alveolar epithelial metaplasia, granulomatous alveolar inflammation, and interstitial fibrosis were observed in the lung in all exposed groups. Nonneoplastic lesions of the nose and larynx were also attributed to exposure to all concentrations of cobalt sulfate. In 3.0 mg/m3 male rats and in female rats exposed to 1.0 or 3.0 mg/m3, the incidences of alveolar/bronchiolar neoplasms were increased over those in the control groups. Lung tumors occurred with significant positive trends in both sexes. The incidences of adrenal pheochromocytoma in 1.0 mg/m3 male rats and in 3.0 mg/m3 female rats were increased. Nonneoplastic lesions of the respiratory tract were less severe in mice than in rats. In mice, alveolar/bronchiolar neoplasms in 3.0 mg/m3 males and females were greater than those in the controls, and lung tumors occurred with significantly positive trends. Male mice had liver lesions consistent with a Helicobacter hepaticus infection. Incidences of liver hemangiosarcomas were increased in exposed groups of male mice; however, because of the infection, no conclusion could be reached concerning an association between liver hemangiosarcomas and cobalt sulfate. In summary, exposure to cobalt sulfate by inhalation

  18. Mice lacking the PACAP type I receptor have impaired photic entrainment and negative masking

    DEFF Research Database (Denmark)

    Hannibal, Jens; Brabet, Philippe; Fahrenkrug, Jan

    2008-01-01

    phase delays, which was prominent at low light intensities. The data obtained at late night indicated that PACAP/PAC1 receptor signaling is less important during the phase-advancing part of the phase-response curve. Finally, the PAC1 KO mice showed impaired negative masking behavior at low light...

  19. Turning Back the Aging Clock -- in Mice

    Science.gov (United States)

    ... 164250.html Turning Back the Aging Clock -- in Mice Elderly rodents treated with cellular therapy regained lost fur, became ... 2017 THURSDAY, March 23, 2017 (HealthDay News) -- Aging mice became more youthful following a new cellular therapy ...

  20. Modified Protein Improves Vitiligo Symptoms in Mice

    Science.gov (United States)

    ... 2013 (historical) Modified Protein Improves Vitiligo Symptoms in Mice Altering a key protein involved in the development ... pigmentation loss associated with the skin disorder in mice, according to recent research funded by the NIH’s ...

  1. Nanoparticles Ease Aching Joints in Mice

    Science.gov (United States)

    ... page: https://medlineplus.gov/news/fullstory_161188.html Nanoparticles Ease Aching Joints in Mice Treatment might one ... News) -- New research in mice suggests that tiny nanoparticles might one day be a better way to ...

  2. Characterization of Lethal Zika Virus Infection in AG129 Mice.

    Directory of Open Access Journals (Sweden)

    Matthew T Aliota

    2016-04-01

    Full Text Available Mosquito-borne Zika virus (ZIKV typically causes a mild and self-limiting illness known as Zika fever, which often is accompanied by maculopapular rash, headache, and myalgia. During the current outbreak in South America, ZIKV infection during pregnancy has been hypothesized to cause microcephaly and other diseases. The detection of ZIKV in fetal brain tissue supports this hypothesis. Because human infections with ZIKV historically have remained sporadic and, until recently, have been limited to small-scale epidemics, neither the disease caused by ZIKV nor the molecular determinants of virulence and/or pathogenicity have been well characterized. Here, we describe a small animal model for wild-type ZIKV of the Asian lineage.Using mice deficient in interferon α/β and Ɣ receptors (AG129 mice, we report that these animals were highly susceptible to ZIKV infection and disease, succumbing within seven to eight days. Rapid viremic dissemination was observed in visceral organs and brain; but only was associated with severe pathologies in the brain and muscle. Finally, these results were consistent across challenge routes, age of mice, and inoculum doses. These data represent a mouse model for ZIKV that is not dependent on adapting ZIKV to intracerebral passage in mice.Foot pad injection of AG129 mice with ZIKV represents a biologically relevant model for studying ZIKV infection and disease development following wild-type virus inoculation without the requirement for adaptation of the virus or intracerebral delivery of the virus. This newly developed Zika disease model can be exploited to identify determinants of ZIKV virulence and reveal molecular mechanisms that control the virus-host interaction, providing a framework for rational design of acute phase therapeutics and for vaccine efficacy testing.

  3. Compensatory eye movements in mice

    NARCIS (Netherlands)

    A.M. van Alphen (Adriaan)

    2002-01-01

    textabstractThis thesis will address the generation of compensatory eye movements in naturally mutated or genetically modified mice. The reason for generating compensatory eye movements is solely related to the requirements for good vision. In a subject moving through its environment the projection

  4. Progress on Cherenkov Reconstruction in MICE

    CERN Document Server

    Kaplan, Daniel M; Rajaram, Durga; Winter, Miles; Cremaldi, Lucien; Sanders, David; Summers, Don

    2016-01-01

    Two beamline Cherenkov detectors (Ckov-a,-b) support particle identification in the MICE beamline. Electrons and high-momentum muons and pions can be identified with good efficiency. We report on the Ckov-a,-b performance in detecting pions and muons with MICE Step I data and derive an upper limit on the pion contamination in the standard MICE muon beam.

  5. Electromagnetic treatment to old Alzheimer's mice reverses β-amyloid deposition, modifies cerebral blood flow, and provides selected cognitive benefit.

    Directory of Open Access Journals (Sweden)

    Gary W Arendash

    Full Text Available Few studies have investigated physiologic and cognitive effects of "long-term" electromagnetic field (EMF exposure in humans or animals. Our recent studies have provided initial insight into the long-term impact of adulthood EMF exposure (GSM, pulsed/modulated, 918 MHz, 0.25-1.05 W/kg by showing 6+ months of daily EMF treatment protects against or reverses cognitive impairment in Alzheimer's transgenic (Tg mice, while even having cognitive benefit to normal mice. Mechanistically, EMF-induced cognitive benefits involve suppression of brain β-amyloid (Aβ aggregation/deposition in Tg mice and brain mitochondrial enhancement in both Tg and normal mice. The present study extends this work by showing that daily EMF treatment given to very old (21-27 month Tg mice over a 2-month period reverses their very advanced brain Aβ aggregation/deposition. These very old Tg mice and their normal littermates together showed an increase in general memory function in the Y-maze task, although not in more complex tasks. Measurement of both body and brain temperature at intervals during the 2-month EMF treatment, as well as in a separate group of Tg mice during a 12-day treatment period, revealed no appreciable increases in brain temperature (and no/slight increases in body temperature during EMF "ON" periods. Thus, the neuropathologic/cognitive benefits of EMF treatment occur without brain hyperthermia. Finally, regional cerebral blood flow in cerebral cortex was determined to be reduced in both Tg and normal mice after 2 months of EMF treatment, most probably through cerebrovascular constriction induced by freed/disaggregated Aβ (Tg mice and slight body hyperthermia during "ON" periods. These results demonstrate that long-term EMF treatment can provide general cognitive benefit to very old Alzheimer's Tg mice and normal mice, as well as reversal of advanced Aβ neuropathology in Tg mice without brain heating. Results further underscore the potential for EMF

  6. Electromagnetic treatment to old Alzheimer's mice reverses β-amyloid deposition, modifies cerebral blood flow, and provides selected cognitive benefit.

    Science.gov (United States)

    Arendash, Gary W; Mori, Takashi; Dorsey, Maggie; Gonzalez, Rich; Tajiri, Naoki; Borlongan, Cesar

    2012-01-01

    Few studies have investigated physiologic and cognitive effects of "long-term" electromagnetic field (EMF) exposure in humans or animals. Our recent studies have provided initial insight into the long-term impact of adulthood EMF exposure (GSM, pulsed/modulated, 918 MHz, 0.25-1.05 W/kg) by showing 6+ months of daily EMF treatment protects against or reverses cognitive impairment in Alzheimer's transgenic (Tg) mice, while even having cognitive benefit to normal mice. Mechanistically, EMF-induced cognitive benefits involve suppression of brain β-amyloid (Aβ) aggregation/deposition in Tg mice and brain mitochondrial enhancement in both Tg and normal mice. The present study extends this work by showing that daily EMF treatment given to very old (21-27 month) Tg mice over a 2-month period reverses their very advanced brain Aβ aggregation/deposition. These very old Tg mice and their normal littermates together showed an increase in general memory function in the Y-maze task, although not in more complex tasks. Measurement of both body and brain temperature at intervals during the 2-month EMF treatment, as well as in a separate group of Tg mice during a 12-day treatment period, revealed no appreciable increases in brain temperature (and no/slight increases in body temperature) during EMF "ON" periods. Thus, the neuropathologic/cognitive benefits of EMF treatment occur without brain hyperthermia. Finally, regional cerebral blood flow in cerebral cortex was determined to be reduced in both Tg and normal mice after 2 months of EMF treatment, most probably through cerebrovascular constriction induced by freed/disaggregated Aβ (Tg mice) and slight body hyperthermia during "ON" periods. These results demonstrate that long-term EMF treatment can provide general cognitive benefit to very old Alzheimer's Tg mice and normal mice, as well as reversal of advanced Aβ neuropathology in Tg mice without brain heating. Results further underscore the potential for EMF treatment

  7. Effect of repeated benzene inhalation exposures on benzene metabolism, binding to hemoglobin, and induction of micronuclei.

    Science.gov (United States)

    Sabourin, P J; Sun, J D; MacGregor, J T; Wehr, C M; Birnbaum, L S; Lucier, G; Henderson, R F

    1990-05-01

    Metabolism of benzene is thought to be necessary to produce the toxic effects, including carcinogenicity, associated with benzene exposure. To extrapolate from the results of rodent studies to potential health risks in man, one must know how benzene metabolism is affected by species, dose, dose rate, and repeated versus single exposures. The purpose of our studies was to determine the effect of repeated inhalation exposures on the metabolism of [14C]benzene by rodents. Benzene metabolism was assessed by characterizing and quantitating urinary metabolites, and by quantitating 14C bound to hemoglobin and micronuclei induction. F344/N rats and B6C3F1 mice were exposed, nose-only, to 600 ppm benzene or to air (control) for 6 hr/day, 5 days/week for 3 weeks. On the last day, both benzene-pretreated and control animals were exposed to 600 ppm, 14C-labeled benzene for 6 hr. Individual benzene metabolites in urine collected for 24 hr after the exposure were analyzed. There was a significant decrease in the respiratory rate of mice (but not rats) pretreated with benzene which resulted in lower levels of urinary [14C]benzene metabolites. The analyses indicated that the only effects of benzene pretreatment on the metabolite profile in rat or mouse urine were a slight shift from glucuronidation to sulfation in mice and a shift from sulfation to glucuronidation in rats. Benzene pretreatment also had no effect, in either species, on formation of [14C]benzene-derived hemoglobin adducts. Mice and rats had similar levels of hemoglobin adduct binding, despite the higher metabolism of benzene by mice. This indicates that hemoglobin adduct formation occurs with higher efficiency in rats. After 1 week of exposure to 600 ppm benzene, the frequency of micronucleated, polychromatic erythrocytes (PCEs) in mice was significantly increased. Exposure to the same level of benzene for an additional 2 weeks did not further increase the frequency of micronuclei in PCEs. These results indicate

  8. MPO B593110 - Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Brooksby, C

    2011-07-25

    National Security Technologies, LLC (NSTec) shall provide one (1) Mechanical Engineer to support the Linear Collider Subsystem Development Program at Lawrence Livermore National Security, LLC (LLNS). The NSTec Mechanical Engineer's efforts will include engineering, design, and drawing support for the Vacuum Seal Test. NSTec will also provide a final report of the setup and input to LLNL's project management on project status. The NSTec Mechanical Engineer's efforts will also include engineering, design, and drawing support to the conceptual design for manufacturing of the Flux Concentrator Magnet. NSTec will also contribute to LLNS's final report on the Flux Concentrator Magnet. The deliverables are drawings, sketches, engineering documents, and final reports delivered to the LLNS Technical Representative.

  9. Bone marrow-derived cells rescue salivary gland function in mice with head and neck irradiation.

    Science.gov (United States)

    Sumita, Yoshinori; Liu, Younan; Khalili, Saeed; Maria, Ola M; Xia, Dengsheng; Key, Sharon; Cotrim, Ana P; Mezey, Eva; Tran, Simon D

    2011-01-01

    Treatment for most patients with head and neck cancers includes ionizing radiation. A consequence of this treatment is irreversible damage to salivary glands (SGs), which is accompanied by a loss of fluid-secreting acinar-cells and a considerable decrease of saliva output. While there are currently no adequate conventional treatments for this condition, cell-based therapies are receiving increasing attention to regenerate SGs. In this study, we investigated whether bone marrow-derived cells (BMDCs) can differentiate into salivary epithelial cells and restore SG function in head and neck irradiated mice. BMDCs from male mice were transplanted into the tail-vein of 18Gy-irradiated female mice. Salivary output was increased in mice that received BMDCs transplantation at week 8 and 24 post-irradiation. At 24 weeks after irradiation (IR), harvested SGs (submandibular and parotid glands) of BMDC-treated mice had greater weights than those of non-treated mice. Histological analysis shows that SGs of treated mice demonstrated an increased level of tissue regenerative activity such as blood vessel formation and cell proliferation, while apoptotic activity was increased in non-transplanted mice. The expression of stem cell markers (Sca-1 or c-kit) was detected in BMDC-treated SGs. Finally, we detected an increased ratio of acinar-cell area and approximately 9% of Y-chromosome-positive (donor-derived) salivary epithelial cells in BMDC-treated mice. We propose here that cell therapy using BMDCs can rescue the functional damage of irradiated SGs by direct differentiation of donor BMDCs into salivary epithelial cells.

  10. [Model of meningococcal sepsis in mice].

    Science.gov (United States)

    Krasnoproshina, L I; Ermakova, L G; Belova, T N; Filippov, Iu V; Efimov, D D

    1978-11-01

    The authors studied a possibility of obtaining experimental meningococcus sepsis model on mice. The use of cyclophosphane, iron compounds, yolk medium produced no significant organism. When 4--5% mucine was injected intraperitoneally together with meningococcus culture mice died with sepsis phenomena. Differences were revealed in the sensitivity of linear and mongrel mice to meningococcus infection--AKR mice proved to be more sensitive. At the same time it was found that mongrel mice weighing from 10 to 12 g could be used to induce meningococcus sepsis.

  11. Final disposal of radioactive waste

    Science.gov (United States)

    Freiesleben, H.

    2013-06-01

    In this paper the origin and properties of radioactive waste as well as its classification scheme (low-level waste - LLW, intermediate-level waste - ILW, high-level waste - HLW) are presented. The various options for conditioning of waste of different levels of radioactivity are reviewed. The composition, radiotoxicity and reprocessing of spent fuel and their effect on storage and options for final disposal are discussed. The current situation of final waste disposal in a selected number of countries is mentioned. Also, the role of the International Atomic Energy Agency with regard to the development and monitoring of international safety standards for both spent nuclear fuel and radioactive waste management is described.

  12. Sprint final pour le LEP

    CERN Document Server

    CERN Press Office. Geneva

    2000-01-01

    Director General's Status Report The Director General, Prof. Luciano Maiani, began his report with the performance of the Laboratory's flagship accelerator, the Large Electron-Positron collider, LEP, during its final year. LEP is achieving its highest energy collisions ever with beams of over 104 GeV, well exceeding its design energy and giving experiments a final chance of discovering the still-elusive Higgs particles before the end of it's experimental programme in September. Thanks to precision data from LEP and elsewhere, scientists already know that Higgs particles, if they exist, must be within range of LEP's successor, the LHC.

  13. A New Comprehensive Final Exam

    Science.gov (United States)

    Bhavsar, Suketu P.

    2015-01-01

    Instructors aspire for students to master all the material covered. The final exam should assess the breadth and depth of their learning and be a significant basis for the final grade. I insist on a comprehensive final because I want students to review early material in light of later topics. I believe that this helps students create connections, integrate understanding, and retain knowledge for the long term. For non-science majors, reviewing and retaining the large amount of astronomy material is daunting. I experimented with a final exam format that calmed their fears and encouraged thorough review. It is only practical for a class of about twenty students or less. I provided a number of challenging conceptual and problem solving questions (at least as many as there were students), crafted to interconnect and span the entire range of topics. The order of the questions reflected the sequence in which the topics had been discussed. Students received these questions in ample time to prepare prior to the final. A student could bring up to 5 standard sheets of notes to the final. At the final, each student picked a number out of a hat. This was the question they had to answer in a 5-minute presentation. They were allowed 15 minutes for a final preparation during which they could use their 5 pages of notes. The presentations were given in order, 1- 20. Written comments on at least 10 other talks, explaining what was missed or correcting a mistake were required. They were graded both on their talk and on their comments. This format required students to be prepared for any question and encouraged interaction and communication while studying. Knowing the questions beforehand provided a guide to their studying as well as allayed their fears about what could be asked. The students also received guidance to what constituted a good answer, namely accuracy (correct scientific argument, appropriate facts, no irrelevant material), thoroughness (answered the complete questions

  14. Delay of ZGA initiation occurred in 2-cell blocked mouse embryos

    Institute of Scientific and Technical Information of China (English)

    JIA JING QIU; WU WEN ZHANG; ZHI LI WU; YI HONG WANG; MIN QIAN; YI PING LI

    2003-01-01

    One-cell mouse embryos from KM strain and B6C3F1 strain were cultured in M16 medium, in which2-cell block generally occurs. Embryos of KM strain exhibited 2-cell block, whereas B6C3F1 embryos,which are regarded as a nonblocking strain, proceeded to the 4-cell stage in our culture condition. It is oftenassumed that the block of early development is due to the failure of zygotic gene activation (ZGA) in culturedembryos. In this study we examined protein synthesis patterns by two-dimensional gel electrophoresis of[35S] methionine radiolabeled 2-cell embryos. Embryos from the blocking strain and the nonblocking strainwere compared in their development both in vitro and in vivo. The detection of TRC expression, a markerof ZGA, at 42 h post hCG in KM embryos developed in vitro suggested that ZGA was also initiated even inthe 2-cell arrested embryos. Nevertheless, a significant delay of ZGA was observed in KM strain as comparedwith normally developed B6C3F1 embryos. At the very beginning of major ZGA as early as 36 h post hCG,TRC has already been expressed in B6C3F1 embryos developed in vitro and KM embryos developed in vivo.But for 2-cell blocked KM embryos, TRC was still not detectable even at 38 h post hCG. These evidencessuggest that 2-cell-blocked embryos do initiate ZGA, and that 2-cell block phenomenon is due not to thedisability in initiating ZGA, but to a delay of ZGA.

  15. Socially induced morphine pseudosensitization in adolescent mice.

    Science.gov (United States)

    Hodgson, Stephen R; Hofford, Rebecca S; Roberts, Kris W; Wellman, Paul J; Eitan, Shoshana

    2010-03-01

    Given that social influences are among the strongest predictors of adolescents' drug use, this study examined the effect of social interaction on morphine-induced hyperlocomotion in both adolescent and adult mice. Three experimental groups of adolescent and adult male mice were examined (i) morphine-treated mice (twice daily, 10-40 mg/kg, subcutaneous), (ii) saline-injected mice housed together with the morphine-treated mice ('saline cage-mates'), and (iii) saline-injected mice housed physically and visually separated from the morphine-treated mice ('saline alone'). After the treatment period, mice were tested individually for their locomotor response to 10 mg/kg morphine (subcutaneous). Adolescent saline cage-mates, though administered morphine for the very first time, exhibited an enhanced hyperlocomotion response similar to the locomotor sensitization response exhibited by the morphine-treated mice. This was not observed in adults. In adults, there were no significant differences in morphine-induced hyperlocomotion between saline alone and saline cage-mates. As expected, morphine-treated adults and adolescents both exhibited locomotor sensitization. These results show a vulnerability to social influences in adolescent mice, which does not exist in adult mice.

  16. TRAPPING PROTOCOLS, SAMPLING, AND VIABILITY ANALYSES FOR THE ALABAMA BEACH MICE (PEROMYSCUS POLIONOTUS AMMOBATES): FINAL REPORT

    Data.gov (United States)

    US Fish and Wildlife Service, Department of the Interior — We performed a comprehensive critique of trapping protocols, data analysis, and population viability analyses conducted to date for the Alabama beach mouse...

  17. MINIMARS conceptual design: Final report

    Energy Technology Data Exchange (ETDEWEB)

    Lee, J.D. (ed.)

    1986-09-01

    This volume contains the following sections: (1) fueling systems; (2) blanket; (3) alternative blanket concepts; (4) halo scraper/direct converter system study and final conceptual design; (5) heat-transport and power-conversion systems; (6) tritium systems; (7) minimars air detritiation system; (8) appropriate radiological safety design criteria; and (9) cost estimate. (MOW)

  18. Final OSWER Vapor Intrusion Guidance

    Science.gov (United States)

    EPA is preparing to finalize its guidance on assessing and addressing vapor intrusion, which is defined as migration of volatile constituents from contaminated media in the subsurface (soil or groundwater) into the indoor environment. In November 2002, EPA issued draft guidance o...

  19. Module Utilization Committee. Final report

    Energy Technology Data Exchange (ETDEWEB)

    None

    1984-03-01

    Photovoltaic collector modules were declared surplus to the needs of the US Department of Energy. The Module Utilization Committee was formed to make appropriate disposition of the surplus modules. The final report of that committee accounts for that disposition. The membership and activities of the committee are set forth and the results of its activities are reported.

  20. Report on Final Workshop results

    DEFF Research Database (Denmark)

    Cavalli, Valentino; Dyer, John; Robertson, Dale;

    The SERENATE project held its Final Workshop in Bad Nauheim, Germany on 16-17 June 2003. More than ninety representatives of research and education networking organisations, national governments and funding bodies, network operators, equipment manufacturers and the scientific and education...

  1. Agribusiness Industry Study Final Report

    Science.gov (United States)

    2005-01-01

    Instituto Riograndense do Arroz, Rio Grande do Sul, Brazil Empresa Bunge Alimentos, Rio Grande do Sul, Brazil Universal Leaf Tobacos Ltda., Rio...become a networked web . A final note on the industry defined. This study focuses primarily on the portion of the agribusiness industry concerned

  2. The reconstruction software for the MICE scintillating fibre trackers

    CERN Document Server

    Dobbs, A; Long, K; Santos, E; Uchida, M A; Kyberd, P; Heidt, C; Blot, S; Overton, E

    2016-01-01

    The Muon Ionization Cooling Experiment (MICE) will demonstrate the principle of muon beam phase-space reduction via ionization cooling. Muon beam cooling will be required for the proposed Neutrino Factory or Muon Collider. The phase-space before and after the cooling cell must be measured precisely. This is achieved using two scintillating-fibre trackers, each placed in a solenoidal magnetic field. This paper describes the software reconstruction for the fibre trackers: the GEANT4 based simulation; the implementation of the geometry; digitisation; space-point reconstruction; pattern recognition; and the final track fit based on a Kalman filter. The performance of the software is evaluated by means of Monte Carlo studies and the precision of the final track reconstruction is evaluated.

  3. Cholesterol-Lowering Effect of Allicin on Hypercholesterolemic ICR Mice

    Directory of Open Access Journals (Sweden)

    Yin Lu

    2012-01-01

    Full Text Available Allicin was discussed as an active compound with regard to the beneficial effects of garlic in atherosclerosis. The aim of this study was to investigate the cholesterol-lowering properties of allicin. In order to examine its effects on hypercholesterolemia in male ICR mice, this compound with doses of 5, 10, or 20 mg/kg body weight was given orally daily for 12 weeks. Changes in body weight and daily food intake were measured regularly during the experimental period. Final contents of serum cholesterol, triglyceride, glucose, and hepatic cholesterol storage were determined. Following a 12-week experimental period, the body weights of allicin-fed mice were less than those of control mice on a high-cholesterol diet by 38.24±7.94% (P<0.0001 with 5 mg/kg allicin, 39.28±5.03% (P<0.0001 with 10 mg/kg allicin, and 41.18±5.00% (P<0.0001 with 20 mg/kg allicin, respectively. A decrease in daily food consumption was also noted in most of the treated animals. Meanwhile, allicin showed a favorable effect in reducing blood cholesterol, triglycerides, and glucose levels and caused a significant decrease in lowering the hepatic cholesterol storage. Accordingly, both in vivo and in vitro results demonstrated a potential value of allicin as a pronounced cholesterol-lowering candidate, providing protection against the onset of atherosclerosis.

  4. Postnatal Hematopoiesis and Gut Microbiota in NOD Mice Deviate from C57BL/6 Mice

    Directory of Open Access Journals (Sweden)

    Dina Silke Malling Damlund

    2016-01-01

    Full Text Available Neonatal studies in different mouse strains reveal that early life colonization affects the development of adaptive immunity in mice. The nonobese diabetic (NOD mouse spontaneously develops autoimmune diabetes, but neonatal studies of NOD mice are lacking. We hypothesized that NOD mice deviate from another much used mouse strain, C57BL/6, with respect to postnatal microbiota and/or hematopoiesis and compared this in newborn mice of dams housed under the same conditions. A distinct bacteria profile rich in staphylococci was found at postnatal days (PND 1–4 in NOD mice. Furthermore, a distinct splenic cell profile high in a granulocytic phenotype was evident in the neonatal NOD mice whereas neonatal C57BL/6 mice showed a profile rich in monocytes. Neonatal expression of Reg3g and Muc2 in the gut was deviating in NOD mice and coincided with fewer bacteria attaching to the Mucosal surface in NOD compared to C57BL/6 mice.

  5. Expedited technology demonstration project final report: final forms

    Energy Technology Data Exchange (ETDEWEB)

    Hopper, R W

    1999-05-01

    ETDP Final Forms was an attempt to demonstrate the fabrication and performance of a ceramic waste form immobilizing the hazardous and radioactive elements of the MSO/SR mineral residues. The ceramic material had been developed previously. The fabrication system was constructed and functioned as designed except for the granulator. Fabrication of our particular ceramic, however, proved unsatisfactory. The ceramic material design was therefore changed toward the end of the project, replacing nepheline with zircon as the sink for silica. Preliminary results were encouraging, but more development is needed. Fabrication of the new ceramic requires major changes in the processing: Calcination and granulation would be replaced by spray drying; and sintering would be at higher temperature. The main goal of the project--demonstrating the fabrication and performance of the waste form--was not achieved. This report summarizes Final Forms' activities. The problem of immobilizing the MSO/SR mineral residues is discussed.

  6. Remodeling of the Cervix and Parturition in Mice Lacking the Progesterone Receptor B Isoform1

    Science.gov (United States)

    Yellon, Steven M.; Oshiro, Bryan T.; Chhaya, Tejas Y.; Lechuga, Thomas J.; Dias, Rejane M.; Burns, Alexandra E.; Force, Lindsey; Apostolakis, Ede M.

    2011-01-01

    Withdrawal of progestational support for pregnancy is part of the final common pathways for parturition, but the role of nuclear progesterone receptor (PGR) isoforms in this process is not known. To determine if the PGR-B isoform participates in cervical remodeling at term, cervices were obtained from mice lacking PGR-B (PGR-BKO) and from wild-type (WT) controls before or after birth. PGR-BKO mice gave birth to viable pups at the same time as WT controls during the early morning of Day 19 postbreeding. Morphological analyses indicated that by the day before birth, cervices from PGR-BKO and WT mice had increased in size, with fewer cell nuclei/area as well as diminished collagen content and structure, as evidenced by optical density of picrosirius red-stained sections, compared to cervices from nonpregnant mice. Moreover, increased numbers of resident macrophages, but not neutrophils, were found in the prepartum cervix of PGR-BKO compared to nonpregnant mice, parallel to findings in WT mice. These results suggest that PGR-B does not contribute to the growth or degradation of the extracellular matrix or proinflammatory processes associated with recruitment of macrophages in the cervix leading up to birth. Rather, other receptors may contribute to the progesterone-dependent mechanism that promotes remodeling of the cervix during pregnancy and in the proinflammatory process associated with ripening before parturition. PMID:21613631

  7. Number of X-chromosome genes influences social behavior and vasopressin gene expression in mice.

    Science.gov (United States)

    Cox, Kimberly H; Quinnies, Kayla M; Eschendroeder, Alex; Didrick, Paula M; Eugster, Erica A; Rissman, Emilie F

    2015-01-01

    Sex differences in behavior are widespread and often caused by hormonal differences between the sexes. In addition to hormones, the composition and numbers of the sex chromosomes also affect a variety of sex differences. In humans, X-chromosome genes are implicated in neurobehavioral disorders (i.e. fragile-X, autism). To investigate the role of X-chromosome genes in social behavior, we used a mouse model that has atypical sex chromosome configurations resembling Turner (45, XO) and Klinefelter syndromes (47, XXY). We examined a number of behaviors in juvenile mice. Mice with only one copy of most X-chromosome genes, regardless of gonadal sex, were less social in dyadic interaction and social preference tasks. In the elevated plus maze, mice with one X-chromosome spent less time in the distal ends of the open arms as compared to mice with two copies of X-chromosome genes. Using qRTPCR, we noted that amygdala from female mice with one X-chromosome had higher expression levels of vasopressin (Avp) as compared to mice in the other groups. Finally, in plasma from girls with Turner syndrome we detected reduced vasopressin (AVP) concentrations as compared to control patients. These novel findings link sex chromosome genes with social behavior via concentrations of AVP in brain, adding to our understanding of sex differences in neurobehavioral disorders.

  8. Role of Fyn-mediated NMDA receptor function in prediabetic neuropathy in mice.

    Science.gov (United States)

    Suo, Meng; Wang, Ping; Zhang, Mengyuan

    2016-08-01

    Diabetic neuropathy is a common complication of diabetes. This study evaluated the role of Fyn kinase and N-methyl-d-aspartate receptors (NMDARs) in the spinal cord in diabetic neuropathy using an animal model of high-fat diet-induced prediabetes. We found that prediabetic wild-type mice exhibited tactile allodynia and thermal hypoalgesia after a 16-wk high-fat diet, relative to normal diet-fed wild-type mice. Furthermore, prediabetic wild-type mice exhibited increased tactile allodynia and thermal hypoalgesia at 24 wk relative to 16 wk. Such phenomena were correlated with increased expression and activation of NR2B subunit of NMDARs, as well as Fyn-NR2B interaction in the spinal cord. Fyn(-/-) mice developed prediabetes after 16-wk high-fat diet treatment and exhibited thermal hypoalgesia, without showing tactile allodynia or altered expression and activation of NR2B subunit, relative to normal diet-fed Fyn(-/-) mice. Finally, intrathecal administrations of Ro 25-6981 (selective NR2B subunit-containing NMDAR antagonist) dose-dependently alleviated tactile allodynia, but not thermal hypoalgesia, at 16 and 24 wk in prediabetic wild-type mice. Our results suggested that Fyn-mediated NR2B signaling plays a critical role in regulation of prediabetic neuropathy and that the increased expression/function of NR2B subunit-containing NMDARs may contribute to the progression of neuropathy in type 2 diabetes.

  9. Intermittent injections of osteocalcin improve glucose metabolism and prevent type 2 diabetes in mice.

    Science.gov (United States)

    Ferron, Mathieu; McKee, Marc D; Levine, Robert L; Ducy, Patricia; Karsenty, Gérard

    2012-02-01

    The uncarboxylated form of the osteoblast-specific secreted molecule osteocalcin is a hormone favoring glucose handling and increasing energy expenditure. As a result, the absence of osteocalcin leads to glucose intolerance in mice, while genetically modified mice with an increase in uncarboxylated osteocalcin are protected from type 2 diabetes and obesity. Here, we tested in the mouse the therapeutic potential of intermittent administration of osteocalcin. We found that daily injections of osteocalcin at either 3 or 30 ng/g/day significantly improved glucose tolerance and insulin sensitivity in mice fed a normal diet. This was attributable, in part, to an increase in both β-cell mass and insulin secretion. When mice were fed a high-fat diet (HFD), daily injections of osteocalcin partially restored insulin sensitivity and glucose tolerance. Moreover, mice treated with intermittent osteocalcin injections displayed additional mitochondria in their skeletal muscle, had increased energy expenditure and were protected from diet-induced obesity. Finally, the hepatic steatosis induced by the HFD was completely rescued in mice receiving osteocalcin daily. Overall, these results provide evidence that daily injections of osteocalcin can improve glucose handling and prevent the development of type 2 diabetes.

  10. Sex-Specific Regulation of Depression, Anxiety-Like Behaviors and Alcohol Drinking in Mice Lacking ENT1.

    Science.gov (United States)

    Ruby, Christina L; Walker, Denise L; An, Joyce; Kim, Jason; Choi, Doo-Sup

    2011-12-25

    OBJECTIVES: Adenosine signaling has been implicated in the pathophysiology of several psychiatric disorders including alcoholism, depression, and anxiety. Adenosine levels are controlled in part by transport across the cell membrane by equilibrative nucleoside transporters (ENTs). Recent evidence showed that a polymorphism in the gene encoding ENT1 is associated with comorbid depression and alcoholism in women. We have previously shown that deletion of ENT1 reduces ethanol intoxication and elevates alcohol intake in mice. Interestingly, ENT1 null mice display decreased anxiety-like behavior compared to wild-type littermates. However, our behavioral studies were performed only in male mice. Here, we extend our research to include female mice, and test the effect of ENT1 knockout on other behavioral correlates of alcohol drinking, including depressive and compulsive behavior, in mice. METHODS: To assess depression-like behavior, we used a forced swim test modified for mice. We examined anxiety-like behavior and locomotor activity in open field chambers, and perseverant behavior using the marble-burying test. Finally, we investigated alcohol consumption and preference in female mice using a two-bottle choice paradigm. RESULTS: ENT1 null mice of both sexes showed reduced immobility time in the forced swim test and increased time in the center of the open field compared to wild-type littermates. ENT1 null mice of both sexes showed similar locomotor activity levels and habituation to the open field chambers. Female ENT1 null mice displayed increased marble-burying compared to female wild-types, but no genotype difference was evident in males. Female ENT1 null mice showed increased ethanol consumption and preference compared to female wild-types. CONCLUSIONS: Our findings suggest that ENT1 contributes to several important behaviors involved in psychiatric disorders. Inhibition of ENT1 may be beneficial in treating depression and anxiety, while enhancement of ENT1 function

  11. Antioxidant properties of lutein contribute to the protection against lipopolysaccharide-induced uveitis in mice

    OpenAIRE

    Yao Xin-Sheng; Yao Nan; Lan Fang; Tsoi Bun; He Rong-Rong; Kurihara Hiroshi

    2011-01-01

    Abstract Background Lutein is an important eye-protective nutrient. This study investigates the protective effects and mechanisms of lutein on lipopolysaccharides (LPS)-induced uveitis in mice. Methods Lutein, suspended in drinking water at a final concentration of 12.5 and 25 mg/mL, was administered to mice at 0.1 mL/10 g body weight for five consecutive days. Control and model group received drinking water only. Uveitis was induced by injecting LPS (100 mg per mouse) into the footpad in the...

  12. Antioxidant properties of lutein contribute to the protection against lipopolysaccharide-induced uveitis in mice

    OpenAIRE

    He, Rong-rong; Tsoi, Bun; Lan, Fang; Yao, Nan; Yao, Xin-Sheng; Kurihara, Hiroshi

    2011-01-01

    Background Lutein is an important eye-protective nutrient. This study investigates the protective effects and mechanisms of lutein on lipopolysaccharides (LPS)-induced uveitis in mice. Methods Lutein, suspended in drinking water at a final concentration of 12.5 and 25 mg/mL, was administered to mice at 0.1 mL/10 g body weight for five consecutive days. Control and model group received drinking water only. Uveitis was induced by injecting LPS (100 mg per mouse) into the footpad in the model an...

  13. Metabolic abnormalities and hypoleptinemia in α-synuclein A53T mutant mice.

    Science.gov (United States)

    Rothman, Sarah M; Griffioen, Kathleen J; Fishbein, Kenneth W; Spencer, Richard G; Makrogiannis, Sokratis; Cong, Wei-Na; Martin, Bronwen; Mattson, Mark P

    2014-05-01

    Parkinson's disease (PD) patients frequently display loss of body fat mass and increased energy expenditure, and several studies have outlined a relationship between these metabolic abnormalities and disease severity, yet energy metabolism is largely unstudied in mouse models of PD. Here we characterize metabolic and physiologic responses to a high calorie diet (HCD) in mice expressing in neurons a mutant form of human α-synuclein (A53T) that causes dominantly inherited familial forms of the disease. A53T (SNCA) and wild type (WT) littermate mice were placed on a HCD for 12 weeks and evaluated for weight gain, food intake, body fat, blood plasma leptin, hunger, glucose tolerance, and energy expenditure. Results were compared with both SNCA and WT mice on a control diet. Despite consuming similar amounts of food, WT mice gained up to 66% of their original body weight on a HCD, whereas SNCA mice gained only 17%. Further, after 12 weeks on a HCD, magnetic resonance imaging analysis revealed that WT mice had significantly greater total and visceral body fat compared with SNCA mice (p < 0.007). At the age of 24 weeks SNCA mice displayed significantly increased hunger compared with WT (p < 0.03). At the age of 36 weeks, SNCA mice displayed significant hypoleptinemia compared with WT, both on a normal diet and a HCD (p < 0.03). The HCD induced insulin insensitivity in WT, but not SNCA mice, as indicated by an oral glucose tolerance test. Finally, SNCA mice displayed greater energy expenditure compared with WT, as measured in a Comprehensive Laboratory Animal Monitoring System, after 12 weeks on a HCD. Thus, SNCA mice are resistant to HCD-induced obesity and insulin resistance and display reduced body fat, increased hunger, hypoleptinemia and increased energy expenditure. Our findings reveal a profile of metabolic dysfunction in a mouse model of PD that is similar to that of human PD patients, thus providing evidence that α-synuclein pathology is sufficient to drive such

  14. Final disposal of radioactive waste

    Directory of Open Access Journals (Sweden)

    Freiesleben H.

    2013-06-01

    Full Text Available In this paper the origin and properties of radioactive waste as well as its classification scheme (low-level waste – LLW, intermediate-level waste – ILW, high-level waste – HLW are presented. The various options for conditioning of waste of different levels of radioactivity are reviewed. The composition, radiotoxicity and reprocessing of spent fuel and their effect on storage and options for final disposal are discussed. The current situation of final waste disposal in a selected number of countries is mentioned. Also, the role of the International Atomic Energy Agency with regard to the development and monitoring of international safety standards for both spent nuclear fuel and radioactive waste management is described.

  15. p-Cymene reduces orofacial nociceptive response in mice

    Directory of Open Access Journals (Sweden)

    Michele F. Santana

    2011-12-01

    Full Text Available This study investigated the possible antinociceptive effect of p-cymene in different tests of orofacial nociception. The animals (mice were pretreated (i.p. with p-cymene (25, 50, 100 mg/kg, morphine (5 mg/kg, or vehicle (0.2% Tween 80+saline, and were then subsequently administered, subcutaneously into their upper lip: formalin, capsaicin, and glutamate. The nociceptive behavior response was characterized by the time in s that the mice remained rubbing the orofacial region, for a period of 40 min in the formalin test (first phase, 0-6 min; and second phase, 21-40 min, and for 42 and 15 min in the capsaicin and glutamate tests, respectively. To verify the possible opioid involvement in the antinociceptive effects, naloxone (i.p. was administered into the mice 15 min prior to the pretreatment with p-cymene (100 mg/kg. Finally, whether or not the p-cymene evoked any change in motor performance in the Rota-rod test was evaluated. The results showed that the treatment with p-cymene, at all doses, reduced (p<0.001 the nociceptive behavior in all nociception tests. The antinociceptive effect of p-cymene was antagonized by naloxone (1.5 mg/kg. Additionally, mice treated with p-cymene did not show any change in motor performance. In conclusion, p-cymene attenuated orofacial nociception, suggesting an involvement of the opioid system in this effect. Thus, p-cymene might represent an important biomolecule for management and/or treatment of orofacial pain.

  16. NONLINEAR DYNAMICAL SYSTEMS - Final report

    Energy Technology Data Exchange (ETDEWEB)

    Philip Holmes

    2005-12-31

    This document is the final report on the work completed on DE-FG02-95ER25238 since the start of the second renewal period: Jan 1, 2001. It supplements the annual reports submitted in 2001 and 2002. In the renewal proposal I envisaged work in three main areas: Analytical and topological tools for studying flows and maps Low dimensional models of fluid flow Models of animal locomotion and I describe the progess made on each project.

  17. Correlation between thyroid hormone status and hepatic hyperplasia and hypertrophy caused by the peroxisome proliferator-activated receptor alpha agonist Wy-14,643

    Directory of Open Access Journals (Sweden)

    Wang C

    2004-05-01

    Full Text Available Abstract Background The metabolic inhibitor rotenone inhibits hepatocellular proliferation and the incidence of liver cancer resulting from exposure to the PPARα agonist Wy-14,643, via unknown mechanisms. Since the absence of thyroid hormones diminishes hepatomegaly, an early biomarker for the hepatocarcinogenicity induced by PPARα agonists, this study was undertaken to investigate whether rotenone might interference with the ability of Wy-14,643 to alter the animal thyroid status. Methods Male B6C3F1 mice were given Wy-14,643 (100 ppm, rotenone (600 ppm or a mixture of both, in the feed for 7 days. Bromodeoxyuridine (BrDU, marker of cell replication, was delivered through subcutaneously implanted osmotic mini-pumps. At the end of the experiment, sera were collected and corticosterone and thyroid hormone levels were measured by solid-phase radioimmunoassay kits. In addition, liver tissue samples were stained immunohistochemically for BrDU to determine percentages of labeled cells. Further, cell surface area was determined from images generated by a Zeiss Axioplan microscope equipped with a plan Neofluar ×40 0.75 na objective. Tracings of individual hepatocyte perimeters were then analyzed and cell-surface areas were calculated using MicroMeasure FL-4000. Results Wy-14,643 caused a significant increase in liver weights, hepatocyte BrDU labeling index (LI, and hepatocyte surface area. In animals which received both Wy-14,643 and rotenone simultaneously, all of these effects were significantly less pronounced compared with mice that received Wy-14,643 alone. Rotenone alone decreased liver weights, LI and surface area. The Free Thyroid Index (FTI, which provides an accurate reflection of the animal's thyroid status, was 5.0 ± 0.3 in control mice. In animals exposed to rotenone, these values decreased to 2.0 ± 0.9, but in animals which received Wy-14,643, levels increased significantly to 7.7 ± 0.9. FTI values decreased to 3.4 ± 0.8 in mice

  18. CETP Expression Protects Female Mice from Obesity-Induced Decline in Exercise Capacity.

    Directory of Open Access Journals (Sweden)

    David A Cappel

    Full Text Available Pharmacological approaches to reduce obesity have not resulted in dramatic reductions in the risk of coronary heart disease (CHD. Exercise, in contrast, reduces CHD risk even in the setting of obesity. Cholesteryl Ester Transfer Protein (CETP is a lipid transfer protein that shuttles lipids between serum lipoproteins and tissues. There are sexual-dimorphisms in the effects of CETP in humans. Mice naturally lack CETP, but we previously reported that transgenic expression of CETP increases muscle glycolysis in fasting and protects against insulin resistance with high-fat diet (HFD feeding in female but not male mice. Since glycolysis provides an important energy source for working muscle, we aimed to define if CETP expression protects against the decline in exercise capacity associated with obesity. We measured exercise capacity in female mice that were fed a chow diet and then switched to a HFD. There was no difference in exercise capacity between lean, chow-fed CETP female mice and their non-transgenic littermates. Female CETP transgenic mice were relatively protected against the decline in exercise capacity caused by obesity compared to WT. Despite gaining similar fat mass after 6 weeks of HFD-feeding, female CETP mice showed a nearly two-fold increase in run distance compared to WT. After an additional 6 weeks of HFD-feeding, mice were subjected to a final exercise bout and muscle mitochondria were isolated. We found that improved exercise capacity in CETP mice corresponded with increased muscle mitochondrial oxidative capacity, and increased expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α. These results suggest that CETP can protect against the obesity-induced impairment in exercise capacity and may be a target to improve exercise capacity in the context of obesity.

  19. CETP Expression Protects Female Mice from Obesity-Induced Decline in Exercise Capacity.

    Science.gov (United States)

    Cappel, David A; Lantier, Louise; Palmisano, Brian T; Wasserman, David H; Stafford, John M

    2015-01-01

    Pharmacological approaches to reduce obesity have not resulted in dramatic reductions in the risk of coronary heart disease (CHD). Exercise, in contrast, reduces CHD risk even in the setting of obesity. Cholesteryl Ester Transfer Protein (CETP) is a lipid transfer protein that shuttles lipids between serum lipoproteins and tissues. There are sexual-dimorphisms in the effects of CETP in humans. Mice naturally lack CETP, but we previously reported that transgenic expression of CETP increases muscle glycolysis in fasting and protects against insulin resistance with high-fat diet (HFD) feeding in female but not male mice. Since glycolysis provides an important energy source for working muscle, we aimed to define if CETP expression protects against the decline in exercise capacity associated with obesity. We measured exercise capacity in female mice that were fed a chow diet and then switched to a HFD. There was no difference in exercise capacity between lean, chow-fed CETP female mice and their non-transgenic littermates. Female CETP transgenic mice were relatively protected against the decline in exercise capacity caused by obesity compared to WT. Despite gaining similar fat mass after 6 weeks of HFD-feeding, female CETP mice showed a nearly two-fold increase in run distance compared to WT. After an additional 6 weeks of HFD-feeding, mice were subjected to a final exercise bout and muscle mitochondria were isolated. We found that improved exercise capacity in CETP mice corresponded with increased muscle mitochondrial oxidative capacity, and increased expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). These results suggest that CETP can protect against the obesity-induced impairment in exercise capacity and may be a target to improve exercise capacity in the context of obesity.

  20. Effect of adiponectin deficiency on intestinal damage and hematopoietic responses of mice exposed to gamma radiation

    Energy Technology Data Exchange (ETDEWEB)

    Ponemone, Venkatesh; Fayad, Raja; Gove, Melissa E.; Pini, Maria [Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL 60612 (United States); Fantuzzi, Giamila, E-mail: giamila@uic.edu [Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL 60612 (United States)

    2010-08-07

    Adiponectin (APN) is an adipose tissue-derived cytokine that regulates insulin sensitivity and inflammation. It is also involved in modulation of cell proliferation by binding to various growth factors. Based on its known effects in modulating cell proliferation and oxidative stress, APN may potentially be involved in regulating tissue damage and repair following irradiation. Adiponectin KO mice and their WT littermates were exposed to a single whole-body dose of 3 or 6 Gy gamma radiation. Radiation-induced alterations were studied in jejunum, blood, bone marrow and thymus at days 1 and 5 post-irradiation and compared with sham-irradiated groups. In WT mice, irradiation did not significantly alter serum APN levels while inducing a significant decrease in serum leptin. Irradiation caused a significant reduction in thymocyte cellularity, with concomitant decrease in CD4{sup +}, CD8{sup +} and CD4{sup +}CD8{sup +} T cell populations, with no significant differences between WT and APN KO mice. Irradiation resulted in a significantly higher increase in the frequency of micronucleated reticulocytes in the blood of APN KO compared with WT mice, whereas frequency of micronucleated normochromatic erythrocytes in the bone marrow at day 5 was significantly higher in WT compared with APN KO mice. Finally, irradiation induced similar alterations in villus height and crypt cell proliferation in the jejunum of WT and APN KO mice. Jejunum explants from sham-irradiated APN KO mice produced higher levels of IL-6 compared with tissue from WT animals, but the difference was no longer apparent following irradiation. Our data indicate that APN deficiency does not play a significant role in modulating radiation-induced gastrointestinal injury in mice, while it may participate in regulation of damage to the hematopoietic system.

  1. Brain serotonin signaling does not determine sexual preference in male mice.

    Directory of Open Access Journals (Sweden)

    Mariana Angoa-Pérez

    Full Text Available It was reported recently that male mice lacking brain serotonin (5-HT lose their preference for females (Liu et al., 2011, Nature, 472, 95-100, suggesting a role for 5-HT signaling in sexual preference. Regulation of sex preference by 5-HT lies outside of the well established roles in this behavior established for the vomeronasal organ (VNO and the main olfactory epithelium (MOE. Presently, mice with a null mutation in the gene for tryptophan hydroxylase 2 (TPH2, which are depleted of brain 5-HT, were tested for sexual preference. When presented with inanimate (urine scents from male or estrous female or animate (male or female mouse in estrus sexual stimuli, TPH2-/- males show a clear preference for female over male stimuli. When a TPH2-/- male is offered the simultaneous choice between an estrous female and a male mouse, no sexual preference is expressed. However, when confounding behaviors that are seen among 3 mice in the same cage are controlled, TPH2-/- mice, like their TPH2+/+ counterparts, express a clear preference for female mice. Female TPH2-/- mice are preferred by males over TPH2+/+ females but this does not lead to increased pregnancy success. In fact, if one or both partners in a mating pair are TPH2-/- in genotype, pregnancy success rates are significantly decreased. Finally, expression of the VNO-specific cation channel TRPC2 and of CNGA2 in the MOE of TPH2-/- mice is normal, consistent with behavioral findings that sexual preference of TPH2-/- males for females is intact. In conclusion, 5-HT signaling in brain does not determine sexual preference in male mice. The use of pharmacological agents that are non-selective for the 5-HT neuronal system and that have serious adverse effects may have contributed historically to the stance that 5-HT regulates sexual behavior, including sex partner preference.

  2. 14 CFR 1214.1105 - Final ranking.

    Science.gov (United States)

    2010-01-01

    ... 14 Aeronautics and Space 5 2010-01-01 2010-01-01 false Final ranking. 1214.1105 Section 1214.1105... Recruitment and Selection Program § 1214.1105 Final ranking. Final rankings will be based on a combination of... preference will be included in this final ranking in accordance with applicable regulations....

  3. Postnatal hematopoiesis and gut microbiota in NOD mice deviate from C57BL/6 mice

    DEFF Research Database (Denmark)

    Damlund, Dina Silke Malling; Metzdorff, Stine Broeng; Hasselby, Jane Preuss

    2016-01-01

    Neonatal studies in different mouse strains reveal that early life colonization affects the development of adaptive immunity in mice. The nonobese diabetic (NOD) mouse spontaneously develops autoimmune diabetes, but neonatal studies of NOD mice are lacking. We hypothesized that NOD mice deviate f...

  4. New Approaches to Final Cooling

    Energy Technology Data Exchange (ETDEWEB)

    Neuffer, David [Fermilab

    2014-11-10

    A high-energy muon collider scenario require a “final cooling” system that reduces transverse emittances by a factor of ~10 while allowing longitudinal emittance increase. The baseline approach has low-energy transverse cooling within high-field solenoids, with strong longitudinal heating. This approach and its recent simulation are discussed. Alternative approaches which more explicitly include emittance exchange are also presented. Round-to-flat beam transform, transverse slicing, and longitudinal bunch coalescence are possible components of the alternative approach. A more explicit understanding of solenoidal cooling beam dynamics is introduced.

  5. Virtualized Network Control. Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Ghani, Nasir [Univ. of New Mexico, Albuquerque, NM (United States)

    2013-02-01

    This document is the final report for the Virtualized Network Control (VNC) project, which was funded by the United States Department of Energy (DOE) Office of Science. This project was also informally referred to as Advanced Resource Computation for Hybrid Service and TOpology NEtworks (ARCHSTONE). This report provides a summary of the project's activities, tasks, deliverable, and accomplishments. It also provides a summary of the documents, software, and presentations generated as part of this projects activities. Namely, the Appendix contains an archive of the deliverables, documents, and presentations generated a part of this project.

  6. Hydroprocessing SRC. Final technical report

    Energy Technology Data Exchange (ETDEWEB)

    Bronfenbrenner, J.C.; Garg, D.; Harris, C.F.; Znaimer, S.

    1983-09-01

    Catalyst activity and aging rate were studied in ICRC's process development unit (PDU) and at the Wilsonville Advanced Coal Liquefaction Facility under SRC-I Demonstration Plant hydroprocessing conditions. Similar studies using both high- and low-conversion modes were conducted by The Lummus Company. The studies determined variations in SRC conversion, hydrocarbon gas production, hydrogen consumption, and heteroatom removal. Samples of spent catalyst were analyzed to ascertain the reasons for catalyst deactivation. Finally, the ICRC PDU hydroprocessing results were compared with those generated at Lummus and Wilsonville pilot plants.

  7. [Experimental nuclear physics]. Final report

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1991-04-01

    This is the final report of the Nuclear Physics Laboratory of the University of Washington on work supported in part by US Department of Energy contract DE-AC06-81ER40048. It contains chapters on giant dipole resonances in excited nuclei, nucleus-nucleus reactions, astrophysics, polarization in nuclear reactions, fundamental symmetries and interactions, accelerator mass spectrometry (AMS), ultra-relativistic heavy ions, medium energy reactions, work by external users, instrumentation, accelerators and ion sources, and computer systems. An appendix lists Laboratory personnel, a Ph. D. degree granted in the 1990-1991 academic year, and publications. Refs., 41 figs., 7 tabs.

  8. Effects of levamisole on experimental infections by Plasmodium berghei in mice

    Directory of Open Access Journals (Sweden)

    Enrique Melendez C.

    1987-12-01

    Full Text Available Levamisole (phenylimidothiazol, considered a strong immunostimulant, when administered to healthy Swiss mice did not cause a significant increase in -the weight of their thymus, liver and spleen, even though the drug was used at different times before removing such organs. High doses ofdrug used in the 4-day prophylactic scheme had no antimalarial effect. However, when given to malaria infected mice 24 hours before, at the same time, and 24 hours after the inoculation of a chloroquine-sensitive or a chloroquine-resistant strain of Plasmodium berghei small doses of the drug induced a somewhat decreased parasitemia, the dose of 1 mg/kg body weight before the inoculum being the best scheme. The mortality rates by malaria in the levamisole treated groups were also delayed although all mice finally died. The data suggest that levamisole may display a stimulant effect on the depressed immune response caused by malaria.

  9. Hepatotoxic effect of 1-bromopropane and its conjugation with glutathione in male ICR mice.

    Science.gov (United States)

    Lee, Sang Kyu; Jo, Sang Wook; Jeon, Tae Won; Jun, In Hye; Jin, Chun Hua; Kim, Ghee Hwan; Lee, Dong Ju; Kim, Tae-Oh; Lee, Eung-Seok; Jeong, Tae Cheon

    2005-10-01

    The hepatotoxic effects of 1-bromopropane (1-BP) and its conjugation with glutathione were investigated in male ICR mice. A single dose (1000 mg/kg, po) of 1-BP in corn oil to mice significantly increased serum activities of alanine aminotransferase and aspartate aminotransferase. Glutathione (GSH) content was dose-dependently reduced in liver homogenates 12 h after 1-BP treatment. In addition, 1-BP treatment dose-dependently increased levels of S-propyl GSH conjugate at 12 h after treatment, as measured by liquid chromatography-electrospray ionization tandem mass spectrometry. The GSH conjugate was maximally increased in liver at 6 h after 1-BP treatment (1000 mg/kg), with a parallel depletion of hepatic GSH content. Finally, 1-BP induced the production of malondialdehyde in liver. The present results suggest that 1-BP might cause hepatotoxicity, including lipid peroxidation via the depletion of GSH, due to the formation of GSH conjugates in male ICR mice.

  10. AGONISTIC BEHAVIOR OF LABORATORY MICE

    Directory of Open Access Journals (Sweden)

    D. Cinghiţă

    2005-01-01

    Full Text Available In this work we study agonistic behavior of laboratory white mice when they are kept in captivity. For all this experimental work we used direct observation of mice, in small lists, because we need a reduced space to emphasize characteristics of agonistic behavior. Relations between members of the same species that live in organized groups are based in most cases on hierarchical structure. Relations between leader and subservient, decided by fighting, involve a thorough observation between individuals. Each member of a group has its own place on the ierarchical scale depending on resultes of fhights – it can be leader or it can be subsurvient, depending on if it wines or looses the fight. Once hierarchical scale made, every animal will adjust its behavior. After analyzing the obtained data we have enough reasons to believe that after fights the winner, usually, is the massive mouse, but it is also very important the sexual ripeness, so the immature male will be beaten. The leader male had a big exploring area and it checks up all territory.The females can be more aggressive, its fights are more brutal, than male fights are, when they fight for supremacy, but in this case fights are not as frequent as in the case of males. Always the superior female, on hierarchical scale, shows males its own statute, so the strongest genes will be perpetuated.

  11. Mice embryology: a microscopic overview.

    Science.gov (United States)

    Salvadori, Maria Letícia Baptista; Lessa, Thais Borges; Russo, Fabiele Baldino; Fernandes, Renata Avancini; Kfoury, José Roberto; Braga, Patricia Cristina Baleeiro Beltrão; Miglino, Maria Angélica

    2012-10-01

    In this work, we studied the embryology of mice of 12, 14, and 18 days of gestation by gross observation, light microscopy, and scanning electron microscopy. Grossly, the embryos of 12 days were observed in C-shaped region of the brain, eye pigmentation of the retina, first, second, and third pharyngeal arches gill pit nasal region on the fourth ventricle brain, cervical curvature, heart, liver, limb bud thoracic, spinal cord, tail, umbilical cord, and place of the mesonephric ridge. Microscopically, the liver, cardiovascular system and spinal cord were observed. In the embryo of 14 days, we observed structures that make up the liver and heart. At 18 days of gestation fetuses, it was noted the presence of eyes, mouth, and nose in the cephalic region, chest and pelvic region with the presence of well-developed limbs, umbilical cord, and placenta. Scanning electron microscopy in 18 days of gestation fetuses evidenced head, eyes closed eyelids, nose, vibrissae, forelimb, heart, lung, kidney, liver, small bowel, diaphragm, and part of the spine. The results obtained in this work describe the internal and external morphology of mice, provided by an integration of techniques and review of the morphological knowledge of the embryonic development of this species, as this animal is of great importance to scientific studies.

  12. Amylin induces hypoglycemia in mice

    Directory of Open Access Journals (Sweden)

    Luiz H. Guerreiro

    2013-03-01

    Full Text Available Amylin is a 37-aminoacid pancreatic protein that exerts control over several metabolic events such as glycemia and lacticemia. Amylin has long been shown to induce increases in arterial plasma glucose. We decided to investigate whether amylin plays additional roles in the glucose metabolism. We evaluated glucose homeostasis using whole blood from the tail tip of fasting, conscious, unrestrained normal and streptozotocyn-induced diabetic mice following subcutaneous administration of mouse amylin. Subcutaneous injection of 1 μg mouse amylin caused a transient decrease in whole blood glucose in both normal and diabetic mice in the absence of insulin. The blood glucose levels were lowest approximately 2 hours after amylin administration, after that they gradually recovered to the levels of the control group. The hypoglycemic effect followed a dose-dependent response ranging from 0.1 to 50 µg / mouse. These results reveal the ability for amylin in the direct control of glycemia at low doses in the absence of insulin.

  13. Urat1-Uox double knockout mice are experimental animal models of renal hypouricemia and exercise-induced acute kidney injury.

    Science.gov (United States)

    Hosoyamada, Makoto; Tsurumi, Yu; Hirano, Hidenori; Tomioka, Naoko H; Sekine, Yuko; Morisaki, Takayuki; Uchida, Shunya

    2016-12-01

    Renal hypouricemia (RHUC) is a hereditary disease characterized by a low level of plasma urate but with normal urinary urate excretion. RHUC type 1 is caused by mutations of the urate transporter URAT1 gene (SLC22A12). However, the plasma urate levels of URAT1 knockout mice are no different from those of wild-type mice. In the present study, a double knockout mouse, in which the URAT1 and uricase (Uox) genes were deleted (Urat1-Uox-DKO), were used as an experimental animal model of RHUC type 1 to investigate RHUC and excise-induced acute kidney injury (EIAKI). Mice were given a variable content of allopurinol for one week followed by HPLC measurement of urate and creatinine concentrations in spot urine and blood from the tail. The urinary excretion of urate in Urat1-Uox-DKO mice was approximately 25 times higher than those of humans. With allopurinol, the plasma urate levels of Urat1-Uox-DKO mice were lower than those of Uox-KO mice. There were no differences in the urinary urate excretions between Urat1-Uox-DKO and Uox-KO mice administered with 9 mg allopurinol /100 g feed. In the absence of allopurinol, plasma creatinine levels of some Urat1-Uox-DKO mice were higher than those of Uox-KO mice. Consequently, hypouricemia and normouricosuria may indicate that the Urat1-Uox-DKO mouse administered with allopurinol may represent a suitable animal model of RHUC type 1. Urat1-Uox-DKO mice without allopurinol exhibited acute kidney injury, thus providing additional benefit as a potential animal model for EIAKI. Finally, our data indicate that allopurinol appears to provide prophylactic effects for EIAKI.

  14. Using Mode of Action to Assess Health Risks from Mixtures of Chemical/Physical Agents

    Energy Technology Data Exchange (ETDEWEB)

    Bull, Richard J.; Lei, Xingye C.; Sasser, Lyle B.

    2003-01-20

    Interactions between tumor promoters with differing mechanisms of action were examined in male B6C3F1 mice treated with mixtures of dichloroacetate (DCA), trichloroacetate (TCA), and tetrachloride (CT), each of which acts by a different mode of action. Mice were initiated by vinyl carbamate (VC), and then promoted by DCA, TCA, CT, or the pair-wised combinations of the three compounds. The effect of each treatment or treatment combination on tumor number/animal and tumor size was individually assessed at 18, 24, 30 or 36 weeks of treatment. Dose-related increases in tumor size were observed with 20 & 50 mg/kg CT, but each produced equal number of tumors at 36 weeks with the main distinction being a decrease in tumor latency at the higher dose. Overall TCA treatment produced dose-related increases in tumor number at 36 weeks of treatment. Thus, the lower doses of CT and TCA treatments apparently affected tumor size rather than number. Results with DCA were not as clear as a true maximum tumor number was not clearly observed within the experimental period. Treatment of mice receiving a high dose of TCA (2 g/L of drinking water) combined with varying doses of DCA (0.1, 0.5 and 2 g/L) produced increased numbers of tumors at 24 weeks and 36 weeks. However, at 36 weeks of treatment DCA produced a dose-related decrease in the size of tumors promoted by TCA. The low dose of TCA (0.1 g/L) decreased the number of tumors produced by a high dose of DCA, however, higher doses of TCA produced the same number as observed with DCA alone. Since these two chemicals produce lesions with differing phenotypes, the combination would have been expected to be additive with respect to number, but this was obviously not the case. These data suggest that the induction of liver cancer from mixtures of solvents may have predictable outcomes. The major conclusion is that these interactions are generally no more than additive. It was most interesting to note that additivity was only observed when

  15. Sensitization to lipopolysaccharide in mice with asymptomatic viral infection: role of T cell-dependent production of interferon-gamma

    DEFF Research Database (Denmark)

    Nansen, A; Christensen, Jan Pravsgaard; Marker, O

    1997-01-01

    The interplay between viral infection and lipopolysaccharide (LPS) was studied. Infection with a noncytopathogenic virus, lymphocytic choriomeningitis virus (LCMV), was found to sensitize mice to low doses of LPS. In vivo, this hypersensitivity correlated with hyperproduction of tumor necrosis...... was observed in LCMV-infected, T cell-deficient mice and in mice infected with vesicular stomatitis virus, a virus that induces much less T cell activation than does LCMV. Finally, LCMV infection was much less efficient in priming IFN-gamma knockout mice for hyperproduction of TNF-alpha. These findings...... indicate that clinically silent viral infections may induce hypersensitivity to LPS through T cell activation and subsequent production of IFN-gamma; this sensitizes monocytes/macrophages for hyperproduction of TNF-alpha....

  16. Additive effects of lupin protein and phytic acid on aortic calcification in ApoE deficient mice

    Directory of Open Access Journals (Sweden)

    Alexandra Schutkowski

    2015-03-01

    A two-factorial study with ApoE knockout mice was conducted in which mice received lupin protein isolate or casein with or without phytase. Phytic acid was added to the casein diets to a final concentration identical to the lupin protein diets. Here we show that the serum concentrations of cholesterol, lathosterol and desmosterol were lower and the faecal bile acid excretion was higher in the groups fed lupin proteins than in the groups fed casein (p < 0.05. Mice that received the lupin protein diet containing phytic acid were characterized by a lower aortic calcification than mice of the other three groups (p < 0.05. In conclusion, our results show that the cholesterol lowering properties of lupin protein isolate were not caused by phytic acid. However, the hypocalcific action of lupin proteins appears to depend on the combination of lupin proteins and phytic acid.

  17. Bacterial infections in Myd88-deficient mice.

    Science.gov (United States)

    Villano, Jason S; Rong, Fang; Cooper, Timothy K

    2014-04-01

    Three breeding colonies of Myd88(-/-) mice had a history of significant morbidity and mortality. Although strain-specific poor reproductive performance might explain neonatal death and dystocia, mice were found dead or required euthanasia because of moribundity, distended abdomen, head tilt, and seizures. Histopathology results included bacteremia, placentitis, metritis, peritonitis with abscess formation, and suppurative meningoencephalitis. Intralesional gram-negative coccobacilli were present, often in extremely high number. Cultures of samples of the cardiac blood of a mouse and from water-bottle sipper tubes provided to some affected mice grew Pseudomonas aeruginosa. In addition, affected tissues from 2 mice and feces from a third tested PCR-positive for P. aeruginosa. Although the mice had received autoclaved reverse-osmosis-purified drinking water, we suspect that the mice were inoculated with P. aeruginosa through contaminated sipper tubes. Because of the deficiency in most of the Toll-like receptor signaling pathways, these Myd88(-/-) mice were unlikely to have developed competitive innate and adaptive immune responses, resulting in bacterial infections. These clinical cases underscore the importance of understanding how genotype, phenotype and environment affect animal health. Sound husbandry and experimental practices are needed to prevent the exposure of immuno-deficient mice to pathogens.

  18. Euthanasia of neonatal mice with carbon dioxide

    Science.gov (United States)

    Pritchett, K.; Corrow, D.; Stockwell, J.; Smith, A.

    2005-01-01

    Exposure to carbon dioxide (CO2) is the most prevalent method used to euthanize rodents in biomedical research. The purpose of this study was to determine the time of CO2 exposure required to euthanize neonatal mice (0 to 10 days old). Multiple groups of mice were exposed to 100% CO 2 for time periods between 5 and 60 min. Mice were placed in room air for 10 or 20 min after CO2 exposure, to allow for the chance of recovery. If mice recovered at one time point, a longer exposure was examined. Inbred and outbred mice were compared. Results of the study indicated that time to death varied with the age of the animals and could be as long as 50 min on the day of birth and differed between inbred and outbred mice. Institutions euthanizing neonatal mice with CO2 may wish to adjust their CO 2 exposure time periods according the age of the mice and their genetic background. Copyright 2005 by the American Association for Laboratory Animal Science.

  19. Full-thickness splinted skin wound healing models in db/db and heterozygous mice: implications for wound healing impairment.

    Science.gov (United States)

    Park, Shin Ae; Teixeira, Leandro B C; Raghunathan, Vijay Krishna; Covert, Jill; Dubielzig, Richard R; Isseroff, Roslyn Rivkah; Schurr, Michael; Abbott, Nicholas L; McAnulty, Jonathan; Murphy, Christopher J

    2014-01-01

    The excisional dorsal full-thickness skin wound model with or without splinting is widely utilized in wound healing studies using diabetic or normal mice. However, the effects of splinting on dermal wound healing have not been fully characterized, and there are limited data on the direct comparison of wound parameters in the splinted model between diabetic and normal mice. We compared full-thickness excisional dermal wound healing in db/db and heterozygous mice by investigating the effects of splinting, semi-occlusive dressing, and poly(ethylene glycol) treatment. Two 8-mm full-thickness wounds were made with or without splinting in db/db and heterozygous mice. Body weights, splint maintenance, wound contraction, wound closure, and histopathological parameters including reepithelialization, wound bed collagen deposition, and inflammation were compared between groups. Our results show that silicone splint application effectively reduced wound contraction in heterozygous and db/db mice. Splinted wounds, as opposed to nonsplinted wounds, exhibited no significant differences in wound closure between heterozygous and db/db mice. Finally, polyethylene glycol and the noncontact dressing had no significant effect on wound healing in heterozygous or db/db mice. We believe these findings will help investigators in selection of the appropriate wound model and data interpretation with fully defined parameters.

  20. Bovine milk oligosaccharides decrease gut permeability and improve inflammation and microbial dysbiosis in diet-induced obese mice.

    Science.gov (United States)

    Boudry, Gaëlle; Hamilton, M Kristina; Chichlowski, Maciej; Wickramasinghe, Saumya; Barile, Daniela; Kalanetra, Karen M; Mills, David A; Raybould, Helen E

    2017-01-25

    Obesity is characterized by altered gut homeostasis, including dysbiosis and increased gut permeability closely linked to the development of metabolic disorders. Milk oligosaccharides are complex sugars that selectively enhance the growth of specific beneficial bacteria in the gastrointestinal tract and could be used as prebiotics. The aim of the study was to demonstrate the effects of bovine milk oligosaccharides (BMO) and Bifidobacterium longum ssp. infantis (B. infantis) on restoring diet-induced obesity intestinal microbiota and barrier function defects in mice. Male C57/BL6 mice were fed a Western diet (WD, 40% fat/kcal) or normal chow (C, 14% fat/kcal) for 7 wk. During the final 2 wk of the study, the diet of a subgroup of WD-fed mice was supplemented with BMO (7% wt/wt). Weekly gavage of B. infantis was performed in all mice starting at wk 3, yet B. infantis could not be detected in any luminal contents when mice were killed. Supplementation of the WD with BMO normalized the cecal and colonic microbiota with increased abundance of Lactobacillus compared with both WD and C mice and restoration of Allobaculum and Ruminococcus levels to that of C mice. The BMO supplementation reduced WD-induced increase in paracellular and transcellular flux in the large intestine as well as mRNA levels of the inflammatory marker tumor necrosis factor α. In conclusion, BMO are promising prebiotics to modulate gut microbiota and intestinal barrier function for enhanced health.

  1. NTP Toxicology and Carcinogenesis Studies of Trichloroethylene (CAS No. 79-01-6) in Four Strains of Rats (ACI, August, Marshall, Osborne-Mendel) (Gavage Studies).

    Science.gov (United States)

    1988-04-01

    Trichloroethylene is an industrial solvent used primarily for vapor degreasing and cold cleaning. It was selected for study because of its industrial use and for potential for human exposure. (An estimated 3.5 million workers are exposed to trichloroethylene.) In an earlier study trichloroethylene (stabilized with epichlorohydrin and 1,2-epoxybutane) administered by gavage caused hepatocellular carcinomas in male and female B6C3F1 mice. Trichloroethylene administration did not increase the incidence of tumors in male or female Osborne-Mendel rats. However, the survival of dosed rats was reduced, thereby compromising the sensitivity of the study to detect a carcinogenic effect. The studies described in this report were conducted to compare the sensitivities of four strains of rats (ACI, August, Marshall, and Osborne-Mendel) to diisopropylamine-stabilized trichloroethylene. The results of the present studies demonstrate that long-term administration of trichloroethylene produces nephrotoxicity in four strains of rats and that the susceptibilities of these strains to the nephrotoxic effects of the chemical are similar. Because of chemically induced toxicity, reduced survival, and incomplete documentation of the experimental data, the studies are considered inadequate for either comparing or assessing trichloroethylene-induced carcinogenesis in these strains of rats. Toxicology and carcinogenesis studies of trichloroethylene (more than 99% pure, stabilized with 8 ppm diisopropylamine) were conducted by administering the chemical in corn oil gavage at doses of 0, 500, or 1,000 mg/kg per day, 5 day per week, for 103 weeks to groups of 50 male and 50 female ACI, August, Marshall, and Osborne-Mendel rats. The doses were selected on the basis of results from 13-week gavage studies in which groups of 10 male and 10 female ACI, August, and Marshall rats received daily doses or trichloroethylene (male: 125-2,000 mg/kg; female: 63-1,000 mg/kg). Doses for Osborne-Mendel rats

  2. Surfactant protein D is proatherogenic in mice

    DEFF Research Database (Denmark)

    Sorensen, Grith L; Madsen, Jens; Kejling, Karin

    2006-01-01

    Surfactant protein D (SP-D) is an important innate immune defense molecule that mediates clearance of pathogens and modulates the inflammatory response. Moreover, SP-D is involved in lipid homeostasis, and pulmonary accumulation of phospholipids has previously been observed in SP-D-deficient (Spd......-/-) mice. Atherogenesis involves both inflammation and lipid deposition, and we investigated the role of SP-D in the development of atherosclerosis. SP-D synthesis was localized to vascular endothelial cells. Atherosclerotic lesion areas were 5.6-fold smaller in the aortic roots in Spd-/- mice compared...... with wild-type C57BL/6N mice on an atherogenic diet. HDL cholesterol (HDL-C) was significantly elevated in Spd-/- mice. Treatment of Spd-/- mice with a recombinant fragment of human SP-D resulted in decreases of HDL-C (21%) as well as total cholesterol (26%), and LDL cholesterol (28%). Plasma TNF...

  3. Mono pile foundation. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Lyngesen, S.; Brendstrup, C.

    1997-02-01

    The use of mono piles as foundations for maritime structures has been developed during the last decades. The installation requirements within the offshore sector have resulted in equipment enabling driving of piles up to 3-4 m to large penetration depths. The availability of this equipment has made the use of large mono piles feasible as foundations for structures like wind turbines. The mono pile foundations consists of three parts; the bare pile, a conical transition and a boat landing. All parts are prefitted at the yard in order to minimise the installation work that has to be carried out offshore. The study of a mono pile foundations for a 1.5 MW wind turbine has been conducted for two locations, Horns Rev and Roedsand. Three different water depths: 5, 8 and 11 m have been investigated in the study. The on-site welding between pile and conical transition is performed by an automatic welding machine. Final testing and eventually repair of the weld are conducted at least 16 hours after welding. This is followed by final installation of J-tube, tie-in to subsea cables and installation of the impressed current system for corrosive protection of the mono pile. The total cost for procurement and installation of the mono pile using the welded connection is estimated. The price does not include procurement and installation of access platform and boat landing. These costs are estimated to 250.000 DKK. Depending on water depth the cost of the pile ranges from 2,2 to 2,7 million DKK. Procurement and fabrication of the pile are approx. 75% of the total costs. The remaining 25% are due to installation. The total costs are very sensitive to the unit price of pile steel. During the project it became obvious that ice load has a very large influence on the dimensions of the mono pile. (EG)

  4. Memory formation and retention are affected in adult miR-132/212 knockout mice.

    Science.gov (United States)

    Hernandez-Rapp, Julia; Smith, Pascal Y; Filali, Mohammed; Goupil, Claudia; Planel, Emmanuel; Magill, Stephen T; Goodman, Richard H; Hébert, Sébastien S

    2015-01-01

    The miR-132/212 family is thought to play an important role in neural function and plasticity, while its misregulation has been observed in various neurodegenerative disorders. In this study, we analyzed 6-month-old miR-132/212 knockout mice in a battery of cognitive and non-cognitive behavioral tests. No significant changes were observed in reflexes and basic sensorimotor functions as determined by the SHIRPA primary screen. Accordingly, miR-132/212 knockout mice did not differ from wild-type controls in general locomotor activity in an open-field test. Furthermore, no significant changes of anxiety were measured in an elevated plus maze task. However, the mutant mice showed retention phase defects in a novel object recognition test and in the T-water maze. Moreover, the learning and probe phases in the Barnes maze were clearly altered in knockout mice when compared to controls. Finally, changes in BDNF, CREB, and MeCP2 were identified in the miR-132/212-deficient mice, providing a potential mechanism for promoting memory loss. Taken together, these results further strengthen the role of miR-132/212 in memory formation and retention, and shed light on the potential consequences of its deregulation in neurodegenerative diseases.

  5. Autophagy ameliorates cognitive impairment through activation of PVT1 and apoptosis in diabetes mice.

    Science.gov (United States)

    Li, Zhigui; Hao, Shuang; Yin, Hongqiang; Gao, Jing; Yang, Zhuo

    2016-05-15

    The underlying mechanisms of cognitive impairment in diabetes remain incompletely characterized. Here we show that the autophagic inhibition by 3-methyladenine (3-MA) aggravates cognitive impairment in streptozotocin-induced diabetic mice, including exacerbation of anxiety-like behaviors and aggravation in spatial learning and memory, especially the spatial reversal memory. Further neuronal function identification confirmed that both long term potentiation (LTP) and depotentiation (DPT) were exacerbated by autophagic inhibition in diabetic mice, which indicating impairment of synaptic plasticity. However, no significant change of pair-pulse facilitation (PPF) was recorded in diabetic mice with autophagic suppression compared with the diabetic mice, which indicated that presynaptic function was not affected by autophagic inhibition in diabetes. Subsequent hippocampal neuronal cell death analysis showed that the apoptotic cell death, but not the regulated necrosis, significantly increased in autophagic suppression of diabetic mice. Finally, molecular mechanism that may lead to cell death was identified. The long non-coding RNA PVT1 (plasmacytoma variant translocation 1) expression was analyzed, and data revealed that PVT1 was decreased significantly by 3-MA in diabetes. These findings show that PVT1-mediated autophagy may protect hippocampal neurons from impairment of synaptic plasticity and apoptosis, and then ameliorates cognitive impairment in diabetes. These intriguing findings will help pave the way for exciting functional studies of autophagy in cognitive impairment and diabetes that may alter the existing paradigms.

  6. Arrhythmia and cardiac defects are a feature of spinal muscular atrophy model mice.

    Science.gov (United States)

    Heier, Christopher R; Satta, Rosalba; Lutz, Cathleen; DiDonato, Christine J

    2010-10-15

    Proximal spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality. Traditionally, SMA has been described as a motor neuron disease; however, there is a growing body of evidence that arrhythmia and/or cardiomyopathy may present in SMA patients at an increased frequency. Here, we ask whether SMA model mice possess such phenotypes. We find SMA mice suffer from severe bradyarrhythmia characterized by progressive heart block and impaired ventricular depolarization. Echocardiography further confirms functional cardiac deficits in SMA mice. Additional investigations show evidence of both sympathetic innervation defects and dilated cardiomyopathy at late stages of disease. Based upon these data, we propose a model in which decreased sympathetic innervation causes autonomic imbalance. Such imbalance would be characterized by a relative increase in the level of vagal tone controlling heart rate, which is consistent with bradyarrhythmia and progressive heart block. Finally, treatment with the histone deacetylase inhibitor trichostatin A, a drug known to benefit phenotypes of SMA model mice, produces prolonged maturation of the SMA heartbeat and an increase in cardiac size. Treated mice maintain measures of motor function throughout extended survival though they ultimately reach death endpoints in association with a progression of bradyarrhythmia. These data represent the novel identification of cardiac arrhythmia as an early and progressive feature of murine SMA while providing several new, quantitative indices of mouse health. Together with clinical cases that report similar symptoms, this reveals a new area of investigation that will be important to address as we move SMA therapeutics towards clinical success.

  7. Partial protective immunity against toxoplasmosis in mice elicited by recombinant Toxoplasma gondii malate dehydrogenase.

    Science.gov (United States)

    Liu, Zhuanzhuan; Yuan, Fei; Yang, Yanping; Yin, Litian; Liu, Yisheng; Wang, Yanjuan; Zheng, Kuiyang; Cao, Jianping

    2016-02-10

    Toxoplasma gondii can infect humans and wildlife, sometimes causing serious clinical presentations. Currently, no viable vaccine or effective drug strategies exist to prevent and control toxoplasmosis. T. gondii malate dehydrogenase (TgMDH) is a crucial enzyme in cellular redox reactions and has been shown to be an immunogenic compound that could be a potential vaccine candidate. Here, we investigate the protective efficacy of recombinant TgMDH (rTgMDH) against T. gondii infection in BALB/c mice. All mice were vaccinated via the nasal route. We determined the optimal vaccination dose by monitoring systemic and mucosal immune responses. The results showed that mice vaccinated with 30 μg of rTgMDH produced the highest antibody titers in serum, a strong lymphoproliferative response, marked increases in their levels of IL-2 and IFN-γ, and significantly greater levels of specific secretory IgA (sIgA) in mucosal washes. In addition, the vaccinated mice were orally challenged with tachyzoites of the virulent T. gondii RH strain 2 weeks after the final vaccination. Compared to the control group, we found that vaccination with rTgMDH increased the survival rate of infected mice by 47% and also significantly reduced the tachyzoite loads in their liver (by 58%) and brain (by 41%). Therefore, the rTgMDH protein triggers a strong systemic and mucosal immune response and provides partial protection against T. gondii infection.

  8. MCPIP1 deficiency in mice results in severe anemia related to autoimmune mechanisms.

    Directory of Open Access Journals (Sweden)

    Zhou Zhou

    Full Text Available Autoimmune gastritis is an organ-specific autoimmune disease of the stomach associated with pernicious anemia. The previous work from us and other groups identified MCPIP1 as an essential factor controlling inflammation and immune homeostasis. MCPIP1(-/- developed severe anemia. However, the mechanisms underlying this phenotype remain unclear. In the present study, we found that MCPIP1 deficiency in mice resulted in severe anemia related to autoimmune mechanisms. Although MCPIP1 deficiency did not affect erythropoiesis per se, the erythropoiesis in MCPIP1(-/- bone marrow erythroblasts was significantly attenuated due to iron and vitamin B12 (VB12 deficiency, which was mainly resulted from autoimmunity-associated gastritis and parietal cell loss. Consistently, exogenous supplement of iron and VB12 greatly improved the anemia phenotype of MCPIP1(-/- mice. Finally, we have evidence suggesting that autoimmune hemolysis may also contribute to anemia phenotype of MCPIP1(-/- mice. Taken together, our study suggests that MCPIP1 deficiency in mice leads to the development of autoimmune gastritis and pernicious anemia. Thus, MCPIP1(-/- mice may be a good mouse model for investigating the pathogenesis of pernicious anemia and testing the efficacy of some potential drugs for treatment of this disease.

  9. Apolipoprotein D Transgenic Mice Develop Hepatic Steatosis through Activation of PPARγ and Fatty Acid Uptake.

    Directory of Open Access Journals (Sweden)

    Marilyne Labrie

    Full Text Available Transgenic mice (Tg overexpressing human apolipoprotein D (H-apoD in the brain are resistant to neurodegeneration. Despite the use of a neuron-specific promoter to generate the Tg mice, they expressed significant levels of H-apoD in both plasma and liver and they slowly develop hepatic steatosis and insulin resistance. We show here that hepatic PPARγ expression in Tg mice is increased by 2-fold compared to wild type (WT mice. Consequently, PPARγ target genes Plin2 and Cide A/C are overexpressed, leading to increased lipid droplets formation. Expression of the fatty acid transporter CD36, another PPARgamma target, is also increased in Tg mice associated with elevated fatty acid uptake as measured in primary hepatocytes. Elevated expression of AMPK in the liver of Tg leads to phosphorylation of acetyl CoA carboxylase, indicating a decreased activity of the enzyme. Fatty acid synthase expression is also induced but the hepatic lipogenesis measured in vivo is not significantly different between WT and Tg mice. In addition, expression of carnitine palmitoyl transferase 1, the rate-limiting enzyme of beta-oxidation, is slightly upregulated. Finally, we show that overexpressing H-apoD in HepG2 cells in presence of arachidonic acid (AA, the main apoD ligand, increases the transcriptional activity of PPARγ. Supporting the role of apoD in AA transport, we observed enrichment in hepatic AA and a decrease in plasmatic AA concentration. Taken together, our results demonstrate that the hepatic steatosis observed in apoD Tg mice is a consequence of increased PPARγ transcriptional activity by AA leading to increased fatty acid uptake by the liver.

  10. Myocardial mitochondrial and contractile function are preserved in mice lacking adiponectin.

    Directory of Open Access Journals (Sweden)

    Martin Braun

    Full Text Available Adiponectin deficiency leads to increased myocardial infarct size following ischemia reperfusion and to exaggerated cardiac hypertrophy following pressure overload, entities that are causally linked to mitochondrial dysfunction. In skeletal muscle, lack of adiponectin results in impaired mitochondrial function. Thus, it was our objective to investigate whether adiponectin deficiency impairs mitochondrial energetics in the heart. At 8 weeks of age, heart weight-to-body weight ratios were not different between adiponectin knockout (ADQ-/- mice and wildtypes (WT. In isolated working hearts, cardiac output, aortic developed pressure and cardiac power were preserved in ADQ-/- mice. Rates of fatty acid oxidation, glucose oxidation and glycolysis were unchanged between groups. While myocardial oxygen consumption was slightly reduced (-24% in ADQ-/- mice in isolated working hearts, rates of maximal ADP-stimulated mitochondrial oxygen consumption and ATP synthesis in saponin-permeabilized cardiac fibers were preserved in ADQ-/- mice with glutamate, pyruvate or palmitoyl-carnitine as a substrate. In addition, enzymatic activity of respiratory complexes I and II was unchanged between groups. Phosphorylation of AMP-activated protein kinase and SIRT1 activity were not decreased, expression and acetylation of PGC-1α were unchanged, and mitochondrial content of OXPHOS subunits was not decreased in ADQ-/- mice. Finally, increasing energy demands due to prolonged subcutaneous infusion of isoproterenol did not differentially affect cardiac contractility or mitochondrial function in ADQ-/- mice compared to WT. Thus, mitochondrial and contractile function are preserved in hearts of mice lacking adiponectin, suggesting that adiponectin may be expendable in the regulation of mitochondrial energetics and contractile function in the heart under non-pathological conditions.

  11. Adipose-Derived Mesenchymal Stem Cells Restore Impaired Mucosal Immune Responses in Aged Mice.

    Directory of Open Access Journals (Sweden)

    Kazuyoshi Aso

    Full Text Available It has been shown that adipose-derived mesenchymal stem cells (AMSCs can differentiate into adipocytes, chondrocytes and osteoblasts. Several clinical trials have shown the ability of AMSCs to regenerate these differentiated cell types. Age-associated dysregulation of the gastrointestinal (GI immune system has been well documented. Our previous studies showed that impaired mucosal immunity in the GI tract occurs earlier during agingthan is seen in the systemic compartment. In this study, we examined the potential of AMSCs to restore the GI mucosal immune system in aged mice. Aged (>18 mo old mice were adoptively transferred with AMSCs. Two weeks later, mice were orally immunized with ovalbumin (OVA plus cholera toxin (CT three times at weekly intervals. Seven days after the final immunization, when fecal extract samples and plasma were subjected to OVA- and CT-B-specific ELISA, elevated levels of mucosal secretory IgA (SIgA and plasma IgG antibody (Ab responses were noted in aged mouse recipients. Similar results were also seen aged mice which received AMSCs at one year of age. When cytokine production was examined, OVA-stimulated Peyer's patch CD4+ T cells produced increased levels of IL-4. Further, CD4+ T cells from the lamina propria revealed elevated levels of IL-4 and IFN-γ production. In contrast, aged mice without AMSC transfer showed essentially no OVA- or CT-B-specific mucosal SIgA or plasma IgG Ab or cytokine responses. Of importance, fecal extracts from AMSC transferred aged mice showed neutralization activity to CT intoxication. These results suggest that AMSCs can restore impaired mucosal immunity in the GI tract of aged mice.

  12. Chronic psychosocial stress increases the risk for inflammation-related colon carcinogenesis in male mice.

    Science.gov (United States)

    Peters, Sebastian; Grunwald, Nicole; Rümmele, Petra; Endlicher, Esther; Lechner, Anja; Neumann, Inga D; Obermeier, Florian; Reber, Stefan O

    2012-07-01

    Patients with inflammatory bowel diseases (IBDs) have a higher risk of developing colorectal cancer (CRC) than the general population. Furthermore, chronic psychosocial stress increases the likelihood of developing IBD and multiple types of malignant neoplasms, including CRC. Here, for the first time, we investigate the effects of chronic psychosocial stress in male mice on an artificially induced CRC, by employing the chronic subordinate colony (CSC) housing paradigm in combination with the reliable azoxymethane (AOM)/dextran sodium sulfate (DSS) CRC model. Colonoscopy revealed that CSC mice showed accelerated macroscopic suspect lesions. In addition, more CSC mice developed low-grade dysplasia (LGD) and/or high-grade dysplasia (HGD) in the colonic tissue compared to the single-housed control mice (SHC). CSC mice showed an increased number of Ki67+ and a decreased number of terminal deoxynucleotidyl transferase dUTP nick end labeling epithelial cells in colonic tissue. Colonic liver receptor homolog-1 (LRH-1), cyclooxygenase II (COXII), tumor necrosis factor, forkhead box P3 (FoxP3) mRNA as well as colonic ß-catenin, COXII, and LRH-1 protein expression were also increased in CSC compared with SHC mice. Although the number of CD4+ Th cells was increased, a tendency toward a decreased colonic interferon-γ (IFN-γ) mRNA expression was observed. Furthermore, despite an increased percentage of CD3+ cells and CD3+/FoxP3+ double-positive cells within mesenteric lymph node cells of CSC mice, IFN-γ secretion from these cells was unaffected. Altogether, our results suggest that chronic psychosocial stress increases the risk for AOM/DSS-induced and, thus, inflammation-related CRC. Finally, assessment of additional time points may test whether the shift from tumor-protective Th1 cell to regulatory T-cell immunity represents a consequence of increased carcinogenesis or a causal factor involved in its development.

  13. Myocardial mitochondrial and contractile function are preserved in mice lacking adiponectin.

    Science.gov (United States)

    Braun, Martin; Hettinger, Niko; Koentges, Christoph; Pfeil, Katharina; Cimolai, Maria C; Hoffmann, Michael M; Osterholt, Moritz; Doenst, Torsten; Bode, Christoph; Bugger, Heiko

    2015-01-01

    Adiponectin deficiency leads to increased myocardial infarct size following ischemia reperfusion and to exaggerated cardiac hypertrophy following pressure overload, entities that are causally linked to mitochondrial dysfunction. In skeletal muscle, lack of adiponectin results in impaired mitochondrial function. Thus, it was our objective to investigate whether adiponectin deficiency impairs mitochondrial energetics in the heart. At 8 weeks of age, heart weight-to-body weight ratios were not different between adiponectin knockout (ADQ-/-) mice and wildtypes (WT). In isolated working hearts, cardiac output, aortic developed pressure and cardiac power were preserved in ADQ-/- mice. Rates of fatty acid oxidation, glucose oxidation and glycolysis were unchanged between groups. While myocardial oxygen consumption was slightly reduced (-24%) in ADQ-/- mice in isolated working hearts, rates of maximal ADP-stimulated mitochondrial oxygen consumption and ATP synthesis in saponin-permeabilized cardiac fibers were preserved in ADQ-/- mice with glutamate, pyruvate or palmitoyl-carnitine as a substrate. In addition, enzymatic activity of respiratory complexes I and II was unchanged between groups. Phosphorylation of AMP-activated protein kinase and SIRT1 activity were not decreased, expression and acetylation of PGC-1α were unchanged, and mitochondrial content of OXPHOS subunits was not decreased in ADQ-/- mice. Finally, increasing energy demands due to prolonged subcutaneous infusion of isoproterenol did not differentially affect cardiac contractility or mitochondrial function in ADQ-/- mice compared to WT. Thus, mitochondrial and contractile function are preserved in hearts of mice lacking adiponectin, suggesting that adiponectin may be expendable in the regulation of mitochondrial energetics and contractile function in the heart under non-pathological conditions.

  14. Daily energy balance in growth hormone receptor/binding protein (GHR−/−) gene-disrupted mice is achieved through an increase in dark-phase energy efficiency

    Science.gov (United States)

    Longo, Kenneth A.; Berryman, Darlene E.; Kelder, Bruce; Charoenthongtrakul, Soratree; DiStefano, Peter S.; Geddes, Brad J.; Kopchick, John

    2009-01-01

    The goal of this study was to examine factors that contribute to energy balance in female GHR −/− mice. We measured energy intake, energy expenditure (EE), fuel utilization, body mass (Mb) changes and physical activity in 17 month-old female GHR −/− mice and their age-matched wild type littermates. The GHR −/− mice were smaller, consumed more food per unit Mb, had greater EE per unit Mb and had an increase in 24-h EE/Mb that was similar to the increase in their surface-area-to-volume ratio. Locomotor activity (LMA) was reduced in the GHR −/− mice, but the energetic cost associated with their LMA was greater than in wild type controls. Furthermore, Mb and LMA were independent explanatory covariates of most of the variance in EE, and when adjusted for Mb and LMA, the GHR −/− mice had higher EE during both the light and dark phases of the daily cycle. Respiratory quotient was lower in GHR −/− mice during the light phase, which indicated a greater utilization of lipid relative to carbohydrate in these mice. Additionally, GHR −/− mice had higher ratios of caloric intake to EE at several intervals during the dark phase, and this effect was greater and more sustained in the final three hours of the dark phase. Therefore, we conclude that GHR −/− mice are able to overcome the substantial energetic challenges of dwarfism through several mechanisms that promote stable Mb. Relative to wild type mice, the GHR −/− mice consumed more calories per unit Mb, which offset the disproportionate increase in their daily energy expenditure. While GHR −/− mice oxidized a greater proportion of lipid during the light phase in order to meet their energy requirements, they achieved greater energy efficiency and storage during the dark phase through a combination of higher energy consumption and lower LMA. PMID:19747867

  15. IRIS Final Technical Progress Report

    Energy Technology Data Exchange (ETDEWEB)

    M. D. Carelli

    2003-11-03

    OAK-B135 This NERI project, originally started as the Secure Transportable Autonomous Light Water Reactor (STAR-LW) and currently known as the International Reactor Innovative and Secure (IRIS) project, had the objective of investigating a novel type of water-cooled reactor to satisfy the Generation IV goals: fuel cycle sustainability, enhanced reliability and safety, and improved economics. The research objectives over the three-year (1999-2002) program were as follows: First year: Assess various design alternatives and establish main characteristics of a point design; Second year: Perform feasibility and engineering assessment of the selected design solutions; Third year: Complete reactor design and performance evaluation, including cost assessment These objectives were fully attained and actually they served to launch IRIS as a full fledged project for eventual commercial deployment. The program did not terminate in 2002 at the end of the NERI program, and has just entered in its fifth year. This has been made possible by the IRIS project participants which have grown from the original four member, two-countries team to the current twenty members, nine countries consortium. All the consortium members work under their own funding and it is estimated that the value of their in-kind contributions over the life of the project has been of the order of $30M. Currently, approximately 100 people worldwide are involved in the project. A very important constituency of the IRIS project is the academia: 7 universities from four countries are members of the consortium and five more US universities are associated via parallel NERI programs. To date, 97 students have worked or are working on IRIS; 59 IRIS-related graduate theses have been prepared or are in preparation, and 41 of these students have already graduated with M.S. (33) or Ph.D. (8) degrees. This ''final'' report (final only as far as the NERI program is concerned) summarizes the work performed

  16. Growth hormone (GH)-transgenic insulin-like growth factor 1 (IGF1)-deficient mice allow dissociation of excess GH and IGF1 effects on glomerular and tubular growth.

    Science.gov (United States)

    Blutke, Andreas; Schneider, Marlon R; Wolf, Eckhard; Wanke, Rüdiger

    2016-03-01

    Growth hormone (GH)-transgenic mice with permanently elevated systemic levels of GH and insulin-like growth factor 1 (IGF1) reproducibly develop renal and glomerular hypertrophy and subsequent progressive glomerulosclerosis, finally leading to terminal renal failure. To dissociate IGF1-dependent and -independent effects of GH excess on renal growth and lesion development in vivo, the kidneys of 75 days old IGF1-deficient (I(-/-)) and of IGF1-deficient GH-transgenic mice (I(-/-)/G), as well as of GH-transgenic (G) and nontransgenic wild-type control mice (I(+/+)) were examined by quantitative stereological and functional analyses. Both G and I(-/-)/G mice developed glomerular hypertrophy, hyperplasia of glomerular mesangial and endothelial cells, podocyte hypertrophy and foot process effacement, albuminuria, and glomerulosclerosis. However, I(-/-)/G mice exhibited less severe glomerular alterations, as compared to G mice. Compared to I(+/+) mice, G mice exhibited renal hypertrophy with a significant increase in the number without a change in the size of proximal tubular epithelial (PTE) cells. In contrast, I(-/-)/G mice did not display significant PTE cell hyperplasia, as compared to I(-/-) mice. These findings indicate that GH excess stimulates glomerular growth and induces lesions progressing to glomerulosclerosis in the absence of IGF1. In contrast, IGF1 represents an important mediator of GH-dependent proximal tubular growth in GH-transgenic mice.

  17. IL-6 Compared to Young Mice

    Directory of Open Access Journals (Sweden)

    Jihyun Park

    2014-01-01

    Full Text Available Inflamm-aging indicates the chronic inflammatory state resulting from increased secretion of proinflammatory cytokines and mediators such as IL-6 in the elderly. Our principle objective was to identify cell types that were affected with aging concerning IL-6 secretion in the murine model. We compared IL-6 production in spleen cells from both young and aged mice and isolated several types of cells from spleen and investigated IL-6 mRNA expression and protein production. IL-6 protein productions in cultured stromal cells from aged mice spleen were significantly high compared to young mice upon LPS stimulation. IL-6 mRNA expression level of freshly isolated stromal cells from aged mice was high compared to young mice. Furthermore, stromal cells of aged mice highly expressed IL-6 mRNA after LPS injection in vivo. These results suggest that stromal cells play a role in producing IL-6 in aged mice and imply that they contribute to the chronic inflammatory condition in the elderly.

  18. Leukemogenesis in heterozygous PU.1 knockout mice.

    Science.gov (United States)

    Genik, Paula C; Vyazunova, Irina; Steffen, Leta S; Bacher, Jeffery W; Bielefeldt-Ohmann, Helle; McKercher, Scott; Ullrich, Robert L; Fallgren, Christina M; Weil, Michael M; Ray, F Andrew

    2014-09-01

    Most murine radiation-induced acute myeloid leukemias involve biallelic inactivation of the PU.1 gene, with one allele being lost through a radiation-induced chromosomal deletion and the other allele affected by a recurrent point mutation in codon 235 that is likely to be spontaneous. The short latencies of acute myeloid leukemias occurring in nonirradiated mice engineered with PU.1 conditional knockout or knockdown alleles suggest that once both copies of PU.1 have been lost any other steps involved in leukemogenesis occur rapidly. Yet, spontaneous acute myeloid leukemias have not been reported in mice heterozygous for a PU.1 knockout allele, an observation that conflicts with the understanding that the PU.1 codon 235 mutation is spontaneous. Here we describe experiments that show that the lack of spontaneous leukemia in PU.1 heterozygous knockout mice is not due to insufficient monitoring times or mouse numbers or the genetic background of the knockout mice. The results reveal that spontaneous leukemias that develop in mice of the mixed 129S2/SvPas and C57BL/6 background of knockout mice arise by a pathway that does not involve biallelic PU.1 mutation. In addition, the latency of radiation-induced leukemia in PU.1 heterozygous mice on a genetic background susceptible to radiation-induced leukemia indicates that the codon 235 mutation is not a rate-limiting step in radiation leukemogenesis driven by PU.1 loss.

  19. Stathmin is dispensable for tumor onset in mice.

    Science.gov (United States)

    D'Andrea, Sara; Berton, Stefania; Segatto, Ilenia; Fabris, Linda; Canzonieri, Vincenzo; Colombatti, Alfonso; Vecchione, Andrea; Belletti, Barbara; Baldassarre, Gustavo

    2012-01-01

    The microtubule-destabilizing protein stathmin is highly expressed in several types of tumor, thus deserving the name of oncoprotein 18. High levels of stathmin expression and/or activity favor the metastatic spreading and mark the most aggressive tumors, thus representing a realistic marker of poor prognosis. Stathmin is a downstream target of many signaling pathways, including Ras-MAPK, PI3K and p53, involved in both tumor onset and progression. We thus hypothesized that stathmin could also play a role during the early stages of tumorigenesis, an issue completely unexplored. In order to establish whether stathmin expression is necessary for tumor initiation, we challenged wild type (WT), stathmin heterozygous and stathmin knock-out (KO) mice with different carcinogens. Using well-defined mouse models of carcinogenesis of skin, bladder and muscle by the means of 7,12-dimethylbenz[α]antracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA), N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) and 3-methylcholanthrylene (3MC) treatments, respectively, we demonstrated that knock-out of stathmin has no impact on the onset of cancer in mice. No significant difference was noticed either when the Ras oncogene was mutated (skin carcinogenesis model) or when the p53 pathway was inactivated (bladder carcinomas and fibrosarcomas). Finally, we concomitantly impinged on p53 and Ras pathways, by generating WT and stathmin KO mouse embryo fibroblasts transformed with papilloma virus large T antigen (LgTAg) plus the K-Ras(G12V) oncogene. In vivo growth of xenografts from these transformed fibroblasts did not highlight any significant difference depending on the presence or absence of stathmin. Overall, our work demonstrates that stathmin expression is dispensable for tumor onset, at least in mice, thus making stathmin a virtually exclusive marker of aggressive disease and a promising therapeutic target for advanced cancers.

  20. Stathmin is dispensable for tumor onset in mice.

    Directory of Open Access Journals (Sweden)

    Sara D'Andrea

    Full Text Available The microtubule-destabilizing protein stathmin is highly expressed in several types of tumor, thus deserving the name of oncoprotein 18. High levels of stathmin expression and/or activity favor the metastatic spreading and mark the most aggressive tumors, thus representing a realistic marker of poor prognosis. Stathmin is a downstream target of many signaling pathways, including Ras-MAPK, PI3K and p53, involved in both tumor onset and progression. We thus hypothesized that stathmin could also play a role during the early stages of tumorigenesis, an issue completely unexplored. In order to establish whether stathmin expression is necessary for tumor initiation, we challenged wild type (WT, stathmin heterozygous and stathmin knock-out (KO mice with different carcinogens. Using well-defined mouse models of carcinogenesis of skin, bladder and muscle by the means of 7,12-dimethylbenz[α]antracene (DMBA/12-O-tetradecanoylphorbol-13-acetate (TPA, N-butyl-N-(4-hydroxybutyl nitrosamine (BBN and 3-methylcholanthrylene (3MC treatments, respectively, we demonstrated that knock-out of stathmin has no impact on the onset of cancer in mice. No significant difference was noticed either when the Ras oncogene was mutated (skin carcinogenesis model or when the p53 pathway was inactivated (bladder carcinomas and fibrosarcomas. Finally, we concomitantly impinged on p53 and Ras pathways, by generating WT and stathmin KO mouse embryo fibroblasts transformed with papilloma virus large T antigen (LgTAg plus the K-Ras(G12V oncogene. In vivo growth of xenografts from these transformed fibroblasts did not highlight any significant difference depending on the presence or absence of stathmin. Overall, our work demonstrates that stathmin expression is dispensable for tumor onset, at least in mice, thus making stathmin a virtually exclusive marker of aggressive disease and a promising therapeutic target for advanced cancers.

  1. Final report for DESC0004031

    Energy Technology Data Exchange (ETDEWEB)

    Kitchin, John [Carnegie Mellon Univ., Pittsburgh, PA (United States)

    2016-08-08

    In this project we aim to develop new multicomponent oxide-based electrocatalysts for the oxygen evolution reaction using combined theoretical and experimental approaches. We use density functional theory to compute the electronic structure and reactivity proxies of model oxide materials. From the understanding generated from these calculations, we synthesize materials and characterize their oxygen evolution activity. We use in situ spectroscopic methods to characterize oxide electrodes under reaction conditions. We also develop new data sharing strategies to facilitate the reuse of our data by others. Our work has several potential impacts of interest to DOE. First, the discovery of new oxygen evolution electrocatalysts directly affects the efficiency of many energy-related processes from hydrogen generation to air separation and electrochemical fuel synthesis. Second, we have identified new ways to promote the oxygen evolution reaction for some materials through the electrolyte. This opens new pathways to improving the efficiency of processes involving oxygen evolution. The ability to characterize electrodes under operating conditions enables new insights into the actual structure and composition of the materials, which we are finding are not the same as the as prepared materials. Finally, DOE has significant need and interest in improving the ability to share data among researchers.

  2. Customized PEC modules. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Soerensen, Martin B. (DTI, Taastrup (Denmark))

    2012-07-01

    The purpose of the project ''Customized PEC modules'' was to move from the production hand-made individual DSCs (dye-sensitized solar cells) in the laboratory to the production of DSC modules in a semi-automated process. At the same time allowing sufficient variation in the product's specification for real tailoring of the product to the application. The tailoring can be related to the module's electrical output and size, but also to the possibility of designing patterns for decoration or communication purposes by playing around with the shape, size and layout of the individual cells forming the module. This was to be accomplished mainly by screen printing of DSC components on glass substrates at Mekoprint. For reaching this goal the work was divided into a number of steps. The central part of the work done was in the initial conception activity and the following manufacturing activity. An activity regarding optimization included several tasks of optimization and adaptation of the existing laboratory process for manufacturing of the DSCs. Finally, work focused on international activities was done. All the steps needed for the production of customized DSC modules have been demonstrated in this project. In combination with the development of a high performing printable sealant and sealing method all the prerequisites for producing customized DSC modules have been demonstrated. (LN)

  3. Deletion of the Wolfram syndrome-related gene Wfs1 results in increased sensitivity to ethanol in female mice.

    Science.gov (United States)

    Raud, Sirli; Reimets, Riin; Loomets, Maarja; Sütt, Silva; Altpere, Alina; Visnapuu, Tanel; Innos, Jürgen; Luuk, Hendrik; Plaas, Mario; Volke, Vallo; Vasar, Eero

    2015-08-01

    Wolfram syndrome, induced by mutation in WFS1 gene, increases risk of developing mood disorders in humans. In mice, Wfs1 deficiency cause higher anxiety-like behaviour and increased response to anxiolytic-like effect of diazepam, a GABAA receptor agonist. As GABAergic system is also target for ethanol, we analysed its anxiolytic-like and sedative properties in Wfs1-deficient mice using elevated plus-maze test and tests measuring locomotor activity and coordination, respectively. Additionally loss of righting reflex test was conducted to study sedative/hypnotic properties of ethanol, ketamine and pentobarbital. To evaluate pharmacokinetics of ethanol in mice enzymatic colour test was used. Finally, gene expression of alpha subunits of GABAA receptors following ethanol treatment was studied by real-time-PCR. Compared to wild-types, Wfs1-deficient mice were more sensitive to ethanol-induced anxiolytic-like effect, but less responsive to impairment of motor coordination. Ethanol and pentobarbital, but not ketamine, caused longer duration of hypnosis in Wfs1-deficient mice. The expression of Gabra2 subunit at 30 minutes after ethanol injection was significantly increased in the frontal cortex of Wfs1-deficient mice as compared to respective vehicle-treated mice. For the temporal lobe, similar change in Gabra2 mRNA occurred at 60 minutes after ethanol treatment in Wfs1-deficient mice. No changes were detected in Gabra1 and Gabra3 mRNA following ethanol treatment. Taken together, increased anxiolytic-like effect of ethanol in Wfs1-deficient mice is probably related to altered Gabra2 gene expression. Increased anti-anxiety effect of GABAA receptor agonists in the present work and earlier studies (Luuk et al., 2009) further suggests importance of Wfs1 gene in the regulation of emotional behaviour.

  4. Activating transcription factor 4 regulates osteoclast differentiation in mice.

    Science.gov (United States)

    Cao, Huiling; Yu, Shibing; Yao, Zhi; Galson, Deborah L; Jiang, Yu; Zhang, Xiaoyan; Fan, Jie; Lu, Binfeng; Guan, Youfei; Luo, Min; Lai, Yumei; Zhu, Yibei; Kurihara, Noriyoshi; Patrene, Kenneth; Roodman, G David; Xiao, Guozhi

    2010-08-01

    Activating transcription factor 4 (ATF4) is a critical transcription factor for osteoblast (OBL) function and bone formation; however, a direct role in osteoclasts (OCLs) has not been established. Here, we targeted expression of ATF4 to the OCL lineage using the Trap promoter or through deletion of Atf4 in mice. OCL differentiation was drastically decreased in Atf4-/- bone marrow monocyte (BMM) cultures and bones. Coculture of Atf4-/- BMMs with WT OBLs or a high concentration of RANKL failed to restore the OCL differentiation defect. Conversely, Trap-Atf4-tg mice displayed severe osteopenia with dramatically increased osteoclastogenesis and bone resorption. We further showed that ATF4 was an upstream activator of the critical transcription factor Nfatc1 and was critical for RANKL activation of multiple MAPK pathways in OCL progenitors. Furthermore, ATF4 was crucial for M-CSF induction of RANK expression on BMMs, and lack of ATF4 caused a shift in OCL precursors to macrophages. Finally, ATF4 was largely modulated by M-CSF signaling and the PI3K/AKT pathways in BMMs. These results demonstrate that ATF4 plays a direct role in regulating OCL differentiation and suggest that it may be a therapeutic target for treating bone diseases associated with increased OCL activity.

  5. Activating transcription factor 4 regulates osteoclast differentiation in mice

    Science.gov (United States)

    Cao, Huiling; Yu, Shibing; Yao, Zhi; Galson, Deborah L.; Jiang, Yu; Zhang, Xiaoyan; Fan, Jie; Lu, Binfeng; Guan, Youfei; Luo, Min; Lai, Yumei; Zhu, Yibei; Kurihara, Noriyoshi; Patrene, Kenneth; Roodman, G. David; Xiao, Guozhi

    2010-01-01

    Activating transcription factor 4 (ATF4) is a critical transcription factor for osteoblast (OBL) function and bone formation; however, a direct role in osteoclasts (OCLs) has not been established. Here, we targeted expression of ATF4 to the OCL lineage using the Trap promoter or through deletion of Atf4 in mice. OCL differentiation was drastically decreased in Atf4–/– bone marrow monocyte (BMM) cultures and bones. Coculture of Atf4–/– BMMs with WT OBLs or a high concentration of RANKL failed to restore the OCL differentiation defect. Conversely, Trap-Atf4-tg mice displayed severe osteopenia with dramatically increased osteoclastogenesis and bone resorption. We further showed that ATF4 was an upstream activator of the critical transcription factor Nfatc1 and was critical for RANKL activation of multiple MAPK pathways in OCL progenitors. Furthermore, ATF4 was crucial for M-CSF induction of RANK expression on BMMs, and lack of ATF4 caused a shift in OCL precursors to macrophages. Finally, ATF4 was largely modulated by M-CSF signaling and the PI3K/AKT pathways in BMMs. These results demonstrate that ATF4 plays a direct role in regulating OCL differentiation and suggest that it may be a therapeutic target for treating bone diseases associated with increased OCL activity. PMID:20628199

  6. Biological Effect of Magnetic Field in Mice

    Institute of Scientific and Technical Information of China (English)

    Zhao-Wei ZENG

    2005-01-01

    Objective: To study the biological effect of magnetic field in mice bodies. Method: With a piece of permanent magnet embeded in mice bodies beside the femoral artery and vein to measure the electrophoretic velocity(um/s). Result: The magnetic field in mice bodies on the experiment group that the electrophoretic velocity is faster more than control and free group.Conclusion:The magnetic field in animal's body can raise the negative electric charges on the surface of erythrocyte to improve the microcirculation, this is the biological effect of magnetic field.

  7. Extraordinary behavioral entrainment following circadian rhythm bifurcation in mice.

    Science.gov (United States)

    Harrison, Elizabeth M; Walbeek, Thijs J; Sun, Jonathan; Johnson, Jeremy; Poonawala, Qays; Gorman, Michael R

    2016-12-08

    The mammalian circadian timing system uses light to synchronize endogenously generated rhythms with the environmental day. Entrainment to schedules that deviate significantly from 24 h (T24) has been viewed as unlikely because the circadian pacemaker appears capable only of small, incremental responses to brief light exposures. Challenging this view, we demonstrate that simple manipulations of light alone induce extreme plasticity in the circadian system of mice. Firstly, exposure to dim nocturnal illumination (entrainment. Continuation of dim light is unnecessary for T15/30 behavioral entrainment following bifurcation. Finally, neither dim light alone nor a shortened night is sufficient for the extraordinary entrainment observed under bifurcation. Thus, we demonstrate in a non-pharmacological, non-genetic manipulation that the circadian system is far more flexible than previously thought. These findings challenge the current conception of entrainment and its underlying principles, and reveal new potential targets for circadian interventions.

  8. Genetic analysis of beta1 integrin "activation motifs" in mice

    DEFF Research Database (Denmark)

    Czuchra, Aleksandra; Meyer, Hannelore; Legate, Kyle R

    2006-01-01

    tails, leading to tail separation and integrin activation. We analyzed mice in which we mutated the tyrosines of the beta1 tail and the membrane-proximal aspartic acid required for the salt bridge. Tyrosine-to-alanine substitutions abolished beta1 integrin functions and led to a beta1 integrin......-null phenotype in vivo. Surprisingly, neither the substitution of the tyrosines with phenylalanine nor the aspartic acid with alanine resulted in an obvious defect. These data suggest that the NPXY motifs of the beta1 integrin tail are essential for beta1 integrin function, whereas tyrosine phosphorylation......Akey feature of integrins is their ability to regulate the affinity for ligands, a process termed integrin activation. The final step in integrin activation is talin binding to the NPXY motif of the integrin beta cytoplasmic domains. Talin binding disrupts the salt bridge between the alpha/beta...

  9. Experimental osteoarthritis models in mice.

    Science.gov (United States)

    Lorenz, Julia; Grässel, Susanne

    2014-01-01

    Osteoarthritis (OA) is a slowly progressing, degenerative disorder of synovial joints culminating in the irreversible destruction of articular cartilage and subchondral bone. It affects almost everyone over the age of 65 and influences life quality of affected individuals with enormous costs to the health care system. Current therapeutic strategies seek to ameliorate pain and increase mobility; however, to date none of them halts disease progression or regenerates damaged cartilage or bone. Thus, there is an ultimate need for the development of new, noninvasive treatments that could substitute joint replacement for late- or end-stage patients. Therefore, osteoarthritis animal models for mimicking of all OA features are important. Mice develop an OA pathology that is comparable to humans, rapidly develop OA due to the short lifetime and show reproducible OA symptoms. They provide a versatile and widely used animal model for analyzing molecular mechanisms of OA pathology. One major advantage over large animal models is the availability of knockout or transgenic mice strains to examine genetic predispositions/contributions to OA.In this chapter, we describe three widely used instability-inducing murine osteoarthritis models. The most common two methods for surgical induction are: (1) destabilization of the medial meniscus (DMM) and (2) anterior cruciate ligament transection (ACLT). In the DMM model, the medial meniscotibial ligament is transected while in the ACLT model the anterior cruciate ligament is destroyed. In the third, chemical induced instability method, intraarticular collagenase is injected into the knee joint. Intraarticular collagenase weakens articular ligaments which cause instability of the joint, and full-blown OA develops within 6 weeks. For morphological evaluation, we correspond mainly to the recommendations of OARSI for histological assessment of osteoarthritis in mouse. For statistical evaluation summed or mean scores of all four knee areas

  10. The LSST Dome final design

    Science.gov (United States)

    DeVries, J.; Neill, D. R.; Barr, J.; De Lorenzi, Simone; Marchiori, Gianpietro

    2016-07-01

    The Large Synoptic Survey Telescope (LSST) is a large (8.4 meter) wide-field (3.5 degree) survey telescope, which will be located on the Cerro Pachón summit in Chile 1. As a result of the Telescope wide field of view, the optical system is unusually susceptible to stray light 2. In addition, balancing the effect of wind induced telescope vibrations with Dome seeing is crucial. The rotating enclosure system (Dome) includes a moving wind screen and light baffle system. All of the Dome vents include hinged light baffles, which provide exceptional Dome flushing, stray light attenuation, and allows for vent maintenance access from inside the Dome. The wind screen also functions as a light screen, and helps define a clear optical aperture for the Telescope. The Dome must operate continuously without rotational travel limits to accommodate the Telescope cadence and travel. Consequently, the Azimuth drives are located on the fixed lower enclosure to accommodate glycol water cooling without the need for a utility cable wrap. An air duct system aligns when the Dome is in its parked position, and this provides air cooling for temperature conditioning of the Dome during the daytime. A bridge crane and a series of ladders, stairs and platforms provide for the inspection, maintenance and repair of all of the Dome mechanical systems. The contract to build the Dome was awarded to European Industrial Engineering in Mestre, Italy in May 2015. In this paper, we present the final design of this telescope and site sub-system.

  11. Mori Folium and Mori Fructus Mixture Attenuates High-Fat Diet-Induced Cognitive Deficits in Mice

    Directory of Open Access Journals (Sweden)

    Hyo Geun Kim

    2015-01-01

    Full Text Available Obesity has become a global health problem, contributing to various diseases including diabetes, hypertension, cancer, and dementia. Increasing evidence suggests that obesity can also cause neuronal damage, long-term memory loss, and cognitive impairment. The leaves and the fruits of Morus alba L., containing active phytochemicals, have been shown to possess antiobesity and hypolipidemic properties. Thus, in the present study, we assessed their effects on cognitive functioning in mice fed a high-fat diet by performing immunohistochemistry, using antibodies against c-Fos, synaptophysin, and postsynaptic density protein 95 and a behavioral test. C57BL/6 mice fed a high-fat diet for 21 weeks exhibited increased body weight, but mice coadministered an optimized Mori Folium and Mori Fructus extract mixture (2 : 1; MFE for the final 12 weeks exhibited significant body weight loss. Additionally, obese mice exhibited not only reduced neural activity, but also decreased presynaptic and postsynaptic activities, while MFE-treated mice exhibited recovery of these activities. Finally, cognitive deficits induced by the high-fat diet were recovered by cotreatment with MFE in the novel object recognition test. Our findings suggest that the antiobesity effects of MFE resulted in recovery of the cognitive deficits induced by the high-fat diet by regulation of neural and synaptic activities.

  12. Intravenous injections in neonatal mice.

    Science.gov (United States)

    Gombash Lampe, Sara E; Kaspar, Brian K; Foust, Kevin D

    2014-11-11

    Intravenous injection is a clinically applicable manner to deliver therapeutics. For adult rodents and larger animals, intravenous injections are technically feasible and routine. However, some mouse models can have early onset of disease with a rapid progression that makes administration of potential therapies difficult. The temporal (or facial) vein is just anterior to the ear bud in mice and is clearly visible for the first two days after birth on either side of the head using a dissecting microscope. During this window, the temporal vein can be injected with volumes up to 50 μl. The injection is safe and well tolerated by both the pups and the dams. A typical injection procedure is completed within 1-2 min, after which the pup is returned to the home cage. By the third postnatal day the vein is difficult to visualize and the injection procedure becomes technically unreliable. This technique has been used for delivery of adeno-associated virus (AAV) vectors, which in turn can provide almost body-wide, stable transgene expression for the life of the animal depending on the viral serotype chosen.

  13. Mice lacking neurofibromin develop gastric hyperplasia

    Science.gov (United States)

    Lin, Lu; Chen, Jian; Richardson, James A.

    2009-01-01

    Gastrointestinal (GI) neoplasms are among many manifestations of the genetic disease neurofibromatosis type 1 (NF1). However, the physiological and pathological functions of the Nf1 gene in the GI system have not been fully studied, possibly because of a lack of mouse models. In this study, we generated conditional knockout mice with Nf1 deficiency in the GI tract. These mice develop gastric epithelial hyperplasia and inflammation together with increased cell proliferation and apoptosis. The gastric phenotypes observed in these mutant mice seem to be the consequence of loss of Nf1 in gastric fibroblasts, resulting in paracrine hyperactivation of the ERK pathway in the gastric epithelium. These mice provide a useful model to study the pathogenesis of GI lesions in a subset of patients with NF1 and to investigate the role of the Nf1 gene in the development of GI neoplasms. PMID:19661150

  14. Zika Infection Shrinks Testicles in Mice

    Science.gov (United States)

    ... page: https://medlineplus.gov/news/fullstory_163733.html Zika Infection Shrinks Testicles in Mice Study authors unsure ... 22, 2017 WEDNESDAY, Feb. 22, 2017 (HealthDay News) -- Zika virus can be sexually transmitted through semen, and ...

  15. Social transfer of pain in mice

    Science.gov (United States)

    Smith, Monique L.; Hostetler, Caroline M.; Heinricher, Mary M.; Ryabinin, Andrey E.

    2016-01-01

    A complex relationship exists between the psychosocial environment and the perception and experience of pain, and the mechanisms of the social communication of pain have yet to be elucidated. The present study examined the social communication of pain and demonstrates that “bystander” mice housed and tested in the same room as mice subjected to inflammatory pain or withdrawal from morphine or alcohol develop corresponding hyperalgesia. Olfactory cues mediate the transfer of hyperalgesia to the bystander mice, which can be measured using mechanical, thermal, and chemical tests. Hyperalgesia in bystanders does not co-occur with anxiety or changes in corticosterone and cannot be explained by visually dependent emotional contagion or stress-induced hyperalgesia. These experiments reveal the multifaceted relationship between the social environment and pain behavior and support the use of mice as a model system for investigating these factors. In addition, these experiments highlight the need for proper consideration of how experimental animals are housed and tested.

  16. Electroencephalographic changes with age in male mice.

    Science.gov (United States)

    Eleftheriou, B E; Zolovick, A J; Elias, M F

    1975-01-01

    Electroencephalographic (EEG) changes, as measured by the awake state, slow-wave sleep (SWS), rapid-eye movement (REM) patterns and ratio of REM/total sleep, were recorded in aging male mice of DBA/2J and C57BL/6J strains. Results indicate that there is a significant increase in the awake state accompanied by significant decrease in SWS with advancing age for both strains, although these changes appear more pronounced in DBA/2J mice than C57BL/6J mice. Of considerable significance is the finding that REM sleep is absent in mice of DBA/2J strain at 23.5 months of age. Based on these findings, the conclusion was reached that strain DBA/2J ages significantly faster than C57BL/6J. The difference in aging between the two strains emphasizes the need for additional studies dealing with genetic aspects of aging.

  17. Neurobehavioral development of CD-1 mice after combined gestational and postnatal exposure to ozone

    Energy Technology Data Exchange (ETDEWEB)

    Dell`Omo, G. [Section of Behavioral Pathophysiology, Lab. di Fisiopatologia di Organo e di Sistema, Istituto Superiore di Sanita, Rome (Italy); Fiore, M. [Section of Behavioral Pathophysiology, Lab. di Fisiopatologia di Organo e di Sistema, Istituto Superiore di Sanita, Rome (Italy); Petruzzi, S. [Section of Behavioral Pathophysiology, Lab. di Fisiopatologia di Organo e di Sistema, Istituto Superiore di Sanita, Rome (Italy); Alleva, E. [Section of Behavioral Pathophysiology, Lab. di Fisiopatologia di Organo e di Sistema, Istituto Superiore di Sanita, Rome (Italy); Bignami, G. [Section of Behavioral Pathophysiology, Lab. di Fisiopatologia di Organo e di Sistema, Istituto Superiore di Sanita, Rome (Italy)

    1995-09-01

    Outbred CD-1 mice were exposed continuously to ozone (O{sub 3}, 0.6 ppm) from 6 days prior to the formation of breeding pairs to the time of weaning of the offspring on postnatal day 22 (PND 22) or to PND 26. One half of the mice in each of eight O{sub 3} and eight control litters were subjected on PND 24 to a 20-min open-field test after IP treatment by either saline or scopolamine (2 mg/kg). The remaining mice (those exposed until PND 26) were subjected on PNDs 28-31 to a conditioned place preference (CPP) test, using a short schedule with a single IP injection on PND 29 of either d-amphetamine (3.3 mg/kg) or saline. Subsequently, the saline mice of the open-field experiment were used on PND 59 for an activity test in one of the CPP apparatus compartments after IP treatment by either d-amphetamine (same dose) or saline. In addition, the saline mice of the CPP experiment underwent a multitrial, step-through passive avoidance (PA) acquisition test on PND 59 or 60, followed 24 h later by a single-trial retention test. In the absence of effects on reproductive performance (proportion of successful pregnancies, litter size, offspring viability, and sex ratio), O{sub 3} offspring showed a long-lasting reduction in body weight without modification of sec differences. Ozone effects on neurobehavioral development were not large and quite selective, including: attenuation of the sex differences in several responses (rearing and sniffing in the open-field, activity in the final CPP test session); a change in response choices in the final CPP test, in the absence of a main effect on conditioning; a reduction of grooming in the activity test on PND 29; and impairment of PA acquisition limited to the initial period of training. (orig.)

  18. Attenuation of dextran sodium sulphate induced colitis in matrix metalloproteinase-9 deficient mice

    Institute of Scientific and Technical Information of China (English)

    Alfredo Santana; Carlos Medina; Maria Iristina Paz-Cabrera; Federico Díaz-Gonzalez; Esther Farré; Antonio Salas; Marek W Radomski; Enrique Quintero

    2006-01-01

    AIM: To study whether matrix metalloproteinase-9(MMP-9) is a key factor in epithelial damage in the dextran sodium sulphate (DSS) model of colitis in mice.METHODS: MMP-9-deficient and wild-type (wt)mice were given 5% DSS in drinking water for 5 dfollowed by recovery up to 7 d. On d 5 and 12 after induction of colitis, gelatinases,MMP-2 and MMP-9,were measured in homogenates of colonic tissue by zymography and Western blot, whereas Tissue inhibitor of metalloproteinases (TIMPs) were measured by reverse zymography. The gelatinolytic activity was also determined in supernatants of polymorphonuclear leukocytes (PMN) isolated from mice blood. Moreover,intestinal epithelial cells were stimulated with TNF-α to study whether these cells were able to produce MMPs.Finally, colonic mucosal lesions were measured by microscopic examination.RESULTS: On d 5 of colitis, the activity of MMP-9 was increased in homogenates of colonic tissues (0.24±0.1 vs 21.3±6.4,P<0.05) and PMN from peripheral blood in wt (0.5±0.1 vs 10.4±0.7,P<0.05), but not in MMP-9-deficient animals. The MMP-9 activity was also up-regulated by TNF-α in epithelial intestinal cells (2.5±0.5 vs 14.7±3.0, P<0.05). Although colitis also led to increase of TIMP-1 activity, the MMP-9/TIMP-1 balance remained elevated. Finally, in the MMP-9-deficient colitic mice both the extent and severity of intestinal epithelial injury were significantly attenuated when compared with wt mice.CONCLUSION: We conclude that DSS induced colitis is markedly attenuated in animals lacking MMP-9. This suggests that intestinal injury induced by DSS is modulated by MMP-9 and that inhibition of this gelatinase may reduce inflammation.

  19. Antifatigue effect of Gracilaria eucheumoides in mice

    OpenAIRE

    SHAO, JIN-TING; Wang, Mei-Yan; ZHENG, LU-BIN

    2013-01-01

    Gracilaria eucheumoides Linn (Gracilariaceae; G. eucheumoides) is abundant in dietary fiber, which aids the clearance of excess cholesterol from the blood and maintains stable blood glucose levels. The aim of the present study was to investigate the antifatigue effect of G. eucheumoides in mice and the physiological and molecular mechanisms underlying this effect. Mice were randomly divided into four groups and three of the groups were administered different doses of G. eucheumoides extract. ...

  20. Metabolic characteristics of long-lived mice

    Directory of Open Access Journals (Sweden)

    Andrzej eBartke

    2012-12-01

    Full Text Available Genetic suppression of insulin/insulin-like growth factor signaling (IIS can extend longevity in worms, insects, and mammals. In laboratory mice, mutations with the greatest, most consistent, and best documented positive impact on lifespan are those that disrupt growth hormone (GH release or actions. These mutations lead to major alterations in IIS but also have a variety of effects that are not directly related to the actions of insulin or insulin-like growth factor (IGF-1. Long-lived GH-resistant GHRKO mice with targeted disruption of the GH receptor gene, as well as Ames dwarf (Prop1df and Snell dwarf (Pit1dw mice lacking GH (along with prolactin and TSH, are diminutive in size and have major alterations in body composition and metabolic parameters including increased subcutaneous adiposity, increased relative brain weight, small liver, hypoinsulinemia, mild hypoglycemia, increased adiponectin levels and insulin sensitivity, and reduced serum lipids. Body temperature is reduced in Ames, Snell, and female GHRKO mice. Indirect calorimetry revealed that both Ames dwarf and GHRKO mice utilize more oxygen per gram (g of body weight than sex- and age-matched normal animals from the same strain. They also have reduced respiratory quotient (RQ, implying greater reliance on fats, as opposed to carbohydrates, as an energy source. Differences in oxygen consumption (VO2 were seen in animals fed or fasted during the measurements as well as in animals that had been exposed to 30% calorie restriction or every-other-day feeding. However, at the thermoneutral temperature of 30°C, VO2 did not differ between GHRKO and normal mice. Thus, the increased metabolic rate of the GHRKO mice, at a standard animal room temperature of 23°C, is apparently related to increased energy demands for thermoregulation in these diminutive animals. We suspect that increased oxidative metabolism combined with enhanced fatty acid oxidation contribute to the extended longevity of

  1. Pregnant phenotype in aquaporin 8-deficient mice

    Institute of Scientific and Technical Information of China (English)

    Xiao-yan SHA; Zheng-fang XIONG; Hui-shu LIU; Zheng ZHENG; Tong-hui MA

    2011-01-01

    Aim: Aquaporin 8 (AQP8) is expressed within the female reproductive system but its physiological function reminds to be elucidated.This study investigates the role of AQP8 during pregnancy using AQP8-knockout (AQP8-KO) mice.Methods: Homozygous AQP8-KO mice were mated, and the conception rate was recorded. AQP8-KO pregnant mice or their offspring were divided into 5 subgroups according to fetal gestational day (7, 13, 16, 18 GD) and newborn. Wild type C57 pregnant mice served as the control group. The number of pregnant mice, total embryos and atrophic embryos, as well as fetal weight, placental weight and placental area were recorded for each subgroup. The amount of amniotic fluid in each sac at 13, 16, and 18 GD was calculated. Statistical significance was determined by analysis of variance of factorial design and chi-square tests.Results: Conception rates did not differ significantly between AQP8-KO and wild type mice. AQP8-KO pregnant mice had a significantly higher number of embryos compared to wild type controls. Fetal/neonatal weight was also significantly greater in the AQP8-KO group compared to age-matched wild type controls. The amount of amniotic fluid was greater in AQP8-KO pregnant mice than wild type controis, although the FM/AFA (fetal weight/amniotic fluid amount) did not differ. While AQP8-KO placental weight was significantly larger than wild type controls, there was no evidence of placental pathology in either group.Conclusion: The results suggest that AQP8 deficiency plays an important role in pregnancy outcome.

  2. Reduced alcohol consumption in mice lacking preprodynorphin.

    OpenAIRE

    Blednov, Yuri A.; Walker, Danielle; Martinez, Marni; Harris, R. Adron

    2006-01-01

    Many studies suggest a role for endogenous opioid peptides and their receptors in regulation of ethanol intake. It is commonly accepted that the κ-opioid receptors and their endogenous ligands, dynorphins, produce a dysphoric state and therefore may be responsible for avoidance of alcohol. We used mutant mice lacking preprodynorphin in a variety of behavioral tests of alcohol actions. Null mutant female, but not male, mice showed significantly lower preference for alcohol and consumed lower a...

  3. Integrated sequence analysis. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Andersson, K.; Pyy, P

    1998-02-01

    The NKS/RAK subprojet 3 `integrated sequence analysis` (ISA) was formulated with the overall objective to develop and to test integrated methodologies in order to evaluate event sequences with significant human action contribution. The term `methodology` denotes not only technical tools but also methods for integration of different scientific disciplines. In this report, we first discuss the background of ISA and the surveys made to map methods in different application fields, such as man machine system simulation software, human reliability analysis (HRA) and expert judgement. Specific event sequences were, after the surveys, selected for application and testing of a number of ISA methods. The event sequences discussed in the report were cold overpressure of BWR, shutdown LOCA of BWR, steam generator tube rupture of a PWR and BWR disturbed signal view in the control room after an external event. Different teams analysed these sequences by using different ISA and HRA methods. Two kinds of results were obtained from the ISA project: sequence specific and more general findings. The sequence specific results are discussed together with each sequence description. The general lessons are discussed under a separate chapter by using comparisons of different case studies. These lessons include areas ranging from plant safety management (design, procedures, instrumentation, operations, maintenance and safety practices) to methodological findings (ISA methodology, PSA,HRA, physical analyses, behavioural analyses and uncertainty assessment). Finally follows a discussion about the project and conclusions are presented. An interdisciplinary study of complex phenomena is a natural way to produce valuable and innovative results. This project came up with structured ways to perform ISA and managed to apply the in practice. The project also highlighted some areas where more work is needed. In the HRA work, development is required for the use of simulators and expert judgement as

  4. Santa Barbara Final Technical Report

    Energy Technology Data Exchange (ETDEWEB)

    Hacker, Angela; Hansen, Sherman; Watkins, Ashley

    2013-11-30

    This report serves as the Final Report for Santa Barbara County’s Energy Efficiency and Conservation Block Grant (EECBG) BetterBuildings Neighborhood Program (BBNP) award from the U.S. Department of Energy (DOE). This report explains how DOE BBNP funding was invested to develop robust program infrastructure designed to help property owners complete energy improvements, thereby generating substantial outcomes for the local environment and economy. It provides an overview of program development and design within the grant period, program accomplishments and challenges to date, and a plan for the future sustainability of emPower, the County’s innovative clean energy and building efficiency program. During the grant period, Santa Barbara County’s emPower program primarily targeted 32,000 owner occupied, single family, detached residential homes over 25 years old within the County. In order to help these homeowners and their contractors overcome market barriers to completing residential energy improvements, the program developed and promoted six voluntary, market-based service areas: 1) low cost residential financing (loan loss reserve with two local credit unions), 2) residential rebates, 3) local customer service, 4) expert energy advising, 5) workforce development and training, and 6) marketing, education and outreach. The main goals of the program were to lower building energy use, create jobs and develop a lasting regional building performance market. These services have generated important early outcomes and lessons after the program’s first two years in service. The DOE BBNP funding was extended through October 2014 to enable Santa Barbara County to generate continued outcomes. In fact, funding related to residential financing remains wholly available for the foreseeable future to continue offering Home Upgrade Loans to approximately 1,300 homeowners. The County’s investment of DOE BBNP funding was used to build a lasting, effective, and innovative

  5. Large Block Test Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Lin, W

    2001-12-01

    . Sections 5 through 9 report the measurements made on the block during the preheating, heating, and cooling phases. These measurements include temperature, thermal conductivity and diffusivity, hydrological measurements (electrical resistivity, neutron logging, gas pressure, and relative humidity), geomechanics, selected chemical analyses, and microbial activity. These sections also include analyses and simulations of the block behavior. Finally, conclusions are presented in Section 10. Complete data sets were submitted during the time the test was conducted. The data tracking numbers (DTNs) of all of the data are presented in Table 1-1.

  6. Final Report Package_Winnebago

    Energy Technology Data Exchange (ETDEWEB)

    Carolyn Stewart, Director, Red Mountain Energy Partners

    2006-10-31

    The Winnebago Tribe of Nebraska energy options study results will be used to advance the Tribe’s near term energy management objectives. The array of energy options identified allows the Tribe to select those activities that best fit its energy strategies, goals and objectives. During the course of the study, Red Mountain analyzed both energy options and energy organizational alternatives suitable for the Tribe, presented findings to the Tribal Council, and made recommendations regarding each. Work products delivered to the Tribe, and provided in the Final Report included: • A matrix of energy management options applicable to the Tribe, which provided descriptions of particular conservation, efficiency, weatherization, and demand management alternatives. The matrix also provided insight about relative costs of the alternatives, cost/benefit efficacy, ease of implementation, resources for implementing, and observations about each. • A matrix of utility service options applicable to the Tribe, describing each of the four alternatives described above. The matrix also provided insight about key benefits of each option, required resources, costs and timeframe for implementation, funding sources and analysis, and key issues for consideration. • Discussion guides prepared for each meeting between the Energy Committee and Council, and the Tribe’s contractor, Red Mountain Energy Partners, which included preliminary analysis and findings. • A Position Description for the Energy Manager position, which was reviewed by the Tribal HR Department, and used by the Tribe to develop a position posting. • A Utility Code designed for Winnebago to use in establishing its Utility Board, and, ultimately, to provide guidance for the Board’s further development. • A project summary book developed to include all key information, deliverables and utility provider data for the project. Winnebago’s growth trends and expansion plans require the Tribe to play a more active

  7. Volatile of alkyd varnish inhibits the expression of neuronal growth associated protein-43 in mice

    Institute of Scientific and Technical Information of China (English)

    Qian Huang; Hongxia Wang; Wei Zou

    2007-01-01

    varnish, and the poisoning method was the same as that of chronic poisoning group.②Experimental evaluation: content of protein in the cortex, cerebellum and hippocampus of mice was measured separately by Bradford method. GAP-43 expression in the hippocampus and cortex was observed separately by SDS-polyacrylamide gel electrophoresis (SDS-PAGE).MAIN OUTCOME MEASURES: Content of protein and expression of GAP-43 in different brain regions of mice.RESULTS: Twenty mice were involved in the final analysis.①Content of protein in the cerebellum and hippocampus of mice in the chronic poisoning group was decreased a little, separately (P>0.05).②GAP-43 expression in the hippocampus of mice of the chronic poisoning group was significantly lower than that of the control group(P<0.05).CONCLUSION: Long-term action of volatile of alkyd varnish can inhibit the brain functions of mice by depressing the GAP-43 expression in hippocampus of mice.

  8. Serum amyloid A regulates monopoiesis in hyperlipidemic Ldlr(-/-) mice.

    Science.gov (United States)

    Krishack, Paulette A; Sontag, Timothy J; Getz, Godfrey S; Reardon, Catherine A

    2016-08-01

    We previously showed that feeding a Western-type diet (WTD) to Ldlr(-/-) mice lacking serum amyloid A (SAA) (Saa(-/-) Ldlr(-/-) mice), the level of total blood monocytes was higher than in Ldlr(-/-) mice. In this investigation we demonstrate that higher levels of bone marrow monocytes and macrophage-dendritic cell progenitor (MDP) cells were found in WTD-fed Saa(-/-) Ldlr(-/-) mice compared to Ldlr(-/-) mice and lower levels of GMP cells and CMP cells in Ldlr(-/-) mice. These data indicate that SAA regulates the level of bone marrow monocytes and their myeloid progenitors in hyperlipidemic Ldlr(-/-) mice.

  9. "Color Timer" mice: visualization of neuronal differentiation with fluorescent proteins

    Directory of Open Access Journals (Sweden)

    Kanki Hiroaki

    2010-02-01

    Full Text Available Abstract The molecular mechanisms governing the differentiation of neural stem cells (NSCs into neuronal progenitor cells and finally into neurons are gradually being revealed. The lack of convenient means for real-time determination of the stages of differentiation of individual neural cells, however, has been hindering progress in elucidating the mechanisms. In order to be able to easily identify the stages of differentiation of neural cells, we have been attempting to establish a mouse system that would allow progression of neuronal differentiation to be visualized based on transitions between fluorescence colors by using a combination of mouse genetics and the ever-expanding repertoire of fluorescent proteins. In this study we report the initial version of such a mouse system, which we call "Color Timer." We first generated transgenic (Tg; nestin/KOr Tg mice in which production of the fluorescent protein Kusabira-Orange (KOr is controlled by the gene regulatory elements within the 2nd intronic enhancer of the nestin gene, which is a good marker for NSCs, so that NSCs would emit orange fluorescence upon excitation. We then confirmed by immunohistochemical and immunocytochemical analyses that the KOr fluorescence closely reflected the presence of the Nestin protein. We also confirmed by a neurosphere formation assay that the intensity of the KOr fluorescence correlated with "stemness" of the cell and it was possible to readily identify NSCs in the two neurogenic regions, namely the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricle, in the brain of adult nestin/KOr Tg mice by the orange fluorescence they emitted. We then crossed nestin/KOr mice with doublecortin-enhanced Green Fluorescent Protein Tg mice, whose immature neurons emit green fluorescence upon excitation, and it was possible to visualize the progress of NSC-to-neuron differentiation by the transition between fluorescence colors from orange to

  10. Modulation of macrophage activation state protects tissue from necrosis during critical limb ischemia in thrombospondin-1-deficient mice.

    Directory of Open Access Journals (Sweden)

    Nicolas Bréchot

    Full Text Available BACKGROUND: Macrophages, key regulators of healing/regeneration processes, strongly infiltrate ischemic tissues from patients suffering from critical limb ischemia (CLI. However pro-inflammatory markers correlate with disease progression and risk of amputation, suggesting that modulating macrophage activation state might be beneficial. We previously reported that thrombospondin-1 (TSP-1 is highly expressed in ischemic tissues during CLI in humans. TSP-1 is a matricellular protein that displays well-known angiostatic properties in cancer, and regulates inflammation in vivo and macrophages properties in vitro. We therefore sought to investigate its function in a mouse model of CLI. METHODS AND FINDINGS: Using a genetic model of tsp-1(-/- mice subjected to femoral artery excision, we report that tsp-1(-/- mice were clinically and histologically protected from necrosis compared to controls. Tissue protection was associated with increased postischemic angiogenesis and muscle regeneration. We next showed that macrophages present in ischemic tissues exhibited distinct phenotypes in tsp-1(-/- and wt mice. A strong reduction of necrotic myofibers phagocytosis was observed in tsp-1(-/- mice. We next demonstrated that phagocytosis of muscle cell debris is a potent pro-inflammatory signal for macrophages in vitro. Consistently with these findings, macrophages that infiltrated ischemic tissues exhibited a reduced postischemic pro-inflammatory activation state in tsp-1(-/- mice, characterized by a reduced Ly-6C expression and a less pro-inflammatory cytokine expression profile. Finally, we showed that monocyte depletion reversed clinical and histological protection from necrosis observed in tsp-1(-/- mice, thereby demonstrating that macrophages mediated tissue protection in these mice. CONCLUSION: This study defines targeting postischemic macrophage activation state as a new potential therapeutic approach to protect tissues from necrosis and promote tissue

  11. Enhanced Th17-cell responses render CCR2-deficient mice more susceptible for autoimmune arthritis.

    Directory of Open Access Journals (Sweden)

    Rishi R Rampersad

    Full Text Available CCR2 is considered a proinflammatory mediator in many inflammatory diseases such as rheumatoid arthritis. However, mice lacking CCR2 develop exacerbated collagen-induced arthritis. To explore the underlying mechanism, we investigated whether autoimmune-associated Th17 cells were involved in the pathogenesis of the severe phenotype of autoimmune arthritis. We found that Th17 cells were expanded approximately 3-fold in the draining lymph nodes of immunized CCR2(-/- mice compared to WT controls (p = 0.017, whereas the number of Th1 cells and regulatory T cells are similar between these two groups of mice. Consistently, levels of the Th17 cell cytokine IL-17A and Th17 cell-associated cytokines, IL-6 and IL-1β were approximately 2-6-fold elevated in the serum and 22-28-fold increased in the arthritic joints in CCR2(-/- mice compared to WT mice (p = 0.04, 0.0004, and 0.01 for IL-17, IL-6, and IL-1β, respectively, in the serum and p = 0.009, 0.02, and 0.02 in the joints. Furthermore, type II collagen-specific antibodies were significantly increased, which was accompanied by B cell and neutrophil expansion in CCR2(-/- mice. Finally, treatment with an anti-IL-17A antibody modestly reduced the disease severity in CCR2(-/- mice. Therefore, we conclude that while we detect markedly enhanced Th17-cell responses in collagen-induced arthritis in CCR2-deficient mice and IL-17A blockade does have an ameliorating effect, factors additional to Th17 cells and IL-17A also contribute to the severe autoimmune arthritis seen in CCR2 deficiency. CCR2 may have a protective role in the pathogenesis of autoimmune arthritis. Our data that monocytes were missing from the spleen while remained abundant in the bone marrow and joints of immunized CCR2(-/- mice suggest that there is a potential link between CCR2-expressing monocytes and Th17 cells during autoimmunity.

  12. Palmoplantar keratoderma in Slurp2-deficient mice

    Science.gov (United States)

    Allan, Christopher M.; Procaccia, Shiri; Tran, Deanna; Tu, Yiping; Barnes, Richard H.; Larsson, Mikael; Allan, Bernard B.; Young, Lorraine C.; Hong, Cynthia; Tontonoz, Peter; Fong, Loren G.; Young, Stephen G.; Beigneux, Anne P.

    2015-01-01

    SLURP1, a member of the Ly6 protein family, is secreted by suprabasal keratinocytes. Mutations in SLURP1 cause a palmoplantar keratoderma (PPK) known as mal de Meleda. Another secreted Ly6 protein, SLURP2, is encoded by a gene located ~20 kb downstream from SLURP1. SLURP2 is produced by suprabasal keratinocytes. To investigate the importance of SLURP2, we first examined Slurp2 knockout mice in which exon 2–3 sequences had been replaced with lacZ and neo cassettes. Slurp2−/− mice exhibited hyperkeratosis on the volar surface of the paws (i.e., PPK), increased keratinocyte proliferation, and an accumulation of lipid droplets in the stratum corneum. They also exhibited reduced body weight and hind limb clasping. These phenotypes are very similar to those of Slurp1−/− mice. To solidify a link between Slurp2 deficiency and PPK and to be confident that the disease phenotypes in Slurp2−/− mice were not secondary to the effects of the lacZ and neo cassettes on Slurp1 expression, we created a new line of Slurp2 knockout mice (Slurp2X−/−) in which Slurp2 was inactivated with a simple nonsense mutation. Slurp2X−/− mice exhibited the same disease phenotypes. Thus, Slurp2 deficiency and Slurp1 deficiencies cause the same disease phenotypes. PMID:26967477

  13. INTERHEMISPHERIC ASYMMETRY OF INDIVIDUAL BEHAVIOR IN MICE

    Directory of Open Access Journals (Sweden)

    V.V. Mikheev

    2009-06-01

    Full Text Available The role of the left and right hemispheres in realization of behavior for SHR, DBA/2 and C57BL/6 males mice in open field was studied. All three lines of mice differed each from other in elements of individual behavior. Comparison of effects of unilateral inactivation in SHR mice revealed domination of the right hemisphere in regulation of total duration of rearings and grooming, the most specialization of hemispheres being registered in regulation of temporary parameters of behavioral reactions. In DBA/2 mice, the left hemisphere dominated in control of rearings, and the right one did on seating. In C57BL/6 mice, the right hemisphere dominated only on locomotion. Therefore, the cortex of the brain (after inactivation did not participate in regulation of individual behavior in the majority of the experiments (11 from 18. In two cases, the symmetric participation of hemispheres in regulation of behavioral reactions was obtained, and in 5 cases, the unilateral domination of hemispheres in control of behavioral elements was registered. Thus, in three lines of mice, the pattern of interhemispheric asymmetry of individual behavior is principally different.

  14. Temperature buffer test. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Aakesson, Mattias [Clay Technology AB, Lund (Sweden)

    2012-04-15

    The Temperature Buffer Test (TBT) is a joint project between SKB/ANDRA and supported by ENRESA (modelling) and DBE (instrumentation), which aims at improving the understanding and to model the thermo-hydro-mechanical behavior of buffers made of swelling clay submitted to high temperatures (over 100 deg C) during the water saturation process. The test has been carried out in a KBS-3 deposition hole at Aspo HRL. It was installed during the spring of 2003. Two steel heaters (3 m long, 0.6 m diameter) and two buffer arrangements have been investigated: the lower heater was surrounded by rings of compacted Wyoming bentonite only, whereas the upper heater was surrounded by a composite barrier, with a sand shield between the heater and the bentonite. The test was dismantled and sampled during the winter of 2009/2010. This report is the final report and a summary of all work performed within the TBT project. The design and the installation of the different components are summarized: the depositions hole, the heating system, the bentonite blocks with emphasis on the initial density and water content in these, the filling of slots with sand or pellets, the retaining construction with the plug, lid and nine anchor cables, the artificial saturation system, and finally the instrumentation. An overview of the operational conditions is presented: the power output from heaters, which was 1,500 W (and also 1,600 W) from each heater during the first {approx}1,700 days, and then changed to 1,000 and 2,000 W, for the upper and lower heater respectively, during the last {approx}600 days. From the start, the bentonite was hydrated with a groundwater from a nearby bore-hole, but this groundwater was replaced with de-ionized water from day {approx}1,500, due to the high flow resistance of the injections points in the filter, which implied that a high filter pressure couldn't be sustained. The sand shield around the upper heater was hydrated from day {approx}1,500 to day {approx}1

  15. Temperature buffer test. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Aakesson, Mattias [Clay Technology AB, Lund (Sweden)

    2012-04-15

    The Temperature Buffer Test (TBT) is a joint project between SKB/ANDRA and supported by ENRESA (modelling) and DBE (instrumentation), which aims at improving the understanding and to model the thermo-hydro-mechanical behavior of buffers made of swelling clay submitted to high temperatures (over 100 deg C) during the water saturation process. The test has been carried out in a KBS-3 deposition hole at Aspo HRL. It was installed during the spring of 2003. Two steel heaters (3 m long, 0.6 m diameter) and two buffer arrangements have been investigated: the lower heater was surrounded by rings of compacted Wyoming bentonite only, whereas the upper heater was surrounded by a composite barrier, with a sand shield between the heater and the bentonite. The test was dismantled and sampled during the winter of 2009/2010. This report is the final report and a summary of all work performed within the TBT project. The design and the installation of the different components are summarized: the depositions hole, the heating system, the bentonite blocks with emphasis on the initial density and water content in these, the filling of slots with sand or pellets, the retaining construction with the plug, lid and nine anchor cables, the artificial saturation system, and finally the instrumentation. An overview of the operational conditions is presented: the power output from heaters, which was 1,500 W (and also 1,600 W) from each heater during the first {approx}1,700 days, and then changed to 1,000 and 2,000 W, for the upper and lower heater respectively, during the last {approx}600 days. From the start, the bentonite was hydrated with a groundwater from a nearby bore-hole, but this groundwater was replaced with de-ionized water from day {approx}1,500, due to the high flow resistance of the injections points in the filter, which implied that a high filter pressure couldn't be sustained. The sand shield around the upper heater was hydrated from day {approx}1,500 to day {approx}1

  16. 75 FR 80068 - Notice of Availability of the Final Environmental Impact Report/Final Environmental Impact...

    Science.gov (United States)

    2010-12-21

    ... Bureau of Land Management Notice of Availability of the Final Environmental Impact Report/ Final Environmental Impact Statement for the Southern California Edison Eldorado-Ivanpah Transmission Project... (CPUC) have prepared a Final Environmental Impact Report (EIR)/Final Environmental Impact Statement...

  17. Deficiency of complement receptors CR2/CR1 in Cr2⁻/⁻ mice reduces the extent of secondary brain damage after closed head injury.

    Science.gov (United States)

    Neher, Miriam D; Rich, Megan C; Keene, Chesleigh N; Weckbach, Sebastian; Bolden, Ashley L; Losacco, Justin T; Patane, Jenée; Flierl, Michael A; Kulik, Liudmila; Holers, V Michael; Stahel, Philip F

    2014-05-24

    Complement activation at the C3 convertase level has been associated with acute neuroinflammation and secondary brain injury after severe head trauma. The present study was designed to test the hypothesis that Cr2-/- mice, which lack the receptors CR2/CD21 and CR1/CD35 for complement C3-derived activation fragments, are protected from adverse sequelae of experimental closed head injury. Adult wild-type mice and Cr2-/- mice on a C57BL/6 genetic background were subjected to focal closed head injury using a standardized weight-drop device. Head-injured Cr2-/- mice showed significantly improved neurological outcomes for up to 72 hours after trauma and a significantly decreased post-injury mortality when compared to wild-type mice. In addition, the Cr2-/- genotype was associated with a decreased extent of neuronal cell death at seven days post-injury. Western blot analysis revealed that complement C3 levels were reduced in the injured brain hemispheres of Cr2-/- mice, whereas plasma C3 levels remained unchanged, compared to wild-type mice. Finally, head-injured Cr2-/- had an attenuated extent of post-injury C3 tissue deposition, decreased astrocytosis and microglial activation, and attenuated immunoglobulin M deposition in injured brains compared to wild-type mice. Targeting of these receptors for complement C3 fragments (CR2/CR1) may represent a promising future approach for therapeutic immunomodulation after traumatic brain injury.

  18. Old Mice Accumulate Activated Effector CD4 T Cells Refractory to Regulatory T Cell-Induced Immunosuppression.

    Science.gov (United States)

    Harpaz, Idan; Bhattacharya, Udayan; Elyahu, Yehezqel; Strominger, Itai; Monsonego, Alon

    2017-01-01

    Chronic low-grade inflammation and reduced lymphocyte potency are implicated in the pathogenesis of major illnesses associated with aging. Whether this immune phenotype results from a loss of cell-mediated regulation or intrinsic dysregulated function of effector T cells (Teffs) requires further research. Here, we report that, as compared with young C57BL6 mice, old mice show an increased frequency of CD4+CD62L- Teffs with a dysregulated activated phenotype and markedly increased effector functions. Analysis of the frequency and suppressive function of CD4+FoxP3+ regulatory T cells (Tregs) indicates an increase in the frequency of FoxP3+ T cells with aging which, however, occurs within the CD4+CD25- T cells. Furthermore, whereas Tregs from young and old mice similarly suppress Teffs from young mice, both have a compromised suppressive capacity of Teffs from old mice, a phenomenon which is partially recovered in the presence of IL-2-producing CD4+CD62L+ non-Teffs. Finally, we observed that Teff subsets from old mice are enriched with IL-17A-producing T cells and exhibit intrinsically dysregulated expression of genes encoding cell-surface molecules and transcription factors, which play a key role in T-cell activation and regulation. We, thus, demonstrate an age-related impairment in the regulation of effector CD4 T cells, which may underlie the higher risk for destructive inflammation associated with aging.

  19. Control of Both Myeloid Cell Infiltration and Angiogenesis by CCR1 Promotes Liver Cancer Metastasis Development in Mice

    Directory of Open Access Journals (Sweden)

    Mathieu Paul Rodero

    2013-06-01

    Full Text Available Expression of the CC chemokine receptor 1 (CCR1 by tumor cells has been associated with protumoral activity; however, its role in nontumoral cells during tumor development remains elusive. Here, we investigated the role of CCR1 deletion on stromal and hematopoietic cells in a liver metastasis tumor model. Metastasis development was strongly impaired in CCR1-deficient mice compared to control mice and was associated with reduced liver monocyte infiltration. To decipher the role of myeloid cells, sublethally irradiated mice were reconstituted with CCR1-deficient bone marrow (BM and showed better survival rates than the control reconstituted mice. These results point toward the involvement of CCR1 myeloid cell infiltration in the promotion of tumor burden. In addition, survival rates were extended in CCR1-deficient mice receiving either control or CCR1-deficient BM, indicating that host CCR1 expression on nonhematopoietic cells also supports tumor growth. Finally, we found defective tumor-induced neoangiogenesis (in vitro and in vivo in CCR1-deficient mice. Overall, our results indicate that CCR1 expression by both hematopoietic and nonhematopoietic cells favors tumor aggressiveness. We propose CCR1 as a potential therapeutical target for liver metastasis therapy.

  20. Gonadal Steroids Negatively Modulate Oxidative Stress in CBA/Ca Female Mice Infected with P. berghei ANKA

    Directory of Open Access Journals (Sweden)

    Néstor Aarón Mosqueda-Romo

    2014-01-01

    Full Text Available We decreased the level of gonadal steroids in female and male mice by gonadectomy. We infected these mice with P. berghei ANKA and observed the subsequent impact on the oxidative stress response. Intact females developed lower levels of parasitaemia and lost weight faster than intact males. Gonadectomised female mice displayed increased levels of parasitaemia, increased body mass, and increased anaemia compared with their male counterparts. In addition, gonadectomised females exhibited lower specific catalase, superoxide dismutase, and glutathione peroxidase activities in their blood and spleen tissues compared with gonadectomised males. To further study the oxidative stress response in P. berghei ANKA-infected gonadectomised mice, nitric oxide levels were assessed in the blood and spleen, and MDA levels were assessed in the spleen. Intact, sham-operated, and gonadectomised female mice exhibited higher levels of nitric oxide in the blood and spleen compared with male mice. MDA levels were higher in all of the female groups. Finally, gonadectomy significantly increased the oxidative stress levels in females but not in males. These data suggest that differential oxidative stress is influenced by oestrogens that may contribute to sexual dimorphism in malaria.

  1. Impact of vitamin C on the cardiometabolic and inflammatory profiles of mice lacking a functional Werner syndrome protein helicase.

    Science.gov (United States)

    Aumailley, Lucie; Dubois, Marie Julie; Garand, Chantal; Marette, André; Lebel, Michel

    2015-12-01

    Werner syndrome (WS) is a premature aging disorder caused by mutations in a DNA helicase/exonuclease. Mice lacking the helicase domain of this protein exhibit metabolic abnormalities that are reversed by vitamin C. In this study, we used a targeted metabolomic approach to identify serum metabolites significantly altered in young mutant mice treated with or without vitamin C. We also measured several serum inflammatory and cardiometabolic factors. We show that young mutant mice exhibit an increase in serum hydroxyproline and plasminogen activator inhibitor-1 (PAI-1), markers of cardiovascular diseases and inflammation, before they exhibit morphological anomalies in different tissues. We also observed an increase in three very long chain lysophosphatidylcholines underlying peroxisome perturbation. Vitamin C reversed the concentrations of these metabolites and PAI-1 to wild type values. Transcriptomic analyses on the liver of mutant mice revealed a decrease in the expression of genes involved in fatty acid degradation compared to wild type animals. Vitamin C treatment increased the expression of genes involved in glutathione metabolism and the synthesis of unsaturated fatty acids in these mice. These results show that changes at the transcriptomic level concord with the alterations of several serum metabolites in these mice. Finally, we found that a mislocalization of the Wrn mutant protein in the liver endoplasmic reticulum fraction increased oxidative stress in that cellular compartment. Vitamin C reversed this oxidative stress. To conclude, this study provides novel potential predictive cardiometabolic biomarkers in WS that will allow the assessment of the impact of vitamin C on patients with WS.

  2. Low translocation of Bacillus thuringiensis israelensis to inner organs in mice after pulmonary exposure to commercial biopesticide

    DEFF Research Database (Denmark)

    Barfod, Kenneth Klingenberg; Ørum-Smidt, Lasse; Krogfelt, Karen A.;

    2010-01-01

    Translocation of viable cells from a Bacillus thuringiensis israelensis-based biopesticide to inner organs in a mouse model was studied. Mice were exposed to the originally formulated product through the lungs and gastrointestinal tract by intratracheal instillation. Colony forming units (CFU) were...... grown from lungs, caecum, spleen and liver on Bacillus cereus-specific agar (BCSA) after 24 h and finally determined to be biopesticide strain B. t. israelensis by large plasmid profile. No CFU were found in spleen or liver of the control mice or in any aerosol background or material. We have shown...

  3. Intestinal SR-BI does not impact cholesterol absorption or transintestinal cholesterol efflux in mice.

    Science.gov (United States)

    Bura, Kanwardeep S; Lord, Caleb; Marshall, Stephanie; McDaniel, Allison; Thomas, Gwyn; Warrier, Manya; Zhang, Jun; Davis, Matthew A; Sawyer, Janet K; Shah, Ramesh; Wilson, Martha D; Dikkers, Arne; Tietge, Uwe J F; Collet, Xavier; Rudel, Lawrence L; Temel, Ryan E; Brown, J Mark

    2013-06-01

    Reverse cholesterol transport (RCT) can proceed through the classic hepatobiliary route or through the nonbiliary transintestinal cholesterol efflux (TICE) pathway. Scavenger receptor class B type I (SR-BI) plays a critical role in the classic hepatobiliary route of RCT. However, the role of SR-BI in TICE has not been studied. To examine the role of intestinal SR-BI in TICE, sterol balance was measured in control mice and mice transgenically overexpressing SR-BI in the proximal small intestine (SR-BI(hApoCIII-ApoAIV-Tg)). SR-BI(hApoCIII-ApoAIV-Tg) mice had significantly lower plasma cholesterol levels compared with wild-type controls, yet SR-BI(hApoCIII-ApoAIV-Tg) mice had normal fractional cholesterol absorption and fecal neutral sterol excretion. Both in the absence or presence of ezetimibe, intestinal SR-BI overexpression had no impact on the amount of cholesterol excreted in the feces. To specifically study effects of intestinal SR-BI on TICE we crossed SR-BI(hApoCIII-ApoAIV-Tg) mice into a mouse model that preferentially utilized the TICE pathway for RCT (Niemann-Pick C1-like 1 liver transgenic), and likewise found no alterations in cholesterol absorption or fecal sterol excretion. Finally, mice lacking SR-BI in all tissues also exhibited normal cholesterol absorption and fecal cholesterol disposal. Collectively, these results suggest that SR-BI is not rate limiting for intestinal cholesterol absorption or for fecal neutral sterol loss through the TICE pathway.

  4. Increased adiposity, dysregulated glucose metabolism and systemic inflammation in Galectin-3 KO mice.

    Directory of Open Access Journals (Sweden)

    Jingbo Pang

    Full Text Available Obesity and type 2 diabetes are associated with increased production of Galectin-3 (Gal-3, a protein that modulates inflammation and clearance of glucose adducts. We used Lean and Diet-induced Obese (DIO WT and Gal-3 KO mice to investigate the role of Gal-3 in modulation of adiposity, glucose metabolism and inflammation. Deficiency of Gal-3 lead to age-dependent development of excess adiposity and systemic inflammation, as indicated by elevated production of acute-phase proteins, number of circulating pro-inflammatory Ly6C(high monocytes and development of neutrophilia, microcytic anemia and thrombocytosis in 20-week-old Lean and DIO male Gal-3 KO mice. This was associated with impaired fasting glucose, heightened response to a glucose tolerance test and reduced adipose tissue expression of adiponectin, Gal-12, ATGL and PPARγ, in the presence of maintained insulin sensitivity and hepatic expression of gluconeogenic enzymes in 20-week-old Gal-3 KO mice compared to their diet-matched WT controls. Expression of PGC-1α and FGF-21 in the liver of Lean Gal-3 KO mice was comparable to that observed in DIO animals. Impaired fasting glucose and altered responsiveness to a glucose load preceded development of excess adiposity and systemic inflammation, as demonstrated in 12-week-old Gal-3 KO mice. Finally, a role for the microflora in mediating the fasting hyperglycemia, but not the excessive response to a glucose load, of 12-week-old Gal-3 KO mice was demonstrated by administration of antibiotics. In conclusion, Gal-3 is an important modulator of glucose metabolism, adiposity and inflammation.

  5. Pharmacokinetics of Polymersomes Composed of Poly(Butadiene-Ethylene Oxide); Healthy versus Tumor-Bearing Mice.

    Science.gov (United States)

    Wang, G; de Kruijff, R M; Abou, D; Ramos, N; Mendes, E; Franken, L E; Wolterbeek, H T; Denkova, A G

    2016-02-01

    Vesicles composed of block copolymers (i.e., polymersomes) are one of the most versatile nano-carriers for medical purposes due to their tuneable physicochemical properties and the possibility to encapsulate simultaneously hydrophobic and hydrophilic substances, allowing, for instance, the combination of therapy and imaging. In cancer treatment, these vesicles need to remain long enough in the blood stream to be sufficiently taken up by tumors. Here, we have investigated the biodistribution and the pharmacokinetics of polymersomes, composed of poly(butadiene-b-ethylene oxide) having dimensions around 80 nm. The polymersomes have been radiolabeled with ¹¹¹In via the so-called active loading method achieving a loading efficiency of 92.9 ± 0.9% with radionuclide retention in mouse serum of more than 95% at 24 h. The optimized ¹¹¹In containing polymersomes have been intravenously administered in healthy and tumor bearing mice for pharmacokinetic determination using microSPECT (Single Photon Emission Computed Tomography). In healthy mice these polymersomes have been found to exhibit relatively long blood circulation (> 6 h), low liver uptake (6 ± 1.5%ID/g, 48 h p.i.) and elevated spleen uptake (188 ± 30%ID/g). The blood circulation in tumor bearing mice is dramatically reduced (< 1.5 h) most likely due to elevated splenic filtration, clearly indicating the importance of in vivo studies in diseased mice. Finally, the polymersomes have been injected subcutaneously in tumor bearing mice revealing retention of 77% in the mice, primarily accumulated at the site of injection, up to 48 hours after administration.

  6. Antiangiogenic effect of angiotensin II type 2 receptor in ischemia-induced angiogenesis in mice hindlimb.

    Science.gov (United States)

    Silvestre, Jean-Sébastien; Tamarat, Radia; Senbonmatsu, Takaaki; Icchiki, Toshihiro; Ebrahimian, Teni; Iglarz, Marc; Besnard, Sandrine; Duriez, Micheline; Inagami, Tadashi; Lévy, Bernard I

    2002-05-31

    This study examined the potential role of angiotensin type 2 (AT(2)) receptor on angiogenesis in a model of surgically induced hindlimb ischemia. Ischemia was produced by femoral artery ligature in both wild-type and AT(2) gene-deleted mice (Agtr2(-)/Y). After 28 days, angiogenesis was quantitated by microangiography, capillary density measurement, and laser Doppler perfusion imaging. Protein levels of vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), Bax, and Bcl-2 were determined by Western blot analysis in hindlimbs. The AT(2) mRNA level (assessed by semiquantitative RT-PCR) was increased in the ischemic hindlimb of wild-type mice. Angiographic vessel density and laser Doppler perfusion data showed significant improvement in ischemic/nonischemic leg ratio, 1.9- and 1.7-fold, respectively, in Agtr2(-)/Y mice compared with controls. In ischemic leg of Agtr2(-)/Y mice, revascularization was associated with an increase in the antiapoptotic protein content, Bcl-2 (211% of basal), and a decrease (60% of basal) in the number of cell death, determined by TUNEL method. Angiotensin II treatment (0.3 mg/kg per day) raised angiogenic score, blood perfusion, and both VEGF and eNOS protein content in ischemic leg of wild-type control but did not modulate the enhanced angiogenic response observed in untreated Agtr2(-)/Y mice. Finally, immunohistochemistry analysis revealed that VEGF was mainly localized to myocyte, whereas eNOS-positive staining was mainly observed in the capillary of ischemic leg of both wild-type and AT(2)-deficient mice. This study demonstrates for the first time that the AT(2) receptor subtype may negatively modulate ischemia-induced angiogenesis through an activation of the apoptotic process.

  7. RhoE deficiency produces postnatal lethality, profound motor deficits and neurodevelopmental delay in mice.

    Directory of Open Access Journals (Sweden)

    Enric Mocholí

    Full Text Available Rnd proteins are a subfamily of Rho GTPases involved in the control of actin cytoskeleton dynamics and other cell functions such as motility, proliferation and survival. Unlike other members of the Rho family, Rnd proteins lack GTPase activity and therefore remain constitutively active. We have recently described that RhoE/Rnd3 is expressed in the Central Nervous System and that it has a role in promoting neurite formation. Despite their possible relevance during development, the role of Rnd proteins in vivo is not known. To get insight into the in vivo function of RhoE we have generated mice lacking RhoE expression by an exon trapping cassette. RhoE null mice (RhoE gt/gt are smaller at birth, display growth retardation and early postnatal death since only half of RhoE gt/gt mice survive beyond postnatal day (PD 15 and 100% are dead by PD 29. RhoE gt/gt mice show an abnormal body position with profound motor impairment and impaired performance in most neurobehavioral tests. Null mutant mice are hypoactive, show an immature locomotor pattern and display a significant delay in the appearance of the hindlimb mature responses. Moreover, they perform worse than the control littermates in the wire suspension, vertical climbing and clinging, righting reflex and negative geotaxis tests. Also, RhoE ablation results in a delay of neuromuscular maturation and in a reduction in the number of spinal motor neurons. Finally, RhoE gt/gt mice lack the common peroneal nerve and, consequently, show a complete atrophy of the target muscles. This is the first model to study the in vivo functions of a member of the Rnd subfamily of proteins, revealing the important role of Rnd3/RhoE in the normal development and suggesting the possible involvement of this protein in neurological disorders.

  8. Ghrelin knockout mice show decreased voluntary alcohol consumption and reduced ethanol-induced conditioned place preference.

    Science.gov (United States)

    Bahi, Amine; Tolle, Virginie; Fehrentz, Jean-Alain; Brunel, Luc; Martinez, Jean; Tomasetto, Catherine-Laure; Karam, Sherif M

    2013-05-01

    Recent work suggests that stomach-derived hormone ghrelin receptor (GHS-R1A) antagonism may reduce motivational aspects of ethanol intake. In the current study we hypothesized that the endogenous GHS-R1A agonist ghrelin modulates alcohol reward mechanisms. For this purpose ethanol-induced conditioned place preference (CPP), ethanol-induced locomotor stimulation and voluntary ethanol consumption in a two-bottle choice drinking paradigm were examined under conditions where ghrelin and its receptor were blocked, either using ghrelin knockout (KO) mice or the specific ghrelin receptor (GHS-R1A) antagonist "JMV2959". We showed that ghrelin KO mice displayed lower ethanol-induced CPP than their wild-type (WT) littermates. Consistently, when injected during CPP-acquisition, JMV2959 reduced CPP-expression in C57BL/6 mice. In addition, ethanol-induced locomotor stimulation was lower in ghrelin KO mice. Moreover, GHS-R1A blockade, using JMV2959, reduced alcohol-stimulated locomotion only in WT but not in ghrelin KO mice. When alcohol consumption and preference were assessed using the two-bottle choice test, both genetic deletion of ghrelin and pharmacological antagonism of the GHS-R1A (JMV2959) reduced voluntary alcohol consumption and preference. Finally, JMV2959-induced reduction of alcohol intake was only observed in WT but not in ghrelin KO mice. Taken together, these results suggest that ghrelin neurotransmission is necessary for the stimulatory effect of ethanol to occur, whereas lack of ghrelin leads to changes that reduce the voluntary intake as well as conditioned reward by ethanol. Our findings reveal a major, novel role for ghrelin in mediating ethanol behavior, and add to growing evidence that ghrelin is a key mediator of the effects of multiple abused drugs.

  9. Donor MHC gene to mitigate rejection of transplantation in recipient mice

    Institute of Scientific and Technical Information of China (English)

    LI Tong; ZHANG Zhi-tai; LI Hui; YAN Jun; TAN Jia-li; L(U) Yue-ping; HOU Sheng-cai; LI Shen-tao; XU Qing; TONG Xue-hong; DING Jie

    2011-01-01

    Background Donor organ rejection continues to be a significant problem for patients receiving transplants.We therefore tested whether transferring a donor's major histocompatibility complex (MHC) gene to the recipient would mitigate the rejection of transplanted hearts in mice.Methods H-2Kkgene from donor mice was amplified using nested polymerase chain reaction (PCR) and ligated into a mammalian expression vector,which was then transfected into thymus ground mass cells collected from the recipients.Clones stably expressing the transgene were then injected into the recipients' thymus visualized using ultrasound.Control mice were administered cells previously transfected with empty vector.Following heart transplantation,cardiac activity was monitored electrocardiographically.Recipient thymus cells were tested for MHC antigenicity using flow cytometry and spleen cells were subjected to mixed lymphocyte culture tests.Finally,the transplanted hearts were sectioned,stained and examined under light microscopy.Results Southern analysis following nested PCR revealed clear expression of H-2Kk gene.Following transplantation,electrocardiosignals were detectable highly significantly longer in recipients administered thymal cells expressing donor H-2Kk than in those receiving control cells.Flow cytometric analysis using an anti-H-2Kk antibody confirmed its expression in H-2Kk treated recipients but not in control mice.Mixed lymphocyte cultures containing H-2Kk treated cells showed significantly less proliferation than those containing control cells.Hearts from control mice showed substantially greater lymphocyte infiltration than those from H-2Kk treated mice and large areas of necrosis.Conclusion Rejection of transplanted hearts can be mitigated substantially by introducing the donor's MHC into the recipient.

  10. Lithium improves hippocampal neurogenesis, neuropathology and cognitive functions in APP mutant mice.

    Directory of Open Access Journals (Sweden)

    Anna Fiorentini

    Full Text Available BACKGROUND: Alzheimer's disease (AD is a neurodegenerative disorder characterized by progressive deterioration of cognitive functions, extracellular β-amyloid (Aβ plaques and intracellular neurofibrillary tangles within neocortex and hippocampus. Adult hippocampal neurogenesis plays an important role in learning and memory processes and its abnormal regulation might account for cognitive impairments associated with AD. METHODOLOGY/PRINCIPAL FINDINGS: The double transgenic (Tg CRND8 mice (overexpressing the Swedish and Indiana mutations in the human amyloid precursor protein, aged 2 and 6 months, were used to examine in vivo the effects of 5 weeks lithium treatment. BrdU labelling showed a decreased neurogenesis in the subgranular zone of Tg mice compared to non-Tg mice. The decrease of hippocampal neurogenesis was accompanied by behavioural deficits and worsened with age and pathology severity. The differentiation into neurons and maturation of the proliferating cells were also markedly impaired in the Tg mice. Lithium treatment to 2-month-old Tg mice significantly stimulated the proliferation and neuron fate specification of newborn cells and fully counteracted the transgene-induced impairments of cognitive functions. The drug, by the inhibition of GSK-3β and subsequent activation of Wnt/ß-catenin signalling promoted hippocampal neurogenesis. Finally, the data show that the lithium's ability to stimulate neurogenesis and cognitive functions was lost in the aged Tg mice, thus indicating that the lithium-induced facilitation of neurogenesis and cognitive functions declines as brain Aβ deposition and pathology increases. CONCLUSIONS: Lithium, when given on time, stimulates neurogenesis and counteracts AD-like pathology.

  11. Impaired synaptic plasticity in the prefrontal cortex of mice with developmentally decreased number of interneurons.

    Science.gov (United States)

    Konstantoudaki, X; Chalkiadaki, K; Tivodar, S; Karagogeos, D; Sidiropoulou, K

    2016-05-13

    Interneurons are inhibitory neurons, which protect neural tissue from excessive excitation. They are interconnected with glutamatergic pyramidal neurons in the cerebral cortex and regulate their function. Particularly in the prefrontal cortex (PFC), interneurons have been strongly implicated in regulating pathological states which display deficits in the PFC. The aim of this study is to investigate the adaptations in the adult glutamatergic system, when defects in interneuron development do not allow adequate numbers of interneurons to reach the cerebral cortex. To this end, we used a mouse model that displays ~50% fewer cortical interneurons due to the Rac1 protein loss from Nkx2.1/Cre expressing cells (Rac1 conditional knockout (cKO) mice), to examine how the developmental loss of interneurons may affect basal synaptic transmission, synaptic plasticity and neuronal morphology in the adult PFC. Despite the decrease in the number of interneurons, basal synaptic transmission, as examined by recording field excitatory postsynaptic potentials (fEPSPs) from layer II networks, is not altered in the PFC of Rac1 cKO mice. However, there is decreased paired-pulse ratio (PPR) and decreased long-term potentiation (LTP), in response to tetanic stimulation, in the layer II PFC synapses of Rac1 cKO mice. Furthermore, expression of N-methyl-d-aspartate (NMDA) subunits is decreased and dendritic morphology is altered, changes that could underlie the decrease in LTP in the Rac1 cKO mice. Finally, we find that treating Rac1 cKO mice with diazepam in early postnatal life can reverse changes in dendritic morphology observed in non-treated Rac1 cKO mice. Therefore, our data show that disruption in GABAergic inhibition alters glutamatergic function in the adult PFC, an effect that could be reversed by enhancement of GABAergic function during an early postnatal period.

  12. PRIMA-X Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Lorenz, Daniel [German Research School for Simulation Sciences GmbH, Aachen (Germany); Wolf, Felix [German Research School for Simulation Sciences GmbH, Aachen (Germany)

    2016-02-17

    Darmstadt) starting February 1st, 2015, the project ended at GRS on January 31st, 2015. This report reflects the work accomplished at GRS until then. The work of GRS is expected to be continued at TU Darmstadt. The first main accomplishment of GRS is the design of different thread-level aggregation techniques. We created a prototype capable of aggregating the thread-level information in performance profiles using these techniques. The next step will be the integration of the most promising techniques into the Score-P measurement system and their evaluation. The second main accomplishment is a substantial increase of Score-P’s scalability, achieved by improving the design of the system-tree representation in Score-P’s profile format. We developed a new representation and a distributed algorithm to create the scalable system tree representation. Finally, we developed a lightweight approach to MPI wait-state profiling. Former algorithms either needed piggy-backing, which can cause significant runtime overhead, or tracing, which comes with its own set of scaling challenges. Our approach works with local data only and, thus, is scalable and has very little overhead.

  13. MGT100 HK1-FINAL EXAM

    OpenAIRE

    Laynebaril1

    2017-01-01

     MGT100 HK1-FINAL EXAM   Click Link Below To Buy: http://hwcampus.com/shop/mgt100-hk1-final-exam/   Take Assessment: Final Exam     Name Final Exam Instructions Multiple Attempts This Test allows 2 attempts. This is attempt number 2. Force Completion This Test can be saved and resumed later.     Question 1 1 points Save The most typical time frame for a budget is one month. three months. six months. one year. five yea...

  14. The effect of age at exposure on the inactivating mechanisms and relative contributions of key tumor suppressor genes in radiation-induced mouse T-cell lymphomas

    Energy Technology Data Exchange (ETDEWEB)

    Sunaoshi, Masaaki [Radiobiology for Children' s Health Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555 (Japan); Department of Biological Sciences, College of Science, Ibaraki University, Bunkyo 2-1-1, Mito, Ibaraki 310-8512 (Japan); Amasaki, Yoshiko; Hirano-Sakairi, Shinobu; Blyth, Benjamin J. [Radiobiology for Children' s Health Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555 (Japan); Morioka, Takamitsu [Radiobiology for Children' s Health Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555 (Japan); Radiation Effect Accumulation and Prevention Project, Fukushima Project Headquarters, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555 (Japan); Kaminishi, Mutsumi [Radiobiology for Children' s Health Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555 (Japan); Shang, Yi [Radiation Effect Accumulation and Prevention Project, Fukushima Project Headquarters, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555 (Japan); Nishimura, Mayumi; Shimada, Yoshiya [Radiobiology for Children' s Health Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555 (Japan); Radiation Effect Accumulation and Prevention Project, Fukushima Project Headquarters, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555 (Japan); Tachibana, Akira [Department of Biological Sciences, College of Science, Ibaraki University, Bunkyo 2-1-1, Mito, Ibaraki 310-8512 (Japan); and others

    2015-09-15

    Highlights: • T-cell lymphoma incidence, latency and weight did not change with age at exposure. • Lymphomas had frequent loss of heterozygosity on chromosomes 4, 11 and 19. • These lesions targeted the Cdkn2a, Ikaros and Pten tumor suppressor genes. • Age at exposure may influence which tumor suppressor genes are lost in each tumor. • The mechanisms of tumor suppressor gene loss were different at each locus. - Abstract: Children are considered more sensitive to radiation-induced cancer than adults, yet any differences in genomic alterations associated with age-at-exposure and their underlying mechanisms remain unclear. We assessed genome-wide DNA copy number and mutation of key tumor suppressor genes in T-cell lymphomas arising after weekly irradiation of female B6C3F1 mice with 1.2 Gy X-rays for 4 consecutive weeks starting during infancy (1 week old), adolescence (4 weeks old) or as young adults (8 weeks old). Although T-cell lymphoma incidence was similar, loss of heterozygosity at Cdkn2a on chromosome 4 and at Ikaros on chromosome 11 was more frequent in the two older groups, while loss at the Pten locus on chromosome 19 was more frequent in the infant-irradiated group. Cdkn2a and Ikaros mutation/loss was a common feature of the young adult-irradiation group, with Ikaros frequently (50%) incurring multiple independent hits (including deletions and mutations) or suffering a single hit predicted to result in a dominant negative protein (such as those lacking exon 4, an isoform we have designated Ik12, which lacks two DNA binding zinc-finger domains). Conversely, Pten mutations were more frequent after early irradiation (60%) than after young adult-irradiation (30%). Homozygous Pten mutations occurred without DNA copy number change after irradiation starting in infancy, suggesting duplication of the mutated allele by chromosome mis-segregation or mitotic recombination. Our findings demonstrate that while deletions on chromosomes 4 and 11 affecting Cdkn2

  15. Using physiologically based pharmacokinetic modeling to address nonlinear kinetics and changes in rodent physiology and metabolism due to aging and adaptation in deriving reference values for propylene glycol methyl ether and propylene glycol methyl ether acetate.

    Energy Technology Data Exchange (ETDEWEB)

    Kirman, C R.; Sweeney, Lisa M.; Corley, Rick A.; Gargas, M L.

    2005-04-01

    Reference values, including an oral reference dose (RfD) and an inhalation reference concentration (RfC), were derived for propylene glycol methyl ether (PGME), and an oral RfD was derived for its acetate (PGMEA). These values were based upon transient sedation observed in F344 rats and B6C3F1 mice during a two-year inhalation study. The dose-response relationship for sedation was characterized using internal dose measures as predicted by a physiologically based pharmacokinetic (PBPK) model for PGME and its acetate. PBPK modeling was used to account for changes in rodent physiology and metabolism due to aging and adaptation, based on data collected during weeks 1, 2, 26, 52, and 78 of a chronic inhalation study. The peak concentration of PGME in richly perfused tissues was selected as the most appropriate internal dose measure based upon a consideration of the mode of action for sedation and similarities in tissue partitioning between brain and other richly perfused tissues. Internal doses (peak tissue concentrations of PGME) were designated as either no-observed-adverse-effect levels (NOAELs) or lowest-observed-adverse-effect levels (LOAELs) based upon the presence or absence of sedation at each time-point, species, and sex in the two year study. Distributions of the NOAEL and LOAEL values expressed in terms of internal dose were characterized using an arithmetic mean and standard deviation, with the mean internal NOAEL serving as the basis for the reference values, which was then divided by appropriate uncertainty factors. Where data were permitting, chemical-specific adjustment factors were derived to replace default uncertainty factor values of ten. Nonlinear kinetics are were predicted by the model in all species at PGME concentrations exceeding 100 ppm, which complicates interspecies and low-dose extrapolations. To address this complication, reference values were derived using two approaches which differ with respect to the order in which these extrapolations

  16. Long-term betamethasone 21-phosphate disodium treatment has distinct effects in CD1 and DBA/2 mice on animal behavior accompanied by opposite effects on neurogenesis.

    Science.gov (United States)

    Aiello, Rossana; Crupi, Rosalia; Leo, Antonio; Chimirri, Serafina; Rispoli, Vincenzo; Marra, Rosario; Citraro, Rita; Cuzzocrea, Salvatore; De Sarro, Giovambattista; Russo, Emilio

    2015-02-01

    One of the most peculiar characteristics of the stress response is the pronounced inter-individual and inter-strain variability both in behavioral and neurochemical outcomes. Several studies confirm that rodents belonging to the same or different strain and/or gender, when exposed to a stressor, may show behavioral and cognitive differences. We compared the effects of long-term betamethasone 21-phosphate disodium (BTM), a widely clinically used corticosteroid, on animal behavior and neurogenesis in CD1 and DBA/2 mice. BTM treatment, in CD1 mice, increased body weight gain and anxiety parameters while having pro-depressant effects. Furthermore, BTM significantly reduced neurogenesis in the dentate gyrus of the hippocampus. Finally, BTM treatment induced a significant impairment in memory and learning performance in the Morris water maze. At odds, BTM administration, in DBA/2 mice, caused a significant reduction in the body weight while not modifying anxiety parameters. In addition, both an increased synaptogenesis and neurogenesis were found. Similarly to CD1 mice, also in DBA/2 mice, memory and learning were impaired. Our data confirm that long-term exposure to corticosteroids can generate or aggravate psychiatric/neurologic disorders such as depression, anxiety, memory and learning. Our study did not reveal significant differences between corticosterone and BTM treatment in CD1 mice. In contrast, BTM treatment in mice with an anxious phenotype (DBA/2 mice) revealed some contrasting results indicating that genetic factors can influence corticosteroids dependent effects. Finally, our data further underline the need for a re-evaluation of neurogenesis role; the increased neurogenesis observed in DBA/2 mice and behavioral effects might be distinguished phenomena.

  17. Dysfunctional dopaminergic neurotransmission in asocial BTBR mice.

    Science.gov (United States)

    Squillace, M; Dodero, L; Federici, M; Migliarini, S; Errico, F; Napolitano, F; Krashia, P; Di Maio, A; Galbusera, A; Bifone, A; Scattoni, M L; Pasqualetti, M; Mercuri, N B; Usiello, A; Gozzi, A

    2014-08-19

    Autism spectrum disorders (ASD) are neurodevelopmental conditions characterized by pronounced social and communication deficits and stereotyped behaviours. Recent psychosocial and neuroimaging studies have highlighted reward-processing deficits and reduced dopamine (DA) mesolimbic circuit reactivity in ASD patients. However, the neurobiological and molecular determinants of these deficits remain undetermined. Mouse models recapitulating ASD-like phenotypes could help generate hypotheses about the origin and neurophysiological underpinnings of clinically relevant traits. Here we used functional magnetic resonance imaging (fMRI), behavioural and molecular readouts to probe dopamine neurotransmission responsivity in BTBR T(+) Itpr3(tf)/J mice (BTBR), an inbred mouse line widely used to model ASD-like symptoms owing to its robust social and communication deficits, and high level of repetitive stereotyped behaviours. C57BL/6J (B6) mice were used as normosocial reference comparators. DA reuptake inhibition with GBR 12909 produced significant striatal DA release in both strains, but failed to elicit fMRI activation in widespread forebrain areas of BTBR mice, including mesolimbic reward and striatal terminals. In addition, BTBR mice exhibited no appreciable motor responses to GBR 12909. DA D1 receptor-dependent behavioural and signalling responses were found to be unaltered in BTBR mice, whereas dramatic reductions in pre- and postsynaptic DA D2 and adenosine A2A receptor function was observed in these animals. Overall these results document profoundly compromised DA D2-mediated neurotransmission in BTBR mice, a finding that is likely to have a role in the distinctive social and behavioural deficits exhibited by these mice. Our results call for a deeper investigation of the role of dopaminergic dysfunction in mouse lines exhibiting ASD-like phenotypes, and possibly in ASD patient populations.

  18. Lovastatin protects against experimental plague in mice.

    Directory of Open Access Journals (Sweden)

    Saravanan Ayyadurai

    Full Text Available BACKGROUND: Plague is an ectoparasite-borne deadly infection caused by Yersinia pestis, a bacterium classified among the group A bioterrorism agents. Thousands of deaths are reported every year in some African countries. Tetracyclines and cotrimoxazole are used in the secondary prophylaxis of plague in the case of potential exposure to Y. pestis, but cotrimoxazole-resistant isolates have been reported. There is a need for additional prophylactic measures. We aimed to study the effectiveness of lovastatin, a cholesterol-lowering drug known to alleviate the symptoms of sepsis, for plague prophylaxis in an experimental model. METHODOLOGY: Lovastatin dissolved in Endolipide was intraperitoneally administered to mice (20 mg/kg every day for 6 days prior to a Y. pestis Orientalis biotype challenge. Non-challenged, lovastatin-treated and challenged, untreated mice were also used as control groups in the study. Body weight, physical behavior and death were recorded both prior to infection and for 10 days post-infection. Samples of the blood, lungs and spleen were collected from dead mice for direct microbiological examination, histopathology and culture. The potential antibiotic effect of lovastatin was tested on blood agar plates. CONCLUSIONS/SIGNIFICANCE: Lovastatin had no in-vitro antibiotic effect against Y. pestis. The difference in the mortality between control mice (11/15; 73.5% and lovastatin-treated mice (3/15; 20% was significant (P<0.004; Mantel-Haenszel test. Dead mice exhibited Y. pestis septicemia and inflammatory destruction of lung and spleen tissues not seen in lovastatin-treated surviving mice. These data suggest that lovastatin may help prevent the deadly effects of plague. Field observations are warranted to assess the role of lovastatin in the prophylaxis of human plague.

  19. Caspase-Mediated Apoptosis in the Cochleae Contributes to the Early Onset of Hearing Loss in A/J Mice

    Directory of Open Access Journals (Sweden)

    Xu Han

    2015-03-01

    Full Text Available A/J and C57BL/6 J (B6 mice share a mutation in Cdh23 (ahl allele and are characterized by age-related hearing loss. However, hearing loss occurs much earlier in A/J mice at about four weeks of age. Recent study has revealed that a mutation in citrate synthase (Cs is one of the main contributors, but the mechanism is largely unknown. In the present study, we showed that A/J mice displayed more severe degeneration of hair cells, spiral ganglion neurons, and stria vascularis in the cochleae compared with B6 mice. Moreover, messenger RNA accumulation levels of caspase-3 and caspase-9 in the inner ears of A/J mice were significantly higher than those in B6 mice at 2 and 8 weeks of age. Immunohistochemistry localized caspase-3 expression mainly to the hair cells, spiral ganglion neurons, and stria vascularis in cochleae. In vitro transfection with Cs short hairpin RNA (shRNA alone or cotransfection with Cs shRNA and Cdh23 shRNA significantly increased the levels of caspase-3 in an inner ear cell line (HEI-OC1. Finally, a pan-caspase inhibitor Z-VAD-FMK could preserve the hearing of A/J mice by lowering about 15 decibels of the sound pressure level for the auditory-evoked brainstem response thresholds. In conclusion, our results suggest that caspase-mediated apoptosis in the cochleae, which may be related to a Cs mutation, contributes to the early onset of hearing loss in A/J mice.

  20. Vaccination with lentiviral vector expressing the nfa1 gene confers a protective immune response to mice infected with Naegleria fowleri.

    Science.gov (United States)

    Kim, Jong-Hyun; Sohn, Hae-Jin; Lee, Jinyoung; Yang, Hee-Jong; Chwae, Yong-Joon; Kim, Kyongmin; Park, Sun; Shin, Ho-Joon

    2013-07-01

    Naegleria fowleri, a pathogenic free-living amoeba, causes fatal primary amoebic meningoencephalitis (PAM) in humans and animals. The nfa1 gene (360 bp), cloned from a cDNA library of N. fowleri, produces a 13.1-kDa recombinant protein which is located on pseudopodia, particularly the food cup structure. The nfa1 gene plays an important role in the pathogenesis of N. fowleri infection. To examine the effect of nfa1 DNA vaccination against N. fowleri infection, we constructed a lentiviral vector (pCDH) expressing the nfa1 gene. For the in vivo mouse study, BALB/c mice were intranasally vaccinated with viral particles of a viral vector expressing the nfa1 gene. To evaluate the effect of vaccination and immune responses of mice, we analyzed the IgG levels (IgG, IgG1, and IgG2a), cytokine induction (interleukin-4 [IL-4] and gamma interferon [IFN-γ]), and survival rates of mice that developed PAM. The levels of both IgG and IgG subclasses (IgG1 and IgG2a) in vaccinated mice were significantly increased. The cytokine analysis showed that vaccinated mice exhibited greater IL-4 and IFN-γ production than the other control groups, suggesting a Th1/Th2 mixed-type immune response. In vaccinated mice, high levels of Nfa1-specific IgG antibodies continued until 12 weeks postvaccination. The mice vaccinated with viral vector expressing the nfa1 gene also exhibited significantly higher survival rates (90%) after challenge with N. fowleri trophozoites. Finally, the nfa1 vaccination effectively induced protective immunity by humoral and cellular immune responses in N. fowleri-infected mice. These results suggest that DNA vaccination using a viral vector may be a potential tool against N. fowleri infection.

  1. Molecular mechanisms mediating a deficit in recall of fear extinction in adult mice exposed to cocaine in utero.

    Directory of Open Access Journals (Sweden)

    Zeeba D Kabir

    Full Text Available Prenatal cocaine exposure has been shown to alter cognitive processes of exposed individuals, presumed to be a result of long-lasting molecular alterations in the brain. In adult prenatal cocaine exposed (PCOC mice we have identified a deficit in recall of fear extinction, a behavior that is dependent on the medial prefrontal cortex (mPFC and the hippocampus. While we observed no change in the constitutive expression of brain derived neurotrophic factor (BDNF protein and mRNA in the mPFC and hippocampus of adult PCOC mice, we observed blunted BDNF signaling in the mPFC of adult PCOC mice after fear extinction compared to the control animals. Specifically, during the consolidation phase of the extinction memory, we observed a decrease in BDNF protein and it's phospho-TrkB receptor expression. Interestingly, at this same time point there was a significant increase in total Bdnf mRNA levels in the mPFC of PCOC mice as compared with controls. In the Bdnf gene, we identified decreased constitutive binding of the transcription factors, MeCP2 and P-CREB at the promoters of Bdnf exons I and IV in the mPFC of PCOC mice, that unlike control mice remained unchanged when measured during the behavior. Finally, bilateral infusion of recombinant BDNF protein into the infralimbic subdivision of the mPFC during the consolidation phase of the extinction memory rescued the behavioral deficit in PCOC mice. In conclusion, these findings extend our knowledge of the neurobiologic impact of prenatal cocaine exposure on the mPFC of mice, which may lead to improved clinical recognition and treatment of exposed individuals.

  2. Brain ischemia changes the long term response to antidepressant drugs in mice.

    Science.gov (United States)

    Deplanque, Dominique; Venna, Venugopal Reddy; Bordet, Régis

    2011-06-01

    Depression is a frequent but often unrecognized and under treated complication of stroke that has scarcely been investigated in animal models particularly regarding treatment issues. Using the Forced Swim Test (FST) and testing spontaneous motor activity, we studied whether a transient focal cerebral ischemia modifies mice behaviours and antidepressant drug effects. We first evaluated whether FST realized 2 days or 1 week after brain reperfusion may be routinely used in male Swiss mice previously submitted to a 15, 30 or 60-min transient occlusion of the right middle cerebral artery. We then evaluated behavioural changes up to 5 weeks in mice previously submitted to a 15-min ischemia. Behaviours according to the administration of imipramine or fluvoxamine at 1 and 5 weeks after a 15-min ischemia were finally evaluated. Transient ischemia was associated with a decrease in immobility in the FST performed 2 days after reperfusion while no changes were observed in 1 and 5 weeks post-ischemia groups. Changes were related neither to brain ischemia duration nor to infarct volume. At both 1 and 5 weeks after brain ischemia, a dramatic decrease in the antidepressant response to imipramine related to a decrease in climbing behaviour was observed while the effects of fluvoxamine were improved through an increase in both climbing and swimming. Behaviours in the FST were unrelated to any spontaneous motor activity changes. Responses to anti-depressant drugs are strongly modified in mice previously submitted to brain ischemia. Present results underline that not all antidepressant drugs are appropriate after ischemic stroke.

  3. Mesenteric resistance arteries in type 2 diabetic db/db mice undergo outward remodeling.

    Directory of Open Access Journals (Sweden)

    Flavia M Souza-Smith

    Full Text Available OBJECTIVE: Resistance vessel remodeling is controlled by myriad of hemodynamic and neurohormonal factors. This study characterized structural and molecular remodeling in mesenteric resistance arteries (MRAs in diabetic (db/db and control (Db/db mice. METHODS: Structural properties were assessed in isolated MRAs from 12 and 16 wk-old db/db and Db/db mice by pressure myography. Matrix regulatory proteins were measured by Western blot analysis. Mean arterial pressure and superior mesenteric blood flow were measured in 12 wk-old mice by telemetry and a Doppler flow nanoprobe, respectively. RESULTS: Blood pressure was similar between groups. Lumen diameter and medial cross-sectional area were significantly increased in 16 wk-old db/db MRA compared to control, indicating outward hypertrophic remodeling. Moreover, wall stress and cross-sectional compliance were significantly larger in diabetic arteries. These remodeling indices were associated with increased expression of matrix regulatory proteins matrix metalloproteinase (MMP-9, MMP-12, tissue inhibitors of matrix metalloproteinase (TIMP-1, TIMP-2, and plasminogen activator inhibitor-1 (PAI-1 in db/db arteries. Finally, superior mesenteric artery blood flow was increased by 46% in 12 wk-old db/db mice, a finding that preceded mesenteric resistance artery remodeling. CONCLUSIONS: These data suggest that flow-induced hemodynamic changes may supersede the local neurohormonal and metabolic milieu to culminate in hypertrophic outward remodeling of type 2 DM mesenteric resistance arteries.

  4. Adipose tissues differentiated by adipose-derived stemcells harvested from transgenic mice

    Institute of Scientific and Technical Information of China (English)

    LU Feng; GAO Jian-hua; Rei Ogawa; Hiroshi Mizuro; Hiki Hykusoku

    2006-01-01

    Objective: To induce adipocyte differentiation in vitro by adipose-derived stromal cells (ASCs) harvested from transgenic mice with green fluorescent protein (GFP)and assess the possibility of constructing adipose tissues via attachment of ASCs to type Ⅰ collagen scaffolds.Methods: Inguinal fat pads from GFP transgenic mice were digested by enzymes for isolation of ASCs (primary culture). After expansion to three passages of ASCs, the cells were incubated in an adipogenic medium for two weeks, and the adipocyte differentiation by ASCs in vitro was assessed by morphological observation and Oil Red O staining. Then they were attached to collagen scaffolds and co-cultured for 12 hours, followed by hypodermic implantation to the dorsal skin of nude mice for 2 months. The newly-formed tissues were detected by HE staining.Results: The cultured primary stem cells were fibroblast-like and showed active proliferation. After being incubated in an adipocyte differentiation medium, the lipid droplets in the cytoplasm accumulated gradually and finally developed into mature adipocytes, which showed positive in Oil Red O staining. A 0.5-cm3 new tissue clot was found under the dorsal skin of the nude mice and it was confirmed as mature adipose tissues by fluorescent observation and HE staining.Conclusions: ASCs can successfully differentiate adipose tissues into mature adipocytes, which exhibit an adipocyte-like morphology and express as intracytoplasmic lipid droplets. It is an efficient model of adipose tissues engineered with ASCs and type Ⅰ collagen scaffolds.

  5. Excess Maternal Fructose Consumption Increases Fetal Loss and Impairs Endometrial Decidualization in Mice.

    Science.gov (United States)

    Saben, Jessica L; Asghar, Zeenat; Rhee, Julie S; Drury, Andrea; Scheaffer, Suzanne; Moley, Kelle H

    2016-02-01

    The most significant increase in metabolic syndrome over the previous decade occurred in women of reproductive age, which is alarming given that metabolic syndrome is associated with reproductive problems including subfertility and early pregnancy loss. Individuals with metabolic syndrome often consume excess fructose, and several studies have concluded that excess fructose intake contributes to metabolic syndrome development. Here, we examined the effects of increased fructose consumption on pregnancy outcomes in mice. Female mice fed a high-fructose diet (HFrD) for 6 weeks developed glucose intolerance and mild fatty liver but did not develop other prominent features of metabolic syndrome such as weight gain, hyperglycemia, and hyperinsulinemia. Upon mating, HFrD-exposed mice had lower pregnancy rates and smaller litters at midgestation than chow-fed controls. To explain this phenomenon, we performed artificial decidualization experiments and found that HFrD consumption impaired decidualization. This appeared to be due to decreased circulating progesterone as exogenous progesterone administration rescued decidualization. Furthermore, HFrD intake was associated with decreased bone morphogenetic protein 2 expression and signaling, both of which were restored by exogenous progesterone. Finally, expression of forkhead box O1 and superoxide dismutase 2 [Mn] proteins were decreased in the uteri of HFrD-fed mice, suggesting that HFrD consumption promotes a prooxidative environment in the endometrium. In summary, these data suggest that excess fructose consumption impairs murine fertility by decreasing steroid hormone synthesis and promoting an adverse uterine environment.

  6. Effect of Pueraria Flavonoid on Diabetes in Mice Complicated by Hyperlipidemia

    Institute of Scientific and Technical Information of China (English)

    孙立红; 邢东明; 孙虹; 李敏; 金文; 杜力军

    2002-01-01

    A new model is presented for hyperglycemia in animals complicated by hyperlipidemia (HD) to study the action of pueraria flavonoids (PF). Kunming mice were treated with alloxan (150 -mg/kg) intraperitoneally and fed a high-fat diet. Glucose (Glu), total cholesterol (TC) and triglycerides (TG) in the plasma were measured at week 0, 1, 2, 4, and 8. PF (600, 400, 200 -mg/kg) was given to the mice for 14 days beginning from week 1. The effects of PF on the lipase activity and the ability to produce cholesterol and glycogen in the cultured hepatic cells were also tested in vitro. In week 1, 2, 4, and 8 following the final alloxan injection, Glu increased by 763%, 504%, 526%, and 641%;TC increased by 269%, 409%, 449%, and 428%; and TG increased by 415%, 485%, 461%, and 418%. These increases in the model were significant compared with those in normal Kunming mice. PF acted effectively as hypoglycemic and hypolipidemic agents on the mice. The results suggest that the model may be suitable for studies of drugs on diabetes complicated by hyperlipidemia and that PF may be a useful drug for patients with diabetes complicated by hyperlipidemia.

  7. Bezafibrate Improves Insulin Sensitivity and Metabolic Flexibility in STZ-Induced Diabetic Mice.

    Science.gov (United States)

    Franko, Andras; Huypens, Peter; Neschen, Susanne; Irmler, Martin; Rozman, Jan; Rathkolb, Birgit; Neff, Frauke; Prehn, Cornelia; Dubois, Guillaume; Baumann, Martina; Massinger, Rebecca; Gradinger, Daniel; Przemeck, Gerhard K H; Repp, Birgit; Aichler, Michaela; Feuchtinger, Annette; Schommers, Philipp; Stöhr, Oliver; Sanchez-Lasheras, Carmen; Adamski, Jerzy; Peter, Andreas; Prokisch, Holger; Beckers, Johannes; Walch, Axel K; Fuchs, Helmut; Wolf, Eckhard; Schubert, Markus; Wiesner, Rudolf J; Hrabě de Angelis, Martin

    2016-09-01

    Bezafibrate (BEZ), a pan activator of peroxisome proliferator-activated receptors (PPARs), has been generally used to treat hyperlipidemia for decades. Clinical trials with type 2 diabetes patients indicated that BEZ also has beneficial effects on glucose metabolism, although the underlying mechanisms of these effects remain elusive. Even less is known about a potential role for BEZ in treating type 1 diabetes. Here we show that BEZ markedly improves hyperglycemia and glucose and insulin tolerance in mice with streptozotocin (STZ)-induced diabetes, an insulin-deficient mouse model of type 1 diabetes. BEZ treatment of STZ mice significantly suppressed the hepatic expression of genes that are annotated in inflammatory processes, whereas the expression of PPAR and insulin target gene transcripts was increased. Furthermore, BEZ-treated mice also exhibited improved metabolic flexibility as well as an enhanced mitochondrial mass and function in the liver. Finally, we show that the number of pancreatic islets and the area of insulin-positive cells tended to be higher in BEZ-treated mice. Our data suggest that BEZ may improve impaired glucose metabolism by augmenting hepatic mitochondrial performance, suppressing hepatic inflammatory pathways, and improving insulin sensitivity and metabolic flexibility. Thus, BEZ treatment might also be useful for patients with impaired glucose tolerance or diabetes.

  8. Blockage of transient receptor potential vanilloid 4 inhibits brain edema in middle cerebral artery occlusion mice.

    Science.gov (United States)

    Jie, Pinghui; Tian, Yujing; Hong, Zhiwen; Li, Lin; Zhou, Libin; Chen, Lei; Chen, Ling

    2015-01-01

    Brain edema is an important pathological process during stroke. Activation of transient receptor potential vanilloid 4 (TRPV4) causes an up-regulation of matrix metalloproteinases (MMPs) in lung tissue. MMP can digest the endothelial basal lamina to destroy blood brain barrier, leading to vasogenic brain edema. Herein, we tested whether TRPV4-blockage could inhibit brain edema through inhibiting MMPs in middle cerebral artery occlusion (MCAO) mice. We found that the brain water content and Evans blue extravasation at 48 h post-MCAO were reduced by a TRPV4 antagonist HC-067047. The increased MMP-2/9 protein expression in hippocampi of MCAO mice was attenuated by HC-067046, but only the increased MMP-9 activity was blocked by HC-067047. The loss of zonula occludens-1 (ZO-1) and occludin protein in MCAO mice was also attenuated by HC-067047. Moreover, MMP-2/9 protein expression increased in mice treated with a TRPV4 agonist GSK1016790A, but only MMP-9 activity was increased by GSK1016790A. Finally, ZO-1 and occludin protein expression was decreased by GSK1016790A, which was reversed by an MMP-9 inhibitor. We conclude that blockage of TRPV4 may inhibit brain edema in cerebral ischemia through inhibiting MMP-9 activation and the loss of tight junction protein.

  9. Mesenteric Resistance Arteries in Type 2 Diabetic db/db Mice Undergo Outward Remodeling

    Science.gov (United States)

    Souza-Smith, Flavia M.; Katz, Paige S.; Trask, Aaron J.; Stewart, James A.; Lord, Kevin C.; Varner, Kurt J.; Vassallo, Dalton V.; Lucchesi, Pamela A.

    2011-01-01

    Objective Resistance vessel remodeling is controlled by myriad of hemodynamic and neurohormonal factors. This study characterized structural and molecular remodeling in mesenteric resistance arteries (MRAs) in diabetic (db/db) and control (Db/db) mice. Methods Structural properties were assessed in isolated MRAs from 12 and 16 wk-old db/db and Db/db mice by pressure myography. Matrix regulatory proteins were measured by Western blot analysis. Mean arterial pressure and superior mesenteric blood flow were measured in 12 wk-old mice by telemetry and a Doppler flow nanoprobe, respectively. Results Blood pressure was similar between groups. Lumen diameter and medial cross-sectional area were significantly increased in 16 wk-old db/db MRA compared to control, indicating outward hypertrophic remodeling. Moreover, wall stress and cross-sectional compliance were significantly larger in diabetic arteries. These remodeling indices were associated with increased expression of matrix regulatory proteins matrix metalloproteinase (MMP)-9, MMP-12, tissue inhibitors of matrix metalloproteinase (TIMP)-1, TIMP-2, and plasminogen activator inhibitor-1 (PAI-1) in db/db arteries. Finally, superior mesenteric artery blood flow was increased by 46% in 12 wk-old db/db mice, a finding that preceded mesenteric resistance artery remodeling. Conclusions These data suggest that flow-induced hemodynamic changes may supersede the local neurohormonal and metabolic milieu to culminate in hypertrophic outward remodeling of type 2 DM mesenteric resistance arteries. PMID:21829729

  10. Lesion profiling at primary isolation in RIII mice is insufficient in distinguishing BSE from classical scrapie.

    Science.gov (United States)

    Beck, Katy E; Chaplin, Melanie; Stack, Michael; Sallis, Rosemary E; Simonini, Sarah; Lockey, Richard; Spiropoulos, John

    2010-03-01

    Primary isolation of bovine spongiform encephalopathy (BSE) in RIII mice generates a lesion profile believed to be reproducible and distinct from that produced by classical scrapie. This profile, which is characterized by peaks at gray matter areas 1, 4 and 7 (dorsal medulla, hypothalamus and septal nuclei), is used to diagnose BSE on primary isolation. The aim of this study was to investigate whether the BSE agent could be present in sheep diagnosed with classical scrapie, using lesion profiles in RIII mice as a discriminatory method. Sixty-two positive scrapie field cases were collected from individual farms between 1996 and 1999 and bioassayed in RIII mice. Fifty-five of these isolates transmitted successfully to at least one mouse. Of the 31 that produced adequate data to allow lesion profile analysis, 10 showed a consistent profile with peaks at brain areas 1, 4 and 7. All inocula for this subgroup were derived from sheep of genotype ARQ/ARQ. While the 1-4-7-scrapie profile exhibited similarities to BSE in RIII mice at primary isolation, it was distinguishable based on histopathology, immunohistochemistry and cluster analysis. We conclude that caution should be taken to distinguish this profile from BSE and that additional parameters should be considered to reach a final diagnosis.

  11. Antioxidant properties of lutein contribute to the protection against lipopolysaccharide-induced uveitis in mice

    Directory of Open Access Journals (Sweden)

    Yao Xin-Sheng

    2011-10-01

    Full Text Available Abstract Background Lutein is an important eye-protective nutrient. This study investigates the protective effects and mechanisms of lutein on lipopolysaccharides (LPS-induced uveitis in mice. Methods Lutein, suspended in drinking water at a final concentration of 12.5 and 25 mg/mL, was administered to mice at 0.1 mL/10 g body weight for five consecutive days. Control and model group received drinking water only. Uveitis was induced by injecting LPS (100 mg per mouse into the footpad in the model and lutein groups on day 5 after the last drug administration. Eyes of the mice were collected 24 hours after the LPS injection for the detection of indicators using commercial kits and reverse transcription-polymerase chain reaction. Results LPS-induced uveitis was confirmed by significant pathological damage and increased the nitric oxide level in eye tissue of BALB/C mice 24 hours after the footpad injection. The elevated nitric oxide level was significantly reduced by oral administration of lutein (125 and 500 mg/kg/d for five days before LPS injection. Moreover, lutein decreased the malondialdehyde content, increased the oxygen radical absorbance capacity level, glutathione, the vitamin C contents and total superoxide dismutase (SOD and glutathione peroxidase (GPx activities. Lutein further increased expressions of copper-zinc SOD, manganese SOD and GPx mRNA. Conclusion The antioxidant properties of lutein contribute to the protection against LPS-induced uveitis, partially through the intervention of inflammation process.

  12. Induction of neutralizing antibodies in mice immunized with scorpion toxins detoxified by liposomal entrapment

    Directory of Open Access Journals (Sweden)

    S.G. Fonseca

    1997-07-01

    Full Text Available The possibility of producing neutralizing antibodies against the lethal effects of scorpion toxins was evaluated in the mouse model by immunization with an immunogen devoid of toxicity. A toxic fraction (5 mg from the venom of the scorpion Tityus serrulatus was entrapped in sphingomyelin-cholesterol liposomes. The liposomes were treated for 1 h at 37oC with a 1% (w/w trypsin solution in 0.2 M sodium carbonate buffer, pH 8.3. This treatment led to a strong reduction in venom toxicity. Immunization was performed as follows: mice were injected sc with 20 µg of the liposome-entrapped toxic fraction on days 1 and 21 and a final injection (20 µg was administered ip on day 36. After injection of the immunogen, all mice developed an IgG response which was shown to be specific for the toxic antigen. The antibodies were measured 10 days after the end of the immunization protocol. In an in vitro neutralization assay we observed that pre-incubation of a lethal dose of the toxic fraction with immune serum strongly reduced its toxicity. In vivo protection assays showed that mice with anti-toxin antibodies could resist the challenge with the toxic fraction, which killed, 30 min after injection, all non-immune control mice

  13. Accelerated tumor progression in mice lacking the ATP receptor P2X7.

    Science.gov (United States)

    Adinolfi, Elena; Capece, Marina; Franceschini, Alessia; Falzoni, Simonetta; Giuliani, Anna L; Rotondo, Alessandra; Sarti, Alba C; Bonora, Massimo; Syberg, Susanne; Corigliano, Domenica; Pinton, Paolo; Jorgensen, Niklas R; Abelli, Luigi; Emionite, Laura; Raffaghello, Lizzia; Pistoia, Vito; Di Virgilio, Francesco

    2015-02-15

    The ATP receptor P2X7 (P2X7R or P2RX7) has a key role in inflammation and immunity, but its possible roles in cancer are not firmly established. In the present study, we investigated the effect of host genetic deletion of P2X7R in the mouse on the growth of B16 melanoma or CT26 colon carcinoma cells. Tumor size and metastatic dissemination were assessed by in vivo calliper and luciferase luminescence emission measurements along with postmortem examination. In P2X7R-deficient mice, tumor growth and metastatic spreading were accelerated strongly, compared with wild-type (wt) mice. Intratumoral IL-1β and VEGF release were drastically reduced, and inflammatory cell infiltration was abrogated nearly completely. Similarly, tumor growth was also greatly accelerated in wt chimeric mice implanted with P2X7R-deficient bone marrow cells, defining hematopoietic cells as a sufficient site of P2X7R action. Finally, dendritic cells from P2X7R-deficient mice were unresponsive to stimulation with tumor cells, and chemotaxis of P2X7R-less cells was impaired. Overall, our results showed that host P2X7R expression was critical to support an antitumor immune response, and to restrict tumor growth and metastatic diffusion.

  14. Demodex musculi Infestation in Genetically Immunomodulated Mice

    Science.gov (United States)

    Smith, Peter C; Zeiss, Caroline J; Beck, Amanda P; Scholz, Jodi A

    2016-01-01

    Demodex musculi, a prostigmatid mite that has been reported infrequently in laboratory mice, has been identified with increasing frequency in contemporary colonies of immunodeficient mice. Here we describe 2 episodes of D. musculi infestation with associated clinical signs in various genetically engineered mouse strains, as well as treatment strategies and an investigation into transmissibility and host susceptibility. The first case involved D. musculi associated with clinical signs and pathologic lesions in BALB/c-Tg(DO11.10)Il13tm mice, which have a defect in type 2 helper T cell (Th2) immunity. Subsequent investigation revealed mite transmission to both parental strains (BALB/c-Tg[DO11.10] and BALB/c-Il13tm), BALB/c-Il13/Il4tm, and wild-type BALB/c. All Tg(DO11.10)Il13tm mice remained infested throughout the investigation, and D. musculi were recovered from all strains when they were cohoused with BALB/c-Tg(DO11.10)Il13tm index mice. However, only Il13tm and Il13/Il4tm mice demonstrated persistent infestation after index mice were removed. Only BALB/c-Tg(DO11.10)Il13tm showed clinical signs, suggesting that the phenotypic dysfunction of Th2 immunity is sufficient for persistent infestation, whereas clinical disease associated with D. musculi appears to be genotype-specific. This pattern was further exemplified in the second case, which involved NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) and C;129S4 Rag2tm1.1Flv Il2rgtm1.1Flv/J mice with varying degrees of blepharitis, conjunctivitis, and facial pruritis. Topical amitraz decreased mite burden but did not eliminate infestation or markedly ameliorate clinical signs. Furthermore, mite burden began to increase by 1 mo posttreatment, suggesting that topical amitraz is an ineffective treatment for D. musculi. These experiences illustrate the need for vigilance regarding opportunistic and uncommon pathogens in rodent colonies, especially among mice with immunologic deficits. PMID:27538858

  15. Demodex musculi Infestation in Genetically Immunomodulated Mice.

    Science.gov (United States)

    Smith, Peter C; Zeiss, Caroline J; Beck, Amanda P; Scholz, Jodi A

    2016-01-01

    Demodex musculi, a prostigmatid mite that has been reported infrequently in laboratory mice, has been identified with increasing frequency in contemporary colonies of immunodeficient mice. Here we describe 2 episodes of D. musculi infestation with associated clinical signs in various genetically engineered mouse strains, as well as treatment strategies and an investigation into transmissibility and host susceptibility. The first case involved D. musculi associated with clinical signs and pathologic lesions in BALB/c-Tg(DO11.10)Il13(tm) mice, which have a defect in type 2 helper T cell (Th2) immunity. Subsequent investigation revealed mite transmission to both parental strains (BALB/c-Tg[DO11.10] and BALB/c-Il13(tm)), BALB/c-Il13/Il4(tm), and wild-type BALB/c. All Tg(DO11.10)Il13(tm) mice remained infested throughout the investigation, and D. musculi were recovered from all strains when they were cohoused with BALB/c-Tg(DO11.10)Il13(tm) index mice. However, only Il13(tm) and Il13/Il4(tm) mice demonstrated persistent infestation after index mice were removed. Only BALB/c-Tg(DO11.10)Il13(tm) showed clinical signs, suggesting that the phenotypic dysfunction of Th2 immunity is sufficient for persistent infestation, whereas clinical disease associated with D. musculi appears to be genotype-specific. This pattern was further exemplified in the second case, which involved NOD.Cg-Prkdc(scid)Il2r(tm1Wjl)/SzJ (NSG) and C;129S4 Rag2(tm1.1Flv) Il2rg(tm1.1Flv)/J mice with varying degrees of blepharitis, conjunctivitis, and facial pruritis. Topical amitraz decreased mite burden but did not eliminate infestation or markedly ameliorate clinical signs. Furthermore, mite burden began to increase by 1 mo posttreatment, suggesting that topical amitraz is an ineffective treatment for D. musculi. These experiences illustrate the need for vigilance regarding opportunistic and uncommon pathogens in rodent colonies, especially among mice with immunologic deficits.

  16. Effectiveness of BCG vaccination to aged mice

    Directory of Open Access Journals (Sweden)

    Ito Tsukasa

    2010-09-01

    Full Text Available Abstract Background The tuberculosis (TB still increases in the number of new cases, which is estimated to approach 10 million in 2010. The number of aged people has been growing all over the world. Ageing is one of risk factors in tuberculosis because of decreased immune responses in aged people. Mycobacterium bovis Bacillus Calmette Guérin (BCG is a sole vaccine currently used for TB, however, the efficacy of BCG in adults is still a matter of debate. Emerging the multidrug resistant Mycobacterium tuberculosis (MDR-TB make us to see the importance of vaccination against TB in new light. In this study, we evaluated the efficacy of BCG vaccination in aged mice. Results The Th1 responses, interferon-γ production and interleukin 2, in BCG inoculated aged mice (24-month-old were comparable to those of young mice (4- to 6-week-old. The protection activity of BCG in aged mice against Mycobacterium tuberculosis H37Rv was also the same as young mice. Conclusion These findings suggest that vaccination in aged generation is still effective for protection against tuberculosis.

  17. Spatial learning by mice in three dimensions.

    Science.gov (United States)

    Wilson, Jonathan J; Harding, Elizabeth; Fortier, Mathilde; James, Benjamin; Donnett, Megan; Kerslake, Alasdair; O'Leary, Alice; Zhang, Ningyu; Jeffery, Kate

    2015-08-01

    We tested whether mice can represent locations distributed throughout three-dimensional space, by developing a novel three-dimensional radial arm maze. The three-dimensional radial maze, or "radiolarian" maze, consists of a central spherical core from which arms project in all directions. Mice learn to retrieve food from the ends of the arms without omitting any arms or re-visiting depleted ones. We show here that mice can learn both a standard working memory task, in which all arms are initially baited, and also a reference memory version in which only a subset are ever baited. Comparison with a two-dimensional analogue of the radiolarian maze, the hexagon maze, revealed equally good working-memory performance in both mazes if all the arms were initially baited, but reduced working and reference memory in the partially baited radiolarian maze. This suggests intact three-dimensional spatial representation in mice over short timescales but impairment of the formation and/or use of long-term spatial memory of the maze. We discuss potential mechanisms for how mice solve the three-dimensional task, and reasons for the impairment relative to its two-dimensional counterpart, concluding with some speculations about how mammals may represent three-dimensional space.

  18. Cacao polyphenols ameliorate autoimmune myocarditis in mice.

    Science.gov (United States)

    Zempo, Hirofumi; Suzuki, Jun-ichi; Watanabe, Ryo; Wakayama, Kouji; Kumagai, Hidetoshi; Ikeda, Yuichi; Akazawa, Hiroshi; Komuro, Issei; Isobe, Mitsuaki

    2016-04-01

    Myocarditis is a clinically severe disease; however, no effective treatment has been established. The aim of this study was to determine whether cacao bean (Theobroma cacao) polyphenols ameliorate autoimmune myocarditis. We used an experimental autoimmune myocarditis (EAM) model in Balb/c mice. Mice with induced EAM were treated with a cacao polyphenol extract (CPE, n=12) or vehicle (n=12). On day 21, hearts were harvested and analyzed. Elevated heart weight to body weight and fibrotic area ratios as well as high cardiac cell infiltration were observed in the vehicle-treated EAM mice. However, these increases were significantly suppressed in the CPE-treated mice. Reverse transcriptase-PCR revealed that mRNA expressions of interleukin (Il)-1β, Il-6, E-selectin, vascular cell adhesion molecule-1 and collagen type 1 were lower in the CPE group compared with the vehicle group. The mRNA expressions of nicotinamide adenine dinucleotide phosphate-oxidase (Nox)2 and Nox4 were increased in the vehicle-treated EAM hearts, although CPE treatment did not significantly suppress the transcription levels. However, compared with vehicle treatment of EAM hearts, CPE treatment significantly suppressed hydrogen peroxide concentrations. Cardiac myeloperoxidase activity, the intensity of dihydroethidium staining and the phosphorylation of nuclear factor-κB p65 were also lower in the CPE group compared with the vehicle group. Our data suggest that CPE ameliorates EAM in mice. CPE is a promising dietary supplement to suppress cardiovascular inflammation and oxidative stress.

  19. Lipid transport in cholecystokinin knockout mice.

    Science.gov (United States)

    King, Alexandra; Yang, Qing; Huesman, Sarah; Rider, Therese; Lo, Chunmin C

    2015-11-01

    Cholecystokinin (CCK) is released in response to lipid feeding and regulates pancreatic digestive enzymes vital to the absorption of nutrients. Our previous reports demonstrated that cholecystokinin knockout (CCK-KO) mice fed for 10 weeks of HFD had reduced body fat mass, but comparable glucose uptake by white adipose tissues and skeletal muscles. We hypothesized that CCK is involved in energy homeostasis and lipid transport from the small intestine to tissues in response to acute treatment with dietary lipids. CCK-KO mice with comparable fat absorption had increased energy expenditure and were resistant to HFD-induced obesity. Using intraduodenal infusion of butter fat and intravenous infusion using Liposyn III, we determined the mechanism of lipid transport from the small intestine to deposition in lymph and adipocytes in CCK-KO mice. CCK-KO mice had delayed secretion of Apo B48-chylomicrons, lipid transport to the lymphatic system, and triglyceride (TG)-derived fatty acid uptake by epididymal fat in response to acute treatment of intraduodenal lipids. In contrast, CCK-KO mice had comparable TG clearance and lipid uptake by white adipocytes in response to TGs in chylomicron-like emulsion. Thus, we concluded that CCK is important for lipid transport and energy expenditure to control body weight in response to dietary lipid feeding.

  20. Final measurement. Deliverable D5.3

    NARCIS (Netherlands)

    Holtzer, A.C.G.; Giessen, A.M. van der; Djurica, M.; Gruber, G.; Krengel, M.; Kokkinos, P.; Varvarigos, M.; Prusa, J.; Schulting, H.W.; Holzmann-Kaiser, U.; Schmoll, C.; Hatzakis, I.; Silva, F.M. da; Reymund, A.; Strebler, R.; Moreno, J.J.R.; Munoz, C.G.; Gheorghe, G.; Nikolopoulos, V.; Mavridis, T.; Bektas, O.; Yuce, E.; Volk, M.; Sterle, J.; Skarmeta, A.

    2015-01-01

    This deliverable D5.3 presents the GEN6 Final Measurement. It describes the outputs, outcomes and impact of the GEN6 project, based on other project deliverables inputs of the pilot leaders of the active GEN6 pilots and the individual consortium partners. The final measurement aims to show the amoun

  1. 33 CFR 20.1101 - Finality.

    Science.gov (United States)

    2010-07-01

    ... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Finality. 20.1101 Section 20.1101 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY GENERAL RULES OF PRACTICE, PROCEDURE, AND EVIDENCE FOR FORMAL ADMINISTRATIVE PROCEEDINGS OF THE COAST GUARD Finality, Petitions for Hearing, and Availability of Orders §...

  2. FameLab - Swiss Semi Finals

    CERN Document Server

    Corinne Pralavorio

    2012-01-01

    Twenty-two young scientists participated in the FameLab semi-final at CERN's Globe of Science and Innovation on 4 February, supported by a large audience and by more than 100 fans following via webcast. A panel of judges chose Lemmer and four other candidates to join five other semi-finalists at the national finals in Zurich on 30 March.

  3. Shaving Ceramic Tiles To Final Dimensions

    Science.gov (United States)

    Shaw, Ernest

    1992-01-01

    Combination of template and routing tool cuts ceramic tiles to final dimensions. Template guides router along precisely defined planes to accurately and uniformly shave chamfers on edge of tiles. Legs of template temporarily bonded to workpiece by double-backed adhesive tape. Adaptable to in-situ final machining of other nominally flat, narrow surfaces.

  4. 5 CFR 295.206 - Final determination.

    Science.gov (United States)

    2010-01-01

    ... 5 Administrative Personnel 1 2010-01-01 2010-01-01 false Final determination. 295.206 Section 295.206 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT CIVIL SERVICE REGULATIONS TESTIMONY BY OPM... for Testimony and Production of Documents § 295.206 Final determination. The General Counsel makes...

  5. 19 CFR 122.85 - Final airport.

    Science.gov (United States)

    2010-04-01

    ... 19 Customs Duties 1 2010-04-01 2010-04-01 false Final airport. 122.85 Section 122.85 Customs... AIR COMMERCE REGULATIONS Procedures for Residue Cargo and Stopover Passengers § 122.85 Final airport. When an aircraft enters at the last domestic airport of discharge, the traveling general...

  6. 75 FR 59989 - Final Flood Elevation Determinations

    Science.gov (United States)

    2010-09-29

    ... Lufkin. downstream of Bonita Street. Approximately 230 feet +304 upstream of Martin Luther King Drive... SECURITY Federal Emergency Management Agency 44 CFR Part 67 Final Flood Elevation Determinations AGENCY... (FEMA) makes the final determinations listed below for the modified BFEs for each community...

  7. Indian Child Welfare Act Proceedings. Final rule.

    Science.gov (United States)

    2016-06-14

    This final rule adds a new subpart to the Department of the Interior's (Department) regulations implementing the Indian Child Welfare Act (ICWA), to improve ICWA implementation. The final rule addresses requirements for State courts in ensuring implementation of ICWA in Indian child-welfare proceedings and requirements for States to maintain records under ICWA.

  8. Multiple non-cell-autonomous defects underlie neocortical callosal dysgenesis in Nfib-deficient mice

    Directory of Open Access Journals (Sweden)

    Sunn Nana

    2009-12-01

    Full Text Available Abstract Background Agenesis of the corpus callosum is associated with many human developmental syndromes. Key mechanisms regulating callosal formation include the guidance of axons arising from pioneering neurons in the cingulate cortex and the development of cortical midline glial populations, but their molecular regulation remains poorly characterised. Recent data have shown that mice lacking the transcription factor Nfib exhibit callosal agenesis, yet neocortical callosal neurons express only low levels of Nfib. Therefore, we investigate here how Nfib functions to regulate non-cell-autonomous mechanisms of callosal formation. Results Our investigations confirmed a reduction in glial cells at the midline in Nfib-/- mice. To determine how this occurs, we examined radial progenitors at the cortical midline and found that they were specified correctly in Nfib mutant mice, but did not differentiate into mature glia. Cellular proliferation and apoptosis occurred normally at the midline of Nfib mutant mice, indicating that the decrease in midline glia observed was due to deficits in differentiation rather than proliferation or apoptosis. Next we investigated the development of callosal pioneering axons in Nfib-/- mice. Using retrograde tracer labelling, we found that Nfib is expressed in cingulate neurons and hence may regulate their development. In Nfib-/- mice, neuropilin 1-positive axons fail to cross the midline and expression of neuropilin 1 is diminished. Tract tracing and immunohistochemistry further revealed that, in late gestation, a minor population of neocortical axons does cross the midline in Nfib mutants on a C57Bl/6J background, forming a rudimentary corpus callosum. Finally, the development of other forebrain commissures in Nfib-deficient mice is also aberrant. Conclusion The formation of the corpus callosum is severely delayed in the absence of Nfib, despite Nfib not being highly expressed in neocortical callosal neurons. Our

  9. [Investigation of the presence of Francisella tularensis by culture, serology and molecular methods in mice of Thrace Region, Turkey].

    Science.gov (United States)

    Unal Yilmaz, Gülizar; Gurcan, Saban; Ozkan, Beytullah; Karadenizli, Aynur

    2014-04-01

    Tularemia is a disease that has been reported in Turkey since 1936. Although mice are considered to have a role in the transmission of Francisella tularensis to man, this has not been exactly confirmed yet. The aim of this study was to investigate the presence of F. tularensis in mice by using culture, serology and molecular methods. For this purpose, four villages (Edirne-Demirkoy, Kirklareli-Kaynarca, Tekirdag-Muzruplu, Tekirdag-Sinanli) were selected in Thrace Region of Turkey where tularemia cases had been reported previously. A total of 126 live-catch mouse traps were established in warehouses, barns, areas near wells, water tanks and creeks in the villages in December 2012. Traps were kept overnight and the next day the animals collected were identified at species-level. The live-captured mice were anesthetized and their heart blood samples were obtained. Subsequently, liver and spleen tissues were removed from every mouse under aseptic conditions in the class-2 safety cabinet. These tissues were cultivated in Francis medium containing 5% sheep blood, 0.1% cystein, 1% glucose and incubated for seven days in both normal atmosphere and 5% carbondioxide incubator at 37°C. Tularemia microagglutination test was performed by using the sera which were obtained from live-captured mice. Finally, DNAs were isolated from both liver and spleen tissues of mice, and real-time polymerase chain reaction (Tularemia RT-PCR; Public Health Agency of Turkey, Ankara) were performed. In our study, a total of 19 mice were captured and of these 11 were alive. Ten mice were identified as Apodemus flavicollis, seven were Mus macedonicus and two were Mus musculus. There were no Francisella tularensis isolation in the cultures of mice liver and spleen tissues. Serological tests yielded negative results for 10 mice whose serum samples could be obtained. In RT-PCR, positivity were detected in spleen tissues of two mice which were captured from Kaynarca where first tularemia cases in

  10. Socially-induced morphine pseudo-sensitization in adolescent mice

    OpenAIRE

    Hodgson, Stephen R.; Hofford, Rebecca S.; Roberts, Kris W.; Wellman, Paul J.; Eitan, Shoshana

    2010-01-01

    Given that social influences are among the strongest predictors of adolescents’ drug use, this study examined the effect of social interaction on morphine-induced hyper-locomotion in both adolescent and adult mice. Three experimental groups of adolescent and adult male mice were examined: 1) morphine-treated mice (twice daily, 10–40 mg/kg, s.c.), 2) saline-injected mice housed together with the morphine-treated mice (‘saline cage-mates’), and 3) saline-injected mice housed physically and visu...

  11. The measurement of rectal and testis temperature in conscious mice, with observations on the effect of direct heating.

    Science.gov (United States)

    Cairnie, A B; Prud'homme-Lalonde, L F; Harding, R K; Zuker, M

    1980-03-01

    The application of Newton's law of cooling to freshly killed mice was found not to measure accurately their rectal or testis temperature. Improvements in the fitting process gave satisfactory results for rectal temperature only. A diffusion model was applied to testis cooling but was of no avail. Finally a satisfactory correction factor was determined empirically. This method was applied to conscious mice whose hindquarters were immersed in a stirred oilbath at 34 to 42 degrees C for 1 h, and to controls. It was found that both rectal and testis temperatures increased with bath temperature, producing a graph with a slope of only 0.5, indicating a regulatory capacity. Conscious mice, but not anaesthetised, can maintain a testis temperature of 39 degrees C in a bath at 42 degrees C.

  12. Phenylthiocarbamide produces conditioned taste aversions in mice.

    Science.gov (United States)

    St John, Steven J; Pour, Lindsay; Boughter, John D

    2005-06-01

    Previous work has demonstrated that SWR/J (SW) mice avoid phenylthiocarbamide (PTC) to a greater degree than C3HeB/FeJ mice in 48 h, two-bottle preference tests given in ascending series. The authors hypothesized, based also on previous work, that SW mice might form a conditioned taste aversion over time due to the toxic properties of PTC. We directly tested this hypothesis by attempting to condition a taste aversion to sucrose by injections of PTC. In experiment 1, PTC was nearly as effective as a strong dose of LiCl in reducing sucrose drinking. In experiment 2, the sucrose aversions were parametrically modified by both sucrose concentration and PTC dose, a hallmark of conditioned taste aversion. We conclude that PTC can cause a conditioned taste aversion and discuss the importance of considering toxic effects of aversive tastants when analyzing behavioral strain differences.

  13. Ghrelin reverses experimental diabetic neuropathy in mice

    Energy Technology Data Exchange (ETDEWEB)

    Kyoraku, Itaru; Shiomi, Kazutaka [Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki 889-1692 (Japan); Kangawa, Kenji [Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka 565-8565 (Japan); Nakazato, Masamitsu, E-mail: nakazato@med.miyazaki-u.ac.jp [Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki 889-1692 (Japan)

    2009-11-20

    Ghrelin, an acylated peptide produced in the stomach, increases food intake and growth hormone secretion, suppresses inflammation and oxidative stress, and promotes cell survival and proliferation. We investigated the pharmacological potential of ghrelin in the treatment of polyneuropathy in uncontrolled streptozotocin (STZ)-induced diabetes in mice. Ghrelin or desacyl-ghrelin was administered daily for 4 weeks after STZ-induced diabetic polyneuropathy had developed. Ghrelin administration did not alter food intake, body weight gain, blood glucose levels, or plasma insulin levels when compared with mice given saline or desacyl-ghrelin administration. Ghrelin administration ameliorated reductions in motor and sensory nerve conduction velocities in diabetic mice and normalized their temperature sensation and plasma concentrations of 8-isoprostaglandin {alpha}, an oxidative stress marker. Desacyl-ghrelin failed to have any effect. Ghrelin administration in a mouse model of diabetes ameliorated polyneuropathy. Thus, ghrelin's effects represent a novel therapeutic paradigm for the treatment of this otherwise intractable disorder.

  14. Atrial tachyarrhythmia in Rgs5-null mice.

    Directory of Open Access Journals (Sweden)

    Mu Qin

    Full Text Available AIMS: The aim of this study was to elucidate the effects of regulator of G-protein signaling 5 (Rgs5, a negative regulator of G protein-mediated signaling, on atrial repolarization and tachyarrhythmia (ATA in mice. METHODS AND RESULTS: In present study, the incidence of ATA were increased in Rgs5(-/- Langendorff-perfused mouse hearts during program electrical stimulation (PES (46.7%, 7 of 15 and burst pacing (26.7%, 4 of 15 compared with wild-type (WT mice (PES: 7.1%,1 of 14; burst:7.1%,1 of 14 (P30 s but none of them observed in WT mice. Atrial prolonged repolarization was observed in Rgs5(-/- hearts including widened P wave in surface ECG recording, increased action potential duration (APD and atrial effective refractory periods (AERP, all of them showed significant difference with WT mice (P<0.05. At the cellular level, whole-cell patch clamp recorded markedly decreased densities of repolarizing K(+ currents including I(Kur (at +60 mV: 14.0±2.2 pF/pA and I(to (at +60 mV: 16.7±1.3 pA/pF in Rgs5(-/- atrial cardiomyocytes, compared to those of WT mice (at +60 mV I(to: 20.4±2.0 pA/pF; I(kur: 17.9±2.0 pF/pA (P<0.05. CONCLUSION: These results suggest that Rgs5 is an important regulator of arrhythmogenesis in the mouse atrium and that the enhanced susceptibility to atrial tachyarrhythmias in Rgs5(-/- mice may contribute to abnormalities of atrial repolarization.

  15. Xanthohumol improved cognitive flexibility in young mice.

    Science.gov (United States)

    Zamzow, Daniel R; Elias, Valerie; Legette, LeeCole L; Choi, Jaewoo; Stevens, J Fred; Magnusson, Kathy R

    2014-12-15

    The protein palmitoylation cycle has been shown to be important for protein signaling and synaptic plasticity. Data from our lab showed a change in the palmitoylation status of certain proteins with age. A greater percentage of the NMDA receptor subunits GluN2A and GluN2B, along with Fyn and PSD95 proteins, were palmitoylated in the old mice. The higher level of protein palmitoylation was also associated with poorer learning scores. Xanthohumol is a prenylated flavonoid that has been shown to increase beta-oxidation in the livers of rodents, decreasing circulating free fatty acids in the serum. What is not known is whether the application of xanthohumol could influence the palmitoylation status of proteins. In this study, young and old mice were fed a diet supplemented with xanthohumol for 8 weeks. Spatial memory was assessed with the Morris water maze and protein palmitoylation quantified. The young xanthohumol-treated mice showed a significant improvement in cognitive flexibility. However, this appeared to be associated with the young control mice, on a defined, phytoestrogen-deficient diet, performing as poorly as the old mice and xanthohumol reversing this effect. The old mice receiving xanthohumol did not significantly improve their learning scores. Xanthohumol treatment was unable to affect the palmitoylation of NMDA receptor subunits and associated proteins assessed in this study. This evidence suggests that xanthohumol may play a role in improving cognitive flexability in young animals, but it appears to be ineffective in adjusting the palmitoylation status of neuronal proteins in aged individuals.

  16. Mapping pathological phenotypes in Reelin mutant mice

    Directory of Open Access Journals (Sweden)

    Caterina eMichetti

    2014-09-01

    Full Text Available Autism Spectrum Disorders (ASD are neurodevelopmental disorders with multifactorial origin characterized by social communication and behavioural perseveration deficits. Several studies showed an association between the reelin gene mutation and increased risk of ASD and a reduced reelin expression in some brain regions of ASD subjects, suggesting a role for reelin deficiency in ASD etiology. Reelin is a large extracellular matrix glycoprotein playing important roles during development of the central nervous system. To deeply investigate the role of reelin dysfunction as vulnerability factor in ASD, we investigated the behavioural, neurochemical and brain morphological features of reeler male mice. We recently reported a genotype-dependent deviation in ultrasonic vocal repertoire and a general delay in motor development in reeler pups. We now report that adult male heterozygous reeler mice did not show social behaviour and communication deficits during male-female social interactions. Wildtype and heterozygous mice also showed a typical light/dark locomotor activity profile, with a peak during the central interval of the dark phase. However, when faced with a mild stressful stimulus (a saline injection only heterozygous mice showed an over response to stress. At the end of the behavioural studies, we conducted high performance liquid chromatography and magnetic resonance imaging and spectroscopy to investigate whether reelin mutation influences brain monoamine and metabolites levels in regions involved in ASD. Low levels of dopamine in cortex and high levels of glutamate and taurine in hippocampus were detected in heterozygous mice, in line with clinical data collected on ASD children. Altogether, our data detected subtle but relevant neurochemical abnormalities in reeler mice supporting this mutant line, particularly male subjects, as a valid experimental model to estimate the contribution played by reelin deficiency in the global ASD

  17. Knock out of S1P3 receptor signaling attenuates inflammation and fibrosis in bleomycin-induced lung injury mice model.

    Directory of Open Access Journals (Sweden)

    Ken Murakami

    Full Text Available Sphingosine-1-phosphate (S1P is a bioactive sphingolipid metabolite involved in many critical cellular processes, including proliferation, migration, and angiogenesis, through interaction with a family of five G protein-coupled receptors (S1P1-5. Some reports have implicated S1P as an important inflammatory mediator of the pathogenesis of airway inflammation, but the role of S1P3 in the pathogenesis of lung diseases is not completely understood. We used S1P3-deficient (knockout (KO mice to clarify the role of S1P3 receptor signaling in the pathogenesis of pulmonary inflammation and fibrosis using a bleomycin-induced model of lung injury. On the seventh day after bleomycin administration, S1P3 KO mice exhibited significantly less body weight loss and pulmonary inflammation than wild-type (WT mice. On the 28th day, there was less pulmonary fibrosis in S1P3 KO mice than in WT mice. S1P3 KO mice demonstrated a 56% reduction in total cell count in bronchoalveolar lavage fluid (BALF collected on the seventh day compared with WT mice; however, the differential white blood cell profiles were similar. BALF analysis on the seventh day showed that connective tissue growth factor (CTGF levels were significantly decreased in S1P3 KO mice compared with WT mice, although no differences were observed in monocyte chemotactic protein-1 (MCP-1 or transforming growth factor β1 (TGF-β1 levels. Finally, S1P levels in BALF collected on the 7th day after treatment were not significantly different between WT and S1P3 KO mice. Our results indicate that S1P3 receptor signaling plays an important role in pulmonary inflammation and fibrosis and that this signaling occurs via CTGF expression. This suggests that this pathway might be a therapeutic target for pulmonary fibrosis.

  18. Splenic Stromal Cells from Aged Mice Produce Higher Levels of IL-6 Compared to Young Mice

    Science.gov (United States)

    Park, Jihyun; Miyakawa, Takuya; Shiokawa, Aya; Nakajima-Adachi, Haruyo; Hachimura, Satoshi

    2014-01-01

    Inflamm-aging indicates the chronic inflammatory state resulting from increased secretion of proinflammatory cytokines and mediators such as IL-6 in the elderly. Our principle objective was to identify cell types that were affected with aging concerning IL-6 secretion in the murine model. We compared IL-6 production in spleen cells from both young and aged mice and isolated several types of cells from spleen and investigated IL-6 mRNA expression and protein production. IL-6 protein productions in cultured stromal cells from aged mice spleen were significantly high compared to young mice upon LPS stimulation. IL-6 mRNA expression level of freshly isolated stromal cells from aged mice was high compared to young mice. Furthermore, stromal cells of aged mice highly expressed IL-6 mRNA after LPS injection in vivo. These results suggest that stromal cells play a role in producing IL-6 in aged mice and imply that they contribute to the chronic inflammatory condition in the elderly. PMID:24729663

  19. Whey protein reduces early life weight gain in mice fed a high-fat diet

    DEFF Research Database (Denmark)

    Tranberg, Britt; Hellgren, Lars; Lykkesfeldt, Jens

    2013-01-01

    An increasing number of studies indicate that dairy products, including whey protein, alleviate several disorders of the metabolic syndrome. Here, we investigated the effects of whey protein isolate (whey) in mice fed a high-fat diet hypothesising that the metabolic effects of whey would...... be associated with changes in the gut microbiota composition. Five-week-old male C57BL/6 mice were fed a high-fat diet ad libitum for 14 weeks with the protein source being either whey or casein. Faeces were collected at week 0, 7, and 13 and the fecal microbiota was analysed by denaturing gradient gel...... weight gain was similar resulting in a 15% lower final body weight in the whey group relative to casein (34.0±1.0 g vs. 40.2±1.3 g, Pprotein source throughout the study period. Fasting insulin was lower in the whey group (P

  20. Experimental heteroxenous cycle of Lagochilascaris minor Leiper, 1909 (Nematoda: Ascarididae in white mice and in cats

    Directory of Open Access Journals (Sweden)

    Gregorio S. Volcan

    1992-12-01

    Full Text Available Reports of natural infections of sylvatic carnivores by adult worms of species similar to Lagochilascaris minor in the Neotropical region led to attempts to estabilish experimental cycles in laboratory mice and in cats. Also, larval development was seen in the skeletal muscle of an agouti (Dasyprocta leporina infected per os with incubated eggs of the parasite obtained from a human case. In cats, adult worms develop and fertile eggs are expelled in the feces: in mice, larval stages of the parasite develop, and are encapsulate in the skeletal muscle, and in the adipose and subcutaneous connective tissue. From our observations, we conclude that the larva infective for the mouse is the early 3rd stage, while for the final host the infective form is the later 3rd stage. A single moult was seen in the mouse, giving rise to a small population of 4th stage larvae, long after the initial infection.

  1. Hematotoxicity and concentration-dependent conjugation of phenol in mice following inhalation exposure to benzene.

    Science.gov (United States)

    Wells, M S; Nerland, D E

    1991-04-01

    Benzene is metabolized to one or more hematotoxic species. Saturation of benzene metabolism could limit the production of toxic species. Saturation of phase II enzymes involved in the conjugation of the phenolic metabolites of benzene also could affect the hematotoxicity of benzene. To investigate the latter possibility, we exposed male Swiss mice, via the inhalation route, to various concentrations of benzene for 6 h per day for 5 days. Following termination of the final exposure the mice were killed and the levels of phenylsulfate and phenylglucuronide in the blood determined. Spleen weights were recorded and the number of white blood cells counted. At low benzene exposure concentrations phenylsulfate is the major conjugated form of phenol in the blood. At high exposure concentrations, phenylglucuronide is the predominant species. The reductions in spleen weight and white blood cell numbers correlated with the concentration of phenylsulfate in the blood, but are most probably not causally related.

  2. Effect of the "zero" magnetic field on early embryogenesis in mice.

    Science.gov (United States)

    Fesenko, Evgenii E; Mezhevikina, Ludmila M; Osipenko, Marina A; Gordon, Rita Ya; Khutzian, Sergei S

    2010-06-01

    It was shown that the 250-fold screening of the geomagnetic field (GMF) ("zero" magnetic field with an induction of 0.2 muT) affects early embryogenesis and the reproduction capacity of mice in vivo. Pregnant NMRI mice at the zygote stage placed in this "zero" magnetic field (MF) lost the ability to bear offspring babies although their embryos developed up to the blastocyst stage without any visible deviations from the norm. The abortion of development in the "zero" MF occurred after the exit of the blastocysts from the zona pellicida and invasion into the uterus during implantation. Histological analysis indicates that possible reasons of the abnormalities of postimplantation development are a decrease in the proliferative activity of embryonic cells and the impairment of the interaction between the trophoblast and endometrium, which finally results in the resorption of embryos in the uterus.

  3. The use of germ line-mutated mice in understanding host-pathogen interactions.

    Science.gov (United States)

    Yap, George S; Sher, Alan

    2002-10-01

    Microbial pathogenesis reflects an imbalance between parasite and host factors that favour pathogen multiplication and tissue destruction over those required for microbial elimination and preservation of the integrity of host tissues. In vivo analysis of host-pathogen interactions has been revolutionized by the ability to engineer specific genetic alterations including loss of function mutations and transgenes into the mouse germline. This brief review recapitulates what we have learned about the host response to Toxoplasma gondii infection to illustrate the usefulness of gene-altered mice in microbial pathogenesis research. A consideration of the pitfalls and limitations of experiments in knockout mice and ways of addressing these concerns are discussed. Finally, advances in inducible and tissue-restricted alterations in gene function are presented and their possible applications to microbiology research are considered.

  4. Molecular basis of cleft palates in mice

    Institute of Scientific and Technical Information of China (English)

    Noriko; Funato; Masataka; Nakamura; Hiromi; Yanagisawa

    2015-01-01

    Cleft palate, including complete or incomplete cleft palates, soft palate clefts, and submucosal cleft palates, is the most frequent congenital craniofacial anomaly in humans. Multifactorial conditions, including genetic and environmental factors, induce the formation of cleft palates. The process of palatogenesis is temporospatially regulated by transcription factors, growth factors, extracellular matrix proteins, and membranous molecules; a single ablation of these molecules can result in a cleft palate in vivo. Studies on knockout mice were reviewed in order to identify genetic errors that lead to cleft palates. In this review, we systematically describe these mutant mice and discuss the molecular mechanisms of palatogenesis.

  5. Medicaid program: rescission of School-Based Administration/Transportation final rule, Outpatient Hospital Services final rule, and partial rescission of Case Management Interim final rule. Final rule.

    Science.gov (United States)

    2009-06-30

    This rule finalizes our proposal to rescind the December 28, 2007 final rule entitled, "Elimination of Reimbursement under Medicaid for School Administration Expenditures and Costs Related to Transportation of School-Age Children Between Home and School;" the November 7, 2008 final rule entitled, "Clarification of Outpatient Hospital Facility (Including Outpatient Hospital Clinic) Services Definition;" and certain provisions of the December 4, 2007 interim final rule entitled, "Optional State Plan Case Management Services." These regulations have been the subject of Congressional moratoria and have not yet been implemented (or, with respect to the case management interim final rule, have only been partially implemented) by CMS. In light of concerns raised about the adverse effects that could result from these regulations, in particular, the potential restrictions on services available to beneficiaries and the lack of clear evidence demonstrating that the approaches taken in the regulations are warranted, CMS is rescinding the two final rules in full, and partially rescinding the interim final rule. Rescinding these provisions will permit further opportunity to determine the best approach to further the objectives of the Medicaid program in providing necessary health benefits coverage to needy individuals.

  6. Increased adiposity in annexin A1-deficient mice.

    Directory of Open Access Journals (Sweden)

    Rand T Akasheh

    Full Text Available Production of Annexin A1 (ANXA1, a protein that mediates the anti-inflammatory action of glucocorticoids, is altered in obesity, but its role in modulation of adiposity has not yet been investigated. The objective of this study was to investigate modulation of ANXA1 in adipose tissue in murine models of obesity and to study the involvement of ANXA1 in diet-induced obesity in mice. Significant induction of ANXA1 mRNA was observed in adipose tissue of both C57BL6 and Balb/c mice with high fat diet (HFD-induced obesity versus mice on chow diet. Upregulation of ANXA1 mRNA was independent of leptin or IL-6, as demonstrated by use of leptin-deficient ob/ob mice and IL-6 KO mice. Compared to WT mice, female Balb/c ANXA1 KO mice on HFD had increased adiposity, as indicated by significantly elevated body weight, fat mass, leptin levels, and adipocyte size. Whereas Balb/c WT mice upregulated expression of enzymes involved in the lipolytic pathway in response to HFD, this response was absent in ANXA1 KO mice. A significant increase in fasting glucose and insulin levels as well as development of insulin resistance was observed in ANXA1 KO mice on HFD compared to WT mice. Elevated plasma corticosterone levels and blunted downregulation of 11-beta hydroxysteroid dehydrogenase type 1 in adipose tissue was observed in ANXA1 KO mice compared to diet-matched WT mice. However, no differences between WT and KO mice on either chow or HFD were observed in expression of markers of adipose tissue inflammation. These data indicate that ANXA1 is an important modulator of adiposity in mice, with female ANXA1 KO mice on Balb/c background being more susceptible to weight gain and diet-induced insulin resistance compared to WT mice, without significant changes in inflammation.

  7. Construction of a hepatic stellate cells subtracted cDNA library of differentially expressed genes in normal mice and mice with Schistosomiasis japonica

    Institute of Scientific and Technical Information of China (English)

    Zheng Min; Wu Yi-jun; Cai Wei-min; Weng Hong-lei; Liu Rong-hua

    2005-01-01

    To construct a hepatic stellate cells (HSCs) subtracted cDNA library to find differentially expressed genes in normal mice and mice infected with Schistosomajaponicum (S. japonicum). Suppression subtractive hybridization (SSH) was used. The cDNA fragments of normal mouse were compared to those of schistosoma-infected mice to find differentially expressed genes.Then differentially expressed cDNA fragments were directly inserted into T/A cloning vector to set up the subtractive library.Amplification of the library was carried out with transformation of DH5α. The amplified library contained more than 400 positive bacterial clones, which were then hybridized with forward and backward subtracted probes for differential screening. One hundred positive bacterial clones were randomly selected for sequencing and BLAST analysis. Finally, virtual Northern Blot confirmed such differential expression. The subtracted cDNA library of differentially expressed genes of HSCs was constructed successfully,the library is efficient and lays foundation for screening and cloning new and specific genes of schistosomiasis.

  8. Dynamic changes in thrombin generation in abdominal sepsis in mice.

    Science.gov (United States)

    Wang, Yongzhi; Braun, Oscar O; Zhang, Su; Luo, Lingtao; Norström, Eva; Thorlacius, Henrik

    2014-10-01

    Systemic inflammatory response syndrome and severe infections are associated with major derangements in the coagulation system. The purpose of this study was to examine the dynamic alterations in thrombin generation in abdominal sepsis. Abdominal sepsis was induced by cecal ligation and puncture (CLP) in C57/Bl6 mice. Cecal ligation and puncture caused a systemic inflammatory response, with neutrophil recruitment and tissue damage in the lung as well as thrombocytopenia and leukocytopenia. Thrombin generation, coagulation factors, lung histology, and myeloperoxidase activity was determined 1, 3, 6, and 24 h after induction of CLP. It was found that thrombin generation was increased 1 h after CLP and that thrombin generation started to decrease at 3 h and was markedly reduced 6 and 24 h after CLP induction. Platelet-poor plasma from healthy mice could completely reverse the inhibitory effect of CLP on thrombin generation, suggesting that sepsis caused a decrease in the levels of plasma factors regulating thrombin generation in septic animals. Indeed, it was found that CLP markedly decreased plasma levels of prothrombin, factor V, and factor X at 6 and 24 h. Moreover, we observed that CLP increased plasma levels of activated protein C at 6 h, which returned to baseline levels 24 h after CLP induction. Finally, pretreatment with imipenem/cilastatin attenuated the CLP-evoked decrease in thrombin generation and consumption of prothrombin 24 h after CLP induction. Our novel findings suggest that thrombin generation is initially increased and later decreased in abdominal sepsis. Sepsis-induced reduction in thrombin generation is correlated to changes in the plasma levels of coagulation factors and activated protein C. These findings help explain the dynamic changes in global hemostasis in abdominal sepsis.

  9. Neurotoxicity of perfluorooctane sulfonate to hippocampal cells in adult mice.

    Directory of Open Access Journals (Sweden)

    Yan Long

    Full Text Available Perfluorooctane sulfonate (PFOS is a ubiquitous pollutant and found in the environment and in biota. The neurotoxicity of PFOS has received much concern among its various toxic effects when given during developing period of brain. However, little is known about the neurotoxic effects and potential mechanisms of PFOS in the mature brain. Our study demonstrated the neurotoxicity and the potential mechanisms of PFOS in the hippocampus of adult mice for the first time. The impairments of spatial learning and memory were observed by water maze studies after exposure to PFOS for three months. Significant apoptosis was found in hippocampal cells after PFOS exposure, accompanied with a increase of glutamate in the hippocampus and decreases of dopamine (DA and 3,4-dihydrophenylacetic acid (DOPAC in Caudate Putamen in the 10.75 mg/kg PFOS group. By two-dimensional fluorescence difference in gel electrophoresis (2D-DIGE analysis, seven related proteins in the hippocampus that responded to PFOS exposure were identified, among which, Mib1 protein (an E3 ubiquitin-protein ligase, Herc5 (hect domain and RLD 5 isoform 2 and Tyro3 (TYRO3 protein tyrosine kinase 3 were found down-regulated, while Sdha (Succinate dehydrogenase flavoprotein subunit, Gzma (Isoform HF1 of Granzyme A precursor, Plau (Urokinase-type plasminogen activator precursor and Lig4 (DNA ligase 4 were found up-regulated in the 10.75 mg/kg PFOS-treated group compare with control group. Furthermore, we also found that (i increased expression of caspase-3 protein and decreased expression of Bcl-2, Bcl-XL and survivin proteins, (ii the increased glutamate release in the hippocampus. All these might contribute to the dysfunction of hippocampus which finally account for the impairments of spatial learning and memory in adult mice.

  10. What was the fastest 100m final?

    CERN Document Server

    Mureika, J R

    1997-01-01

    In a previous article (physics/9705004), the best 100m performances in track and field were determined by accounting for wind effects and atmospheric drag. In this report, I seek to ascertain what was the "fastest" 100m final through a statistical analysis of the competitors' times. Considered are the 100 finals from the 1984-1996 Olympic Games, the 1983-1997 World Championships, and the 1996 Grand Prix Final from Lausanne, SWI, in which Frank Fredericks (Namibia) recorded the only sub-9.90s time ever into a head-wind (9.86s, -0.4 m/s).

  11. Citi Innovative English Teaching Competition Final Held

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    <正>Citi Innovative English Teaching Competition Final for teachers in West China sponsored by the CPAFFC was held in Beijing from January 22 to 23,2008.Wang Li,vice president of Citibank China,Professor Zhu Xudong and Ms.Ma Xin with the Beijing Normal University served as judges in the final.Over 50 English teachers of primary and middle schools from Guizhou,Yunnan and Sichuan provinces and Guangxi Zhuang Autonomous Region took part in the finals.Twenty two teachers won prizes.

  12. EDU 382 Week 5 Final Paper Requirements

    OpenAIRE

    Laynebaril

    2017-01-01

    EDU 382 Week 5 Final Paper Requirements Click Link Below To Buy:   http://hwcampus.com/shop/edu-382-week-5-final-paper/ Or Visit www.hwcampus.com   Lesson Plan Revision and Analysis [CLOs: 1, 2, 3, 4]. Due by Day 7. For the final assignment, you will select among one of three lesson plans where you will differentiate the given lesson plan based on student readiness, student interest, and student learning profile for content, process, and product. You will then evaluate...

  13. Involvement of gonadotropins in the induction of hypertrophy-hyperplasia in the interstitial tissues of ovaries in neonatally diethylstilbestrol-treated mice.

    Science.gov (United States)

    Kakuta, Hanako; Tanaka, Masami; Chambon, Pierre; Watanabe, Hajime; Iguchi, Taisen; Sato, Tomomi

    2012-01-01

    Neonatally diethylstilbestrol (DES) treatment causes hypertrophy-hyperplasia in the interstitial tissue of mouse ovaries. To understand the induction mechanism of the hypertrophy, mRNA expression involved in steroidogenesis in the ovary of neonatally DES-treated mice was examined. The expression of StAR and Cyp11a1 was significantly reduced while Cyp19 and Sf-1 were stimulated in the ovary of neonatally DES-treated 3-month-old mice. Expression of those genes was not different between DES- and oil-treated mice after the gonadotropins treatment. Lhb in the pituitary of 3-month-old neonatally DES-treated mice was significantly decreased. Finally, ovaries from DES-treated mice transplanted to neonatally oil-treated hosts had developing follicles at several stages and corpora lutea, whereas grafted ovaries from neonatally oil-treated mice in 3-month-old neonatally DES-treated hosts showed lipid accumulation in the interstitial tissue. Thus, hypertrophy and accumulation of lipid droplets in interstitial cells of neonatally DES-treated mice is caused by impaired steroidogenesis due to the alterations of gonadotropins levels.

  14. Echium Oil Reduces Plasma Triglycerides by Increasing Intravascular Lipolysis in apoB100-Only Low Density Lipoprotein (LDL Receptor Knockout Mice

    Directory of Open Access Journals (Sweden)

    John S. Parks

    2013-07-01

    Full Text Available Echium oil (EO, which is enriched in SDA (18:4 n-3, reduces plasma triglyceride (TG concentrations in humans and mice. We compared mechanisms by which EO and fish oil (FO reduce plasma TG concentrations in mildly hypertriglyceridemic male apoB100-only LDLrKO mice. Mice were fed one of three atherogenic diets containing 0.2% cholesterol and palm oil (PO; 20%, EO (10% EO + 10% PO, or FO (10% FO + 10% PO. Livers from PO- and EO-fed mice had similar TG and cholesteryl ester (CE content, which was significantly higher than in FO-fed mice. Plasma TG secretion was reduced in FO vs. EO-fed mice. Plasma very low density lipoprotein (VLDL particle size was ordered: PO (63 ± 4 nm > EO (55 ± 3 nm > FO (40 ± 2 nm. Post-heparin lipolytic activity was similar among groups, but TG hydrolysis by purified lipoprotein lipase was significantly greater for EO and FO VLDL compared to PO VLDL. Removal of VLDL tracer from plasma was marginally faster in EO vs. PO fed mice. Our results suggest that EO reduces plasma TG primarily through increased intravascular lipolysis of TG and VLDL clearance. Finally, EO may substitute for FO to reduce plasma TG concentrations, but not hepatic steatosis in this mouse model.

  15. Echium oil reduces plasma triglycerides by increasing intravascular lipolysis in apoB100-only low density lipoprotein (LDL) receptor knockout mice.

    Science.gov (United States)

    Forrest, Lolita M; Lough, Christopher M; Chung, Soonkyu; Boudyguina, Elena Y; Gebre, Abraham K; Smith, Thomas L; Colvin, Perry L; Parks, John S

    2013-07-12

    Echium oil (EO), which is enriched in SDA (18:4 n-3), reduces plasma triglyceride (TG) concentrations in humans and mice. We compared mechanisms by which EO and fish oil (FO) reduce plasma TG concentrations in mildly hypertriglyceridemic male apoB100-only LDLrKO mice. Mice were fed one of three atherogenic diets containing 0.2% cholesterol and palm oil (PO; 20%), EO (10% EO + 10% PO), or FO (10% FO + 10% PO). Livers from PO- and EO-fed mice had similar TG and cholesteryl ester (CE) content, which was significantly higher than in FO-fed mice. Plasma TG secretion was reduced in FO vs. EO-fed mice. Plasma very low density lipoprotein (VLDL) particle size was ordered: PO (63 ± 4 nm) > EO (55 ± 3 nm) > FO (40 ± 2 nm). Post-heparin lipolytic activity was similar among groups, but TG hydrolysis by purified lipoprotein lipase was significantly greater for EO and FO VLDL compared to PO VLDL. Removal of VLDL tracer from plasma was marginally faster in EO vs. PO fed mice. Our results suggest that EO reduces plasma TG primarily through increased intravascular lipolysis of TG and VLDL clearance. Finally, EO may substitute for FO to reduce plasma TG concentrations, but not hepatic steatosis in this mouse model.

  16. Anti-Diabetic Effect of Balanced Deep-Sea Water and Its Mode of Action in High-Fat Diet Induced Diabetic Mice

    Directory of Open Access Journals (Sweden)

    Yun Hee Shon

    2013-10-01

    Full Text Available In this study, we investigated the effects of balanced deep-sea water (BDSW on hyperglycemia and glucose intolerance in high-fat diet (HFD-induced diabetic C57BL/6J mice. BDSW was prepared by mixing deep-sea water (DSW mineral extracts and desalinated water to give a final hardness of 500–2000. Mice given an HFD with BDSW showed lowered fasting plasma glucose levels compared to HFD-fed mice. Oral and intraperitoneal glucose tolerance tests showed that BDSW improves impaired glucose tolerance in HFD-fed mice. Histopathological evaluation of the pancreas showed that BDSW recovers the size of the pancreatic islets of Langerhans, and increases the secretion of insulin and glucagon in HFD-fed mice. Quantitative reverse transcription polymerase chain reaction results revealed that the expression of hepatic genes involved in glucogenesis, glycogenolysis and glucose oxidation were suppressed, while those in glucose uptake, β-oxidation, and glucose oxidation in muscle were increased in mice fed HFD with BDSW. BDSW increased AMP-dependent kinase (AMPK phosphorylation in 3T3-L1 pre- and mature adipocytes and improved impaired AMPK phosphorylation in the muscles and livers of HFD-induced diabetic mice. BDSW stimulated phosphoinositol-3-kinase and AMPK pathway-mediated glucose uptake in 3T3-L1 adipocytes. Taken together, these results suggest that BDSW has potential as an anti-diabetic agent, given its ability to suppress hyperglycemia and improve glucose intolerance by increasing glucose uptake.

  17. Elucidating the role of the TRPM7 alpha-kinase: TRPM7 kinase inactivation leads to magnesium deprivation resistance phenotype in mice.

    Science.gov (United States)

    Ryazanova, Lillia V; Hu, Zhixian; Suzuki, Sayuri; Chubanov, Vladimir; Fleig, Andrea; Ryazanov, Alexey G

    2014-12-23

    TRPM7 is an unusual bi-functional protein containing an ion channel covalently linked to a protein kinase domain. TRPM7 is implicated in regulating cellular and systemic magnesium homeostasis. While the biophysical properties of TRPM7 ion channel and its function are relatively well characterized, the function of the TRPM7 enzymatically active kinase domain is not understood yet. To investigate the physiological role of TRPM7 kinase activity, we constructed mice carrying an inactive TRPM7 kinase. We found that these mice were resistant to dietary magnesium deprivation, surviving three times longer than wild type mice; also they displayed decreased chemically induced allergic reaction. Interestingly, mutant mice have lower magnesium bone content compared to wild type mice when fed regular diet; unlike wild type mice, mutant mice placed on magnesium-depleted diet did not alter their bone magnesium content. Furthermore, mouse embryonic fibroblasts isolated from TRPM7 kinase-dead animals exhibited increased resistance to magnesium deprivation and oxidative stress. Finally, electrophysiological data revealed that the activity of the kinase-dead TRPM7 channel was not significantly altered. Together, our results suggest that TRPM7 kinase is a sensor of magnesium status and provides coordination of cellular and systemic responses to magnesium deprivation.

  18. Anti-diabetic effect of balanced deep-sea water and its mode of action in high-fat diet induced diabetic mice.

    Science.gov (United States)

    Ha, Byung Geun; Shin, Eun Ji; Park, Jung-Eun; Shon, Yun Hee

    2013-10-29

    In this study, we investigated the effects of balanced deep-sea water (BDSW) on hyperglycemia and glucose intolerance in high-fat diet (HFD)-induced diabetic C57BL/6J mice. BDSW was prepared by mixing deep-sea water (DSW) mineral extracts and desalinated water to give a final hardness of 500-2000. Mice given an HFD with BDSW showed lowered fasting plasma glucose levels compared to HFD-fed mice. Oral and intraperitoneal glucose tolerance tests showed that BDSW improves impaired glucose tolerance in HFD-fed mice. Histopathological evaluation of the pancreas showed that BDSW recovers the size of the pancreatic islets of Langerhans, and increases the secretion of insulin and glucagon in HFD-fed mice. Quantitative reverse transcription polymerase chain reaction results revealed that the expression of hepatic genes involved in glucogenesis, glycogenolysis and glucose oxidation were suppressed, while those in glucose uptake, β-oxidation, and glucose oxidation in muscle were increased in mice fed HFD with BDSW. BDSW increased AMP-dependent kinase (AMPK) phosphorylation in 3T3-L1 pre- and mature adipocytes and improved impaired AMPK phosphorylation in the muscles and livers of HFD-induced diabetic mice. BDSW stimulated phosphoinositol-3-kinase and AMPK pathway-mediated glucose uptake in 3T3-L1 adipocytes. Taken together, these results suggest that BDSW has potential as an anti-diabetic agent, given its ability to suppress hyperglycemia and improve glucose intolerance by increasing glucose uptake.

  19. Calcium receptor expression and function in oligodendrocyte commitment and lineage progression: potential impact on reduced myelin basic protein in CaR-null mice

    DEFF Research Database (Denmark)

    Chattopadhyay, N.; Espinosa-Jeffrey, A.; Yano, S.;

    2008-01-01

    cellular proliferation. We further observed that high Ca(2+) stimulates the mRNA levels of myelin basic protein in preoligodendrocytes, which is also CaR mediated. Finally, myelin basic protein levels were significantly reduced in the cerebellum of CaR-null mice during development. Our results show that Ca...

  20. Banishing Asthma-Inducing Mice Allergens on The Cheap

    Science.gov (United States)

    ... gov/news/fullstory_163963.html Banishing Asthma-Inducing Mice Allergens on the Cheap Do-it-yourself approach ... in kids with a mouse allergy, researchers say. Mice are a common cause of asthma flare-ups ...

  1. A novel and simple method for endotracheal intubation of mice

    NARCIS (Netherlands)

    Spoelstra, E. N.; Ince, C.; Koeman, A.; Emons, V. M.; Brouwer, L. A.; van Luyn, M. J. A.; Westerink, B. H. C.; Remie, R.

    2007-01-01

    Endotracheal intubation in mice is necessary for experiments involving intratracheal instillation of various substances, repeated pulmonary function assessments and mechanical ventilation. Previously described methods for endotracheal intubation in mice require the use of injection anaesthesia to im

  2. Quercetin prevents progression of disease in elastase/LPS-exposed mice by negatively regulating MMP expression

    Directory of Open Access Journals (Sweden)

    Martinez Fernando J

    2010-09-01

    Full Text Available Abstract Background Chronic obstructive pulmonary disease (COPD is characterized by chronic bronchitis, emphysema and irreversible airflow limitation. These changes are thought to be due to oxidative stress and an imbalance of proteases and antiproteases. Quercetin, a plant flavonoid, is a potent antioxidant and anti-inflammatory agent. We hypothesized that quercetin reduces lung inflammation and improves lung function in elastase/lipopolysaccharide (LPS-exposed mice which show typical features of COPD, including airways inflammation, goblet cell metaplasia, and emphysema. Methods Mice treated with elastase and LPS once a week for 4 weeks were subsequently administered 0.5 mg of quercetin dihydrate or 50% propylene glycol (vehicle by gavage for 10 days. Lungs were examined for elastance, oxidative stress, inflammation, and matrix metalloproteinase (MMP activity. Effects of quercetin on MMP transcription and activity were examined in LPS-exposed murine macrophages. Results Querce